Method for preparing o-methyl phenylacetonitrile ketoxime through continuous flow

Abstract

The invention provides a method for preparing o-methyl benzyl cyanide ketoxime through continuous flow, and belongs to the field of organic synthesis. The method provided by the invention comprises the following steps: when a continuous flow preheater, a continuous flow mixer and a continuous flow reactor reach a circulating temperature, starting each metering pump, and reacting to obtain o-methyl phenylacetonitrile ketoxime. According to the present invention, o-methylbenzyl cyanide is adopted as the raw material to prepare o-methylbenzyl cyanide ketoxime through the continuous flow process, such that the reaction can be ensured to be completed in a short time, and the obtained o-methylbenzyl cyanide ketoxime has high purity and high yield. The method disclosed by the invention is a method for efficiently and safely obtaining o-methyl benzyl cyanide ketoxime, and has a good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for the continuous flow preparation of o-methylacetonitrile oxime. Background Technology

[0002] o-Methylacetonitrile oxime is an organic compound commonly used as an important intermediate in the synthesis of pharmaceuticals, dyes, and pesticides. In the pharmaceutical field, it can be used to synthesize drugs such as flurbiprofen and pyrrolifene, and it can also serve as a raw material for dyes. Furthermore, it can be used to prepare some special functional materials; for example, in the pesticide field, it is a key intermediate in the synthesis of the fungicide oxime ester.

[0003]

[0004] However, current methods for synthesizing o-methylacetonitrile oxime have many drawbacks. For example, some synthetic routes use highly toxic sodium cyanide as a raw material, which not only poses a threat to the environment and operators, but also requires high-level treatment of cyanide-containing wastewater, increasing production costs. Reagents used in certain synthetic steps are expensive, such as monomethyl oxalyl chloride, increasing raw material costs. Some synthetic routes require harsh operating conditions, such as anhydrous operation or high temperature and pressure, which not only places high demands on equipment but also increases production difficulty. Some synthetic steps generate large quantities of wastewater, waste gas, and waste residue, which are difficult to treat and put significant pressure on the environment. The overall yield of some synthetic routes is low, leading to higher production costs and affecting market competitiveness (Li Renhong. Research on the Synthetic Process of Oxime Propylene. Hebei University of Science and Technology. Master's Thesis. 2015).

[0005] Therefore, there is an urgent need to develop a new method for obtaining o-methylacetonitrile oxime that is efficient, safe, and environmentally friendly. Summary of the Invention

[0006] The purpose of this invention is to provide a method for the continuous flow preparation of o-methylacetonitrile oxime.

[0007] This invention provides a continuous flow method for preparing o-tolueneacetonitrile oxime. The method is carried out in a continuous flow reactor. In the continuous flow reactor, a mixed solution of o-tolueneacetonitrile, an alcohol solvent, and a base is connected to metering pump 1; an oxime reagent is connected to metering pump 2; water is connected to metering pump 3; acid is connected to metering pump 4; and an extraction solvent is connected to metering pump 5. Metering pump 1 is connected to a continuous flow preheater; the continuous flow preheater and metering pump 2 are connected to a continuous flow mixer; the continuous flow mixer is sequentially connected to a continuous flow reactor, a continuous concentrator 1, a continuous dissolver, a continuous acid conditioner, a continuous flow extractor, a continuous flow phase separator, and a continuous concentrator 2; metering pump 3 is connected to the continuous dissolver; metering pump 4 is connected to the continuous acid conditioner; and metering pump 5 is connected to the continuous flow extractor.

[0008] The method includes the following steps: when the continuous flow preheater, continuous flow mixer and continuous flow reactor reach the circulation temperature, each metering pump is turned on to react and obtain o-methylacetonitrile oxime.

[0009] Furthermore,

[0010] The alcohol solvent is selected from methanol, ethanol, n-butanol, or isopropanol;

[0011] And / or, the base is an inorganic base;

[0012] And / or, the oxime reagent is a nitrate ester compound;

[0013] And / or, the acid is an organic acid;

[0014] And / or, the extraction solvent is an organic solvent.

[0015] Furthermore,

[0016] The alcohol reagent is methanol;

[0017] And / or, the inorganic base is sodium hydroxide;

[0018] And / or, the nitrate ester compound is selected from n-butyl nitrite, tert-butyl nitrite, or isopropyl nitrite;

[0019] And / or, the organic acid is hydrochloric acid;

[0020] And / or, the organic solvent is ethyl acetate;

[0021] Preferably, the nitrate ester compound is n-butyl nitrite.

[0022] Furthermore, the molar ratio of the o-methylphenylacetonitrile, the oxime reagent, and the base is 1:1 to 2:1 to 2.5;

[0023] And / or, the volume-to-mass ratio of the alcohol solvent to o-methylphenylacetonitrile is (5-10) mL: 1 g. Further, the molar ratio of the o-methylphenylacetonitrile, oxime reagent, and base is 1:1.5:2.4;

[0024] And / or, the volume-to-mass ratio of the alcohol solvent to o-methylphenylacetonitrile is 7.5 mL: 1 g.

[0025] Furthermore, the cycling temperature is 20–50°C;

[0026] Preferably, the cycling temperature is 40°C.

[0027] Furthermore, the flow rate of metering pump 1 is set to 86.0–172.0 ml / min; the flow rate of metering pump 2 is set to 13.0–26.0 ml / min; the flow rate of metering pump 3 is set to 49.5–99.0 ml / min; the flow rate of metering pump 4 is set to 5.8–14.0 ml / min; and the flow rate of metering pump 5 is set to 29.7–59.4 ml / min.

[0028] Furthermore, the flow rate of metering pump 1 is set to 115.0 ml / min; the flow rate of metering pump 2 is set to 17.5 ml / min; the flow rate of metering pump 3 is set to 66.2 ml / min; the flow rate of metering pump 4 is set to 9.3 ml / min; and the flow rate of metering pump 5 is set to 39.7 ml / min.

[0029] Furthermore, when the continuous flow preheater, continuous flow mixer, and continuous flow reactor reach the circulation temperature, the metering pumps are turned on in the following order:

[0030] (1) First turn on metering pump 1, run for 100-150 seconds, then turn on metering pump 2;

[0031] (2) After the metering pump 2 runs for 10 to 20 minutes, the reaction liquid enters the continuous concentrator 1. After the liquid is concentrated under reduced pressure for 20 to 40 seconds, the metering pump 3, metering pump 4 and metering pump 5 are turned on at the same time.

[0032] (3) The operation lasts for 25 to 35 minutes from the start of metering pump 1.

[0033] Furthermore, when the continuous flow preheater, continuous flow mixer, and continuous flow reactor reach the circulation temperature, the metering pumps are turned on in the following order:

[0034] (1) First turn on metering pump 1, run for 130 seconds, then turn on metering pump 2;

[0035] (2) After metering pump 2 runs for 15 minutes, the reaction liquid enters the continuous concentrator 1. After being concentrated under reduced pressure for 30 seconds, metering pump 3, metering pump 4 and metering pump 5 are turned on at the same time.

[0036] (3) The operation will end after a total of 30 minutes from the start of metering pump 1;

[0037] Preferably, the temperature for vacuum concentration is 50–55°C.

[0038] The present invention has achieved the following beneficial effects:

[0039] This invention provides a continuous flow method for preparing o-methylphenylacetonitrile oxime. Using o-methylphenylacetonitrile as a raw material, this invention prepares o-methylphenylacetonitrile oxime via a continuous flow process. This method ensures the reaction is completed in a short time, and the obtained o-methylphenylacetonitrile oxime has high purity and yield. This invention provides an efficient and safe method for obtaining o-methylphenylacetonitrile oxime, and has good application prospects.

[0040] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0041] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0042] Figure 1 This is a process flow diagram for the continuous flow preparation of o-methylacetonitrile oxime according to the present invention. Detailed Implementation

[0043] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0044] The o-methylacetonitrile oxime was prepared according to the following synthetic route:

[0045]

[0046] The process flow diagram for the continuous flow preparation of o-methylacetonitrile oxime according to this invention is shown below. Figure 1 As shown.

[0047] Example 1: Continuous flow preparation of o-methylacetonitrile oxime

[0048] Prepare a mixed solution of methanol (750 ml, 7.5 V), sodium hydroxide (73.2 g, 1.83 mol), and o-tolueneacetonitrile (100 g, 0.76 mol), and connect it to metering pump 1; weigh 118 g of n-butyl nitrite (1.14 mol) and connect it to metering pump 2; weigh 1.0 kg of water (55.55 mol) and connect it to metering pump 3; weigh 162.2 g of concentrated hydrochloric acid (4.4 mol) and connect it to metering pump 4; weigh 600 ml of ethyl acetate (6 V) and connect it to metering pump 5.

[0049] Set the continuous flow preheater 1, continuous flow mixer 1, and continuous flow reactor 1 to a circulating temperature of 40℃ and allow it to stabilize.

[0050] The flow rate of metering pump 1 was set to 115.0 ml / min, the flow rate of metering pump 2 was set to 17.5 ml / min, the flow rate of metering pump 3 was set to 66.2 ml / min, the flow rate of metering pump 4 was set to 9.3 ml / min, and the flow rate of metering pump 5 was set to 39.7 ml / min.

[0051] Metering pump 1 was turned on and ran for 130 seconds. Then metering pump 2 was turned on and ran for 15 minutes. The reaction solution entered continuous concentrator 1 and was concentrated under reduced pressure at 55°C for 30 seconds. Then metering pumps 3, 4, and 5 were turned on simultaneously. The concentrate was dissolved in water in a continuous dissolver and then the pH was adjusted with concentrated hydrochloric acid in a continuous acid adjuster. Then it was extracted with ethyl acetate in a continuous flow extractor and separated by a continuous flow phase separator. The organic phase was concentrated under reduced pressure at 55°C in continuous concentrator 2 until a solid precipitate. After running for a total of 30 minutes from the start of metering pump 1, 129.9 g of product (white solid) was obtained with an HPLC purity of 94% and a yield of 100%. Melting point: 98-101℃; ¹H NMR (300MHz, CDCl₃) δ (ppm): 2.48 (s, H, Ar-CH₃), 7.27-7.38 (m, 3H, Ar-H), 7.40-7.51 (m, H, Ar-H), 11.01 (s, H, N-OH). The yield was calculated as: (amount of product obtained × purity / theoretical amount) × 100%.

[0052] Example 2: Continuous flow preparation of o-methylacetonitrile oxime

[0053] Prepare a mixed solution of methanol (750 ml, 7.5 V), sodium hydroxide (61 g, 1.525 mol), and o-tolueneacetonitrile (100 g, 0.76 mol), and connect it to metering pump 1; weigh 118 g of n-butyl nitrite (1.14 mol) and connect it to metering pump 2; weigh 1.0 kg of water (55.55 mol) and connect it to metering pump 3; weigh 135.2 g of concentrated hydrochloric acid (3.7 mol) and connect it to metering pump 4; weigh 600 ml of ethyl acetate (6 V) and connect it to metering pump 5.

[0054] Set the continuous flow preheater 1, continuous flow mixer 1, and continuous flow reactor 1 to a circulating temperature of 40℃ and allow it to stabilize.

[0055] The flow rate of metering pump 1 was set to 115.0 ml / min, the flow rate of metering pump 2 was set to 17.6 ml / min, the flow rate of metering pump 3 was set to 66.3 ml / min, the flow rate of metering pump 4 was set to 7.8 ml / min, and the flow rate of metering pump 5 was set to 39.7 ml / min.

[0056] Metering pump 1 was turned on and ran for 130 seconds. Then metering pump 2 was turned on and ran for 15 minutes. The reaction solution entered continuous concentrator 1 and was concentrated under reduced pressure at 55°C for 30 seconds. Then metering pumps 3, 4, and 5 were turned on simultaneously. The concentrate was dissolved in water in a continuous dissolver and then the pH was adjusted with concentrated hydrochloric acid in a continuous acid adjuster. It was then extracted with ethyl acetate in a continuous flow extractor and separated by a continuous flow phase separator. The organic phase was concentrated under reduced pressure at 55°C in continuous concentrator 2 until a solid precipitate. After a total of 30 minutes of operation from the start of metering pump 1, 128.6 g of product (white solid) was obtained with an HPLC purity of 86% and a yield of 90.5%. Melting point: 98.5-99℃, HNMR (300MHz, CDCl3) δ (ppm): 2.48 (s, H, Ar-CH3), 7.29-7.38 (m, 3H, Ar-H), 7.40-7.53 (m, H, Ar-H), 11.01 (s, H, N-OH).

[0057] Example 3: Continuous flow preparation of o-methylacetonitrile oxime

[0058] Prepare a mixed solution of methanol (750 ml, 7.5 V), sodium hydroxide (45.7 g, 1.14 mol), and o-tolueneacetonitrile (100 g, 0.76 mol), and connect it to metering pump 1; weigh 118 g of n-butyl nitrite (1.14 mol) and connect it to metering pump 2; weigh 1.0 kg of water (55.55 mol) and connect it to metering pump 3; weigh 101.4 g of concentrated hydrochloric acid (2.78 mol) and connect it to metering pump 4; weigh 600 ml of ethyl acetate (6 V) and connect it to metering pump 5.

[0059] Set the continuous flow preheater 1, continuous flow mixer 1, and continuous flow reactor 1 to a circulating temperature of 40℃ and allow it to stabilize.

[0060] The flow rates of metering pump 1, 2, 3, 4, and 5 were set to 115.0 ml / min, 17.7 ml / min, 66.3 ml / min, 5.8 ml / min, and 39.8 ml / min, respectively.

[0061] Metering pump 1 was turned on and ran for 130 seconds. Then metering pump 2 was turned on and ran for 15 minutes. The reaction solution entered continuous concentrator 1 and was concentrated under reduced pressure at 55°C for 30 seconds. Then metering pumps 3, 4, and 5 were turned on simultaneously. The concentrate was dissolved in water in a continuous dissolver and then the pH was adjusted with concentrated hydrochloric acid in a continuous acid adjuster. It was then extracted with ethyl acetate in a continuous flow extractor and separated by a continuous flow phase separator. The organic phase was concentrated under reduced pressure at 55°C in continuous concentrator 2 until a solid precipitate. After a total of 30 minutes of operation from the start of metering pump 1, 134.5 g of product (off-white solid) was obtained with an HPLC purity of 84% and a yield of 92.5%. Melting point: 98.6-100℃, HNMR (300MHz, CDCl3) δ (ppm): 2.47 (s, H, Ar-CH3), 7.27-7.39 (m, 3H, Ar-H), 7.40-7.51 (m, H, Ar-H), 11.01 (s, H, N-OH).

[0062] Example 4: Continuous flow preparation of o-methylacetonitrile oxime

[0063] Prepare a mixed solution of methanol (750 ml, 7.5 V), sodium hydroxide (73.2 g, 1.83 mol), and o-tolueneacetonitrile (100 g, 0.76 mol), and connect it to metering pump 1; weigh 118 g of n-butyl nitrite (1.14 mol) and connect it to metering pump 2; weigh 1.0 kg of water (55.55 mol) and connect it to metering pump 3; weigh 162.2 g of concentrated hydrochloric acid (4.4 mol) and connect it to metering pump 4; weigh 600 ml of ethyl acetate (6 V) and connect it to metering pump 5.

[0064] Set the continuous flow preheater 1, continuous flow mixer 1, and continuous flow reactor 1 to a circulating temperature of 50℃ and allow it to stabilize.

[0065] The flow rate of metering pump 1 was set to 115.0 ml / min, the flow rate of metering pump 2 was set to 17.5 ml / min, the flow rate of metering pump 3 was set to 66.2 ml / min, the flow rate of metering pump 4 was set to 9.3 ml / min, and the flow rate of metering pump 5 was set to 39.7 ml / min.

[0066] Metering pump 1 was turned on and ran for 130 seconds. Then metering pump 2 was turned on and ran for 15 minutes. The reaction solution entered continuous concentrator 1 and was concentrated under reduced pressure at 55°C for 30 seconds. Then metering pumps 3, 4, and 5 were turned on simultaneously. The concentrate was dissolved in water in a continuous dissolver and then the pH was adjusted with concentrated hydrochloric acid in a continuous acid adjuster. It was then extracted with ethyl acetate in a continuous flow extractor and separated by a continuous flow phase separator. The organic phase was concentrated under reduced pressure at 55°C in continuous concentrator 2 until a solid precipitate. After a total of 30 minutes of operation from the start of metering pump 1, 128.6 g of product (white solid) was obtained with an HPLC purity of 95% and a yield of 100%. Melting point: 98.1-99℃, HNMR (300MHz, CDCl3) δ (ppm): 2.48 (s, H, Ar-CH3), 7.27-7.36 (m, 3H, Ar-H), 7.39-7.51 (m, H, Ar-H), 11.01 (s, H, N-OH).

[0067] Example 5: Continuous flow preparation of o-methylacetonitrile oxime

[0068] Prepare a mixed solution of methanol (750 ml, 7.5 V), sodium hydroxide (73.2 g, 1.83 mol), and o-tolueneacetonitrile (100 g, 0.76 mol), and connect it to metering pump 1; weigh 118 g of n-butyl nitrite (1.14 mol) and connect it to metering pump 2; weigh 1.0 kg of water (55.55 mol) and connect it to metering pump 3; weigh 162.2 g of concentrated hydrochloric acid (4.4 mol) and connect it to metering pump 4; weigh 600 ml of ethyl acetate (6 V) and connect it to metering pump 5.

[0069] Set the continuous flow preheater 1, continuous flow mixer 1, and continuous flow reactor 1 to a circulating temperature of 30°C and allow it to stabilize.

[0070] The flow rate of metering pump 1 was set to 115.0 ml / min, the flow rate of metering pump 2 was set to 17.5 ml / min, the flow rate of metering pump 3 was set to 66.2 ml / min, the flow rate of metering pump 4 was set to 9.3 ml / min, and the flow rate of metering pump 5 was set to 39.7 ml / min.

[0071] Metering pump 1 was turned on and ran for 130 seconds. Then metering pump 2 was turned on and ran for 15 minutes. The reaction solution entered continuous concentrator 1 and was concentrated under reduced pressure at 55°C for 30 seconds. Then metering pumps 3, 4, and 5 were turned on simultaneously. The concentrate was dissolved in water in a continuous dissolver and then the pH was adjusted with concentrated hydrochloric acid in a continuous acid adjuster. It was then extracted with ethyl acetate in a continuous flow extractor and separated by a continuous flow phase separator. The organic phase was concentrated under reduced pressure at 55°C in continuous concentrator 2 until a solid precipitate. After a total of 30 minutes of operation from the start of metering pump 1, 128.6 g of product (white solid) was obtained with an HPLC purity of 93% and a yield of 97.9%. Melting point: 98.2-101℃, HNMR (300MHz, CDCl3) δ (ppm): 2.48 (s, H, Ar-CH3), 7.27-7.38 (m, 3H, Ar-H), 7.40-7.53 (m, H, Ar-H), 11.01 (s, H, N-OH).

[0072] Example 6: Continuous flow preparation of o-methylacetonitrile oxime

[0073] Prepare a mixed solution of methanol (750 ml, 7.5 V), sodium hydroxide (73.2 g, 1.83 mol), and o-tolueneacetonitrile (100 g, 0.76 mol), and connect it to metering pump 1; weigh 118 g of n-butyl nitrite (1.14 mol) and connect it to metering pump 2; weigh 1.0 kg of water (55.55 mol) and connect it to metering pump 3; weigh 162.2 g of concentrated hydrochloric acid (4.4 mol) and connect it to metering pump 4; weigh 600 ml of ethyl acetate (6 V) and connect it to metering pump 5.

[0074] Set the continuous flow preheater 1, continuous flow mixer 1, and continuous flow reactor 1 to a circulating temperature of 20°C and allow them to stabilize.

[0075] The flow rate of metering pump 1 was set to 115.0 ml / min, the flow rate of metering pump 2 was set to 17.5 ml / min, the flow rate of metering pump 3 was set to 66.2 ml / min, the flow rate of metering pump 4 was set to 9.3 ml / min, and the flow rate of metering pump 5 was set to 39.7 ml / min.

[0076] Metering pump 1 was turned on and ran for 130 seconds. Then metering pump 2 was turned on and ran for 15 minutes. The reaction solution entered continuous concentrator 1 and was concentrated under reduced pressure at 55°C for 30 seconds. Then metering pumps 3, 4, and 5 were turned on simultaneously. The concentrate was dissolved in water in a continuous dissolver and then the pH was adjusted with concentrated hydrochloric acid in a continuous acid adjuster. It was then extracted with ethyl acetate in a continuous flow extractor and separated by a continuous flow phase separator. The organic phase was concentrated under reduced pressure at 55°C in continuous concentrator 2 until a solid precipitate. After a total of 30 minutes of operation from the start of metering pump 1, 137.4 g of product (off-white solid) was obtained with an HPLC purity of 80% and a yield of 90%. Melting point: 98.3-101℃, HNMR (300MHz, CDCl3) δ (ppm): 2.48 (s, H, Ar-CH3), 7.27-7.36 (m, 3H, Ar-H), 7.40-7.51 (m, H, Ar-H), 11.03 (s, H, N-OH).

[0077] Example 7: Continuous flow preparation of o-methylacetonitrile oxime

[0078] Prepare a mixed solution of methanol (750 ml, 7.5 V), sodium hydroxide (73.2 g, 1.83 mol), and o-tolueneacetonitrile (100 g, 0.76 mol), and connect it to metering pump 1; weigh tert-butyl nitrite (118 g, 1.14 mol) and connect it to metering pump 2; weigh water (1.0 kg, 55.55 mol) and connect it to metering pump 3; weigh concentrated hydrochloric acid (162.2 g, 4.4 mol) and connect it to metering pump 4; weigh ethyl acetate (600 ml, 6 V) and connect it to metering pump 5.

[0079] Set the continuous flow preheater 1, continuous flow mixer 1, and continuous flow reactor 1 to a circulating temperature of 40℃ and allow it to stabilize.

[0080] The flow rate of metering pump 1 was set to 115.0 ml / min, the flow rate of metering pump 2 was set to 17.5 ml / min, the flow rate of metering pump 3 was set to 66.2 ml / min, the flow rate of metering pump 4 was set to 9.3 ml / min, and the flow rate of metering pump 5 was set to 39.7 ml / min.

[0081] Metering pump 1 was turned on and ran for 130 seconds. Then metering pump 2 was turned on and ran for 15 minutes. The reaction solution entered continuous concentrator 1 and was concentrated under reduced pressure at 55°C for 30 seconds. Then metering pumps 3, 4, and 5 were turned on simultaneously. The concentrate was dissolved in water in a continuous dissolver and then the pH was adjusted with concentrated hydrochloric acid in a continuous acid adjuster. It was then extracted with ethyl acetate in a continuous flow extractor and separated by a continuous flow phase separator. The organic phase was concentrated under reduced pressure at 55°C in continuous concentrator 2 until a solid precipitate. After a total of 30 minutes of operation from the start of metering pump 1, 148 g of product (yellow solid) was obtained with an HPLC purity of 70% and a yield of 84.8%. Melting point: 97-98.9℃, HNMR (300MHz, CDCl3) δ (ppm): 2.47 (s, H, Ar-CH3), 7.27-7.38 (m, 3H, Ar-H), 7.40-7.51 (m, H, Ar-H), 11.00 (s, H, N-OH).

[0082] Example 8: Continuous flow preparation of o-methylacetonitrile oxime

[0083] Prepare a mixed solution of methanol (750 ml, 7.5 V), sodium hydroxide (73.2 g, 1.83 mol), and o-tolueneacetonitrile (100 g, 0.76 mol), and connect it to metering pump 1; weigh isopropyl nitrite (101.8 g, 1.14 mol) and connect it to metering pump 2; weigh water (1.0 kg, 55.55 mol) and connect it to metering pump 3; weigh concentrated hydrochloric acid (162.2 g, 4.4 mol) and connect it to metering pump 4; weigh ethyl acetate (600 ml, 6 V) and connect it to metering pump 5.

[0084] Set the continuous flow preheater 1, continuous flow mixer 1, and continuous flow reactor 1 to a circulating temperature of 40℃ and allow it to stabilize.

[0085] The flow rate of metering pump 1 was set to 119.0 ml / min, the flow rate of metering pump 2 was set to 13.5 ml / min, the flow rate of metering pump 3 was set to 66.2 ml / min, the flow rate of metering pump 4 was set to 9.3 ml / min, and the flow rate of metering pump 5 was set to 39.7 ml / min.

[0086] Metering pump 1 was turned on and ran for 130 seconds. Then metering pump 2 was turned on and ran for 15 minutes. The reaction solution entered continuous concentrator 1 and was concentrated under reduced pressure at 55°C for 30 seconds. Then metering pumps 3, 4, and 5 were turned on simultaneously. The concentrate was dissolved in water in a continuous dissolver and then the pH was adjusted with concentrated hydrochloric acid in a continuous acid adjuster. It was then extracted with ethyl acetate in a continuous flow extractor and separated by a continuous flow phase separator. The organic phase was concentrated under reduced pressure at 55°C in continuous concentrator 2 until a solid precipitate. After running for a total of 30 minutes from the start of metering pump 1, 138.1 g of product (yellow solid) was obtained with an HPLC purity of 80% and a yield of 90.4%. Melting point: 97-99℃, HNMR (300MHz, CDCl3) δ (ppm): 2.48 (s, H, Ar-CH3), 7.27-7.39 (m, 3H, Ar-H), 7.41-7.51 (m, H, Ar-H), 11.01 (s, H, N-OH).

[0087] Example 9: Continuous flow preparation of o-methylacetonitrile oxime

[0088] Prepare a mixed solution of ethanol (750 ml, 7.5 V), sodium hydroxide (73.2 g, 1.83 mol), and o-tolueneacetonitrile (100 g, 0.76 mol), and connect it to metering pump 1; weigh 118 g of n-butyl nitrite (1.14 mol) and connect it to metering pump 2; weigh 1.0 kg of water (55.55 mol) and connect it to metering pump 3; weigh 162.2 g of concentrated hydrochloric acid (4.4 mol) and connect it to metering pump 4; weigh 600 ml of ethyl acetate (6 V) and connect it to metering pump 5.

[0089] Set the continuous flow preheater 1, continuous flow mixer 1, and continuous flow reactor 1 to a circulating temperature of 40℃ and allow it to stabilize.

[0090] The flow rate of metering pump 1 was set to 115.0 ml / min, the flow rate of metering pump 2 was set to 17.5 ml / min, the flow rate of metering pump 3 was set to 66.2 ml / min, the flow rate of metering pump 4 was set to 9.3 ml / min, and the flow rate of metering pump 5 was set to 39.7 ml / min.

[0091] Metering pump 1 was turned on and ran for 130 seconds. Then metering pump 2 was turned on and ran for 15 minutes. The reaction solution entered continuous concentrator 1 and was concentrated under reduced pressure at 55°C for 30 seconds. Then metering pumps 3, 4, and 5 were turned on simultaneously. The concentrate was dissolved in water in a continuous dissolver and then the pH was adjusted with concentrated hydrochloric acid in a continuous acid adjuster. It was then extracted with ethyl acetate in a continuous flow extractor and separated by a continuous flow phase separator. The organic phase was concentrated under reduced pressure at 55°C in continuous concentrator 2 until a solid precipitate. After a total of 30 minutes of operation from the start of metering pump 1, 130.9 g of product (off-white solid) was obtained with an HPLC purity of 90% and a yield of 96.4%. Melting point: 98-99.5℃, HNMR (300MHz, CDCl3) δ (ppm): 2.48 (s, H, Ar-CH3), 7.28-7.38 (m, 3H, Ar-H), 7.40-7.51 (m, H, Ar-H), 11.03 (s, H, N-OH).

[0092] Example 10: Continuous flow preparation of o-methylacetonitrile oxime

[0093] Prepare a mixed solution of n-butanol (750 ml, 7.5 V), sodium hydroxide (73.2 g, 1.83 mol), and o-tolueneacetonitrile (100 g, 0.76 mol), and connect it to metering pump 1; weigh n-butyl nitrite (118 g, 1.14 mol) and connect it to metering pump 2; weigh water (1.0 kg, 55.55 mol) and connect it to metering pump 3; weigh concentrated hydrochloric acid (162.2 g, 4.4 mol) and connect it to metering pump 4; weigh ethyl acetate (600 ml, 6 V) and connect it to metering pump 5.

[0094] Set the continuous flow preheater 1, continuous flow mixer 1, and continuous flow reactor 1 to a circulating temperature of 40℃ and allow it to stabilize.

[0095] The flow rate of metering pump 1 was set to 115.0 ml / min, the flow rate of metering pump 2 was set to 17.5 ml / min, the flow rate of metering pump 3 was set to 66.2 ml / min, the flow rate of metering pump 4 was set to 9.3 ml / min, and the flow rate of metering pump 5 was set to 39.7 ml / min.

[0096] Metering pump 1 was turned on and ran for 130 seconds. Then metering pump 2 was turned on and ran for 15 minutes. The reaction solution entered continuous concentrator 1 and was concentrated under reduced pressure at 55°C for 30 seconds. Then metering pumps 3, 4, and 5 were turned on simultaneously. The concentrate was dissolved in water in a continuous dissolver and then the pH was adjusted with concentrated hydrochloric acid in a continuous acid adjuster. It was then extracted with ethyl acetate in a continuous flow extractor and separated by a continuous flow phase separator. The organic phase was concentrated under reduced pressure at 55°C in continuous concentrator 2 until a solid precipitate. After a total of 30 minutes of operation from the start of metering pump 1, 134.8 g of product (white solid) was obtained with an HPLC purity of 86% and a yield of 94.9%. Melting point: 97-99.6℃, HNMR (300MHz, CDCl3) δ (ppm): 2.47 (s, H, Ar-CH3), 7.27-7.38 (m, 3H, Ar-H), 7.42-7.52 (m, H, Ar-H), 11.01 (s, H, N-OH).

[0097] Example 11: Continuous flow preparation of o-methylacetonitrile oxime

[0098] Prepare a mixed solution of isopropanol (750 ml, 7.5 V), sodium hydroxide (73.2 g, 1.83 mol), and o-tolueneacetonitrile (100 g, 0.76 mol), and connect it to metering pump 1; weigh 118 g of n-butyl nitrite (1.14 mol) and connect it to metering pump 2; weigh 1.0 kg of water (55.55 mol) and connect it to metering pump 3; weigh 162.2 g of concentrated hydrochloric acid (4.4 mol) and connect it to metering pump 4; weigh 600 ml of ethyl acetate (6 V) and connect it to metering pump 5.

[0099] Set the continuous flow preheater 1, continuous flow mixer 1, and continuous flow reactor 1 to a circulating temperature of 40℃ and allow it to stabilize.

[0100] The flow rate of metering pump 1 was set to 115.0 ml / min, the flow rate of metering pump 2 was set to 17.5 ml / min, the flow rate of metering pump 3 was set to 66.2 ml / min, the flow rate of metering pump 4 was set to 9.3 ml / min, and the flow rate of metering pump 5 was set to 39.7 ml / min.

[0101] Metering pump 1 was turned on and ran for 130 seconds. Then metering pump 2 was turned on and ran for 15 minutes. The reaction solution entered continuous concentrator 1 and was concentrated under reduced pressure at 55°C for 30 seconds. Then metering pumps 3, 4, and 5 were turned on simultaneously. The concentrate was dissolved in water in a continuous dissolver and then the pH was adjusted with concentrated hydrochloric acid in a continuous acid adjuster. It was then extracted with ethyl acetate in a continuous flow extractor and separated by a continuous flow phase separator. The organic phase was concentrated under reduced pressure at 55°C in continuous concentrator 2 until a solid precipitate. After a total of 30 minutes of operation from the start of metering pump 1, 124.1 g of product (off-white solid) was obtained with an HPLC purity of 91% and a yield of 92.5%. Melting point: 97.5-100℃, HNMR (300MHz, CDCl3) δ (ppm): 2.49 (s, H, Ar-CH3), 7.26-7.39 (m, 3H, Ar-H), 7.40-7.51 (m, H, Ar-H), 11.01 (s, H, N-OH).

[0102] Example 12: Continuous flow preparation of o-methylacetonitrile oxime

[0103] Prepare a mixed solution of methanol (750 ml, 7.5 V), sodium hydroxide (73.2 g, 1.83 mol), and o-tolueneacetonitrile (100 g, 0.76 mol), and connect it to metering pump 1; weigh 118 g of n-butyl nitrite (1.14 mol) and connect it to metering pump 2; weigh 1.0 kg of water (55.55 mol) and connect it to metering pump 3; weigh 162.2 g of concentrated hydrochloric acid (4.4 mol) and connect it to metering pump 4; weigh 600 ml of ethyl acetate (6 V) and connect it to metering pump 5.

[0104] Set the continuous flow preheater 1, continuous flow mixer 1, and continuous flow reactor 1 to a circulating temperature of 40℃ and allow it to stabilize.

[0105] The flow rate of metering pump 1 was set to 172.0 ml / min, the flow rate of metering pump 2 was set to 26.0 ml / min, the flow rate of metering pump 3 was set to 99.0 ml / min, the flow rate of metering pump 4 was set to 14.0 ml / min, and the flow rate of metering pump 5 was set to 59.4 ml / min.

[0106] Metering pump 1 was turned on and ran for 130 seconds. Then metering pump 2 was turned on and ran for 10 minutes. The reaction solution entered continuous concentrator 1 and was concentrated under reduced pressure at 55°C for 30 seconds. Then metering pumps 3, 4, and 5 were turned on simultaneously. The concentrate was dissolved in water in a continuous dissolver and then the pH was adjusted with concentrated hydrochloric acid in a continuous acid adjuster. It was then extracted with ethyl acetate in a continuous flow extractor and separated by a continuous flow phase separator. The organic phase was concentrated under reduced pressure at 55°C in continuous concentrator 2 until a solid precipitate. After a total of 25 minutes of operation from the start of metering pump 1, 136.2 g of product (yellow solid) was obtained with an HPLC purity of 87% and a yield of 97%. Melting point: 97.4-99.5℃, HNMR (300MHz, CDCl3) δ (ppm): 2.48 (s, H, Ar-CH3), 7.27-7.38 (m, 3H, Ar-H), 7.39-7.51 (m, H, Ar-H), 11.01 (s, H, N-OH).

[0107] Example 13: Continuous flow preparation of o-methylacetonitrile oxime

[0108] Prepare a mixed solution of methanol (750 ml, 7.5 V), sodium hydroxide (73.2 g, 1.83 mol), and o-tolueneacetonitrile (100 g, 0.76 mol), and connect it to metering pump 1; weigh 118 g of n-butyl nitrite (1.14 mol) and connect it to metering pump 2; weigh 1.0 kg of water (55.55 mol) and connect it to metering pump 3; weigh 162.2 g of concentrated hydrochloric acid (4.4 mol) and connect it to metering pump 4; weigh 600 ml of ethyl acetate (6 V) and connect it to metering pump 5.

[0109] Set the continuous flow preheater 1, continuous flow mixer 1, and continuous flow reactor 1 to a circulating temperature of 40℃ and allow it to stabilize.

[0110] The flow rates of metering pump 1, 2, 3, 4, 4, and 5 were set to 86.0 ml / min, 13.0 ml / min, 4, 7.0 ml / min, and 29.7 ml / min, respectively.

[0111] Metering pump 1 was turned on and ran for 130 seconds. Then metering pump 2 was turned on and ran for 20 minutes. The reaction solution entered continuous concentrator 1 and was concentrated under reduced pressure at 55°C for 30 seconds. Then metering pumps 3, 4, and 5 were turned on simultaneously. The concentrate was dissolved in water in a continuous dissolver and then the pH was adjusted with concentrated hydrochloric acid in a continuous acid adjuster. It was then extracted with ethyl acetate in a continuous flow extractor and separated by a continuous flow phase separator. The organic phase was concentrated under reduced pressure at 55°C in continuous concentrator 2 until a solid precipitate. After a total of 35 minutes of operation from the start of metering pump 1, 128.8 g of product (off-white solid) was obtained with an HPLC purity of 94.8% and a yield of 100%. Melting point: 97.1-100℃, HNMR (300MHz, CDCl3) δ (ppm): 2.48 (s, H, Ar-CH3), 7.28-7.38 (m, 3H, Ar-H), 7.42-7.52 (m, H, Ar-H), 11.01 (s, H, N-OH).

[0112] Comparative Example 1: Preparation of o-methylacetonitrile oxime by batch reaction

[0113] In a 2L three-necked flask equipped with a dropping funnel, condenser, and thermometer, add (100g, 0.76mol) o-methylphenylacetonitrile and (750mL, 7.5V) methanol. After stirring to dissolve, add (73.2g, 1.83mol) sodium hydroxide solid under cooling and stir to mix thoroughly. Slowly add (118g, 1.14mol) n-butyl nitrite dropwise under an ice-water bath. After the addition is complete, react at 40℃ for 30 minutes. Take a sample and analyze by thin-layer chromatography until no o-methylphenylacetonitrile raw material remains. After the reaction is complete, pour the mixture into ice water, slowly add industrial hydrochloric acid to adjust the pH to 5-6, add ethyl acetate for extraction, separate the phases, concentrate the organic phase to precipitate a white solid, dry and weigh 120.3g, purity: 95%, calculated yield: 93.6%, melting point: 98-101℃.

[0114] Comparative Example 2: Preparation of o-methylacetonitrile oxime by batch reaction

[0115] In a 2L three-necked flask equipped with a dropping funnel, condenser, and thermometer, add (100g, 0.76mol) o-methylphenylacetonitrile and (750mL, 7.5V) methanol. After stirring to dissolve, add (73.2g, 1.83mol) sodium hydroxide solid under cooling and stir to mix thoroughly. Slowly add (118g, 1.14mol) tert-butyl nitrite dropwise under an ice-water bath. After the addition is complete, react at 40℃ for 30 minutes. Take a sample and analyze by thin-layer chromatography until no o-methylphenylacetonitrile raw material remains. After the reaction is complete, pour the mixture into ice water, slowly add industrial hydrochloric acid to adjust the pH to 5-6, add ethyl acetate for extraction, separate the phases, concentrate the organic phase to precipitate a white solid, dry and weigh 125.23g, purity: 78%, calculated yield: 80%, melting point: 98-101℃.

[0116] Comparative Example 3: Preparation of o-methylacetonitrile oxime by batch reaction

[0117] In a 100 mL three-necked flask equipped with a dropping funnel, condenser, and thermometer, add (100 g, 0.76 mol) o-methylphenylacetonitrile and (750 mL, 7.5 V) methanol. After stirring to dissolve, add (45.7 g, 1.14 mol) sodium hydroxide solid under cooling and stir to mix thoroughly. Slowly add (118 g, 1.14 mol) n-butyl nitrite dropwise under an ice-water bath. After the addition is complete, react at 40 °C. After 1 h, detect the o-methylphenylacetonitrile raw material with thin-layer chromatography until no o-methylphenylacetonitrile remains. After the reaction is complete, pour the mixture into ice water, slowly add industrial hydrochloric acid to adjust the pH to 5-6, add ethyl acetate for extraction, separate the phases, concentrate the organic phase to precipitate a white solid, dry and weigh 119.46 g, purity 92.5%, calculated yield 90.5%, melting point: 98-101 °C.

[0118] according to Figure 1 The process flow diagram shown illustrates the preparation of o-methylphenylacetonitrile oxime. Table 1 compares the reaction conditions of Comparative Examples 1-3 and Examples 1-13. In the table, reaction time represents the running time of metering pump 2, and reaction temperature represents the circulating temperature.

[0119] Table 1. Comparison of reaction conditions between Comparative Examples 1-3 and Examples 1-13

[0120]

[0121]

[0122] Compared to batch reactions, continuous flow reactions have shorter reaction times and higher product yields and purity. Comparing Examples 1, 2, and 3, insufficient sodium hydroxide resulted in excessive residue of the raw material o-methylphenylacetonitrile, leading to lower yields and purity; therefore, the preferred sodium hydroxide dosage is 2.4 eq. Comparing Examples 1, 4, 5, and 6, the yield was 100% at either 40°C or 50°C, with HPLC purity of 94% at 40°C and 95% at 50°C. Lower reaction temperatures resulted in excessive residue of the raw material o-methylphenylacetonitrile, while higher temperatures were detrimental and increased energy consumption; therefore, a reaction temperature of 40°C was preferred. Comparing Examples 1, 7, and 8, tert-butyl nitrite and isopropyl nitrite... The reaction rate is slow, and for the same residence time, the tert-butyl ester and isopropyl ester system has more residual raw materials. Increasing the residence time increases energy consumption. Therefore, the preferred ester is n-butyl nitrite. Comparing Examples 1, 9, 10 and 11, the yield and content of reaction products in the ethanol, n-butanol and tert-butanol systems are not as high as those in the methanol system. Therefore, methanol is the preferred solvent. Comparing Examples 1, 12 and 13, if the residence time of metering pump 2 is too short, more o-methylphenylacetonitrile will remain. If the residence time is too long, there is no significant difference in the remaining raw materials compared to 15 min. That is, if the residence time is too long, energy consumption will increase. Therefore, the preferred residence time of metering pump 2 is 15 min.

[0123] Comparing all the examples, it can be seen that Example 1 has the best reaction conditions: the preferred amount of sodium hydroxide is 2.4 eq, the preferred reaction temperature is 40℃, the preferred ester is n-butyl nitrite, the preferred solvent is methanol, and the preferred residence time is 15 min.

[0124] In summary, this invention provides a continuous flow method for preparing o-methylphenylacetonitrile oxime. Using o-methylphenylacetonitrile as a raw material, this invention prepares o-methylphenylacetonitrile oxime via a continuous flow process. This method ensures the reaction is completed in a short time, and the obtained o-methylphenylacetonitrile oxime has high purity and yield. This invention is an efficient and safe method for obtaining o-methylphenylacetonitrile oxime and has good application prospects.

Claims

1. A process for the continuous flow preparation of o-methylphenylacetonitrile ketoxime, characterized in that: The method is carried out in a continuous flow reaction device, in which a mixed solution of o-methylphenylacetonitrile, an alcohol solvent and a base is connected to metering pump 1, an oximation reagent is connected to metering pump 2, water is connected to metering pump 3, an acid is connected to metering pump 4, and an extraction solvent is connected to metering pump 5; metering pump 1 is connected to a continuous flow preheater, the continuous flow preheater and metering pump 2 are connected to a continuous flow mixer, the continuous flow mixer is sequentially connected to a continuous flow reactor, a continuous concentrator 1, a continuous dissolver, a continuous acid regulator, a continuous flow extractor, a continuous flow phase separator and a continuous concentrator 2; metering pump 3 is connected to the continuous dissolver; metering pump 4 is connected to the continuous acid regulator; and metering pump 5 is connected to the continuous flow extractor. The method comprises the following steps: when the continuous flow preheater, the continuous flow mixer and the continuous flow reactor reach a cycle temperature, starting the metering pumps, and reacting to obtain an o-methylphenylacetonitrile ketoxime.

2. The method of claim 1, wherein: The alcohol solvent is selected from methanol, ethanol, n-butanol or isopropanol; And / or, the base is an inorganic base; And / or, the oximation reagent is a nitrate compound; And / or, the acid is an organic acid; And / or, the extraction solvent is an organic solvent.

3. The method of claim 2, wherein: The alcohol reagent is methanol; And / or, the inorganic base is sodium hydroxide; And / or, the nitrate compound is selected from n-butyl nitrite, tert-butyl nitrite or isopropyl nitrite; And / or, the organic acid is hydrochloric acid; And / or, the organic solvent is ethyl acetate; Preferably, the nitrate compound is n-butyl nitrite.

4. The method according to any one of claims 1 to 3, characterized in that: The molar ratio of the o-methylphenylacetonitrile, the oximation reagent and the base is 1:1-2:1-2.5; And / or, the volume-mass ratio of the alcohol solvent and the o-methylphenylacetonitrile is (5-10) mL:1 g.

5. The method of claim 4, wherein: The molar ratio of the o-methylphenylacetonitrile, the oximation reagent and the base is 1:1.5:2.4; And / or, the volume-mass ratio of the alcohol solvent and the o-methylphenylacetonitrile is 7.5 mL:1 g.

6. The method according to any one of claims 1 to 3, characterized in that: The cycle temperature is 20-50℃; Preferably, the cycle temperature is 40℃.

7. The method according to any one of claims 1 to 3, characterized in that: The flow rate of metering pump 1 is set to 86.0-172.0 ml / min; the flow rate of metering pump 2 is set to 13.0-26.0 ml / min; the flow rate of metering pump 3 is set to 49.5-99.0 ml / min; the flow rate of metering pump 4 is set to 5.8-14.0 ml / min; and the flow rate of metering pump 5 is set to 29.7-59.4 ml / min.

8. The method of claim 7, wherein: The flow rate of metering pump 1 is set to 115.0 ml / min; the flow rate of metering pump 2 is set to 17.5 ml / min; the flow rate of metering pump 3 is set to 66.2 ml / min; the flow rate of metering pump 4 is set to 9.3 ml / min; and the flow rate of metering pump 5 is set to 39.7 ml / min.

9. The method according to any one of claims 1 to 3, characterized in that: The metering pumps are started in the following order when the continuous flow preheater, the continuous flow mixer and the continuous flow reactor reach a cycle temperature: (1) Start metering pump 1 first, and start metering pump 2 after running for 100-150 s; (2) After the reaction solution in metering pump 2 runs for 10-20 min, it enters continuous concentrator 1, and after being concentrated under reduced pressure for 20-40 s, metering pump 3, metering pump 4 and metering pump 5 are opened simultaneously; (3) After a total running time of 25-35 min from the opening of metering pump 1, the process is ended.

10. The method of claim 9, wherein: When the continuous flow preheater, the continuous flow mixer and the continuous flow reactor reach the circulating temperature, the metering pumps are opened in the following order: (1) Metering pump 1 is opened first, and after running for 130 s, metering pump 2 is opened; (2) After metering pump 2 runs for 15 min, the reaction solution enters continuous concentrator 1, and after being concentrated under reduced pressure for 30 s, metering pump 3, metering pump 4 and metering pump 5 are opened simultaneously; (3) After a total running time of 30 min from the opening of metering pump 1, the process is ended; Preferably, the temperature for the concentration under reduced pressure is 50-55°C.

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