Bromination method of passivated aromatic compounds

Abstract

The invention relates to the technical field of organic synthesis, in particular to a passivated aromatic compound bromination method. The bromination method comprises the following step: in an acidic system containing sulfuric acid and liquid organic acid, a passivated aromatic compound, bromine and sodium periodate are in contact for bromination to obtain the aromatic bromide. The bromination method has the advantages of low cost, simple synthesis, mild reaction conditions, high product yield and purity, high applicability and safety.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and more specifically to a method for passivating the bromination of aromatic compounds. Background Technology

[0002] Bromination of aromatic rings is a well-established organic reaction in organic synthesis, having been studied, applied, and improved by countless scientists since its discovery in the 19th century. Aromatic brominated compounds are an important class of intermediates, widely used not only as precursors for organometallic reagents in the synthesis of pharmaceuticals, pesticide intermediates, and natural products, but also playing a crucial role in the chemical industries of dyes, semiconductors, and liquid crystal materials. Due to the broad synthetic potential of aromatic brominated compounds, economical, efficient, highly selective, safe, and environmentally friendly methods for bromination of aromatic rings remain a widely pursued goal in the chemical engineering field.

[0003] The synthesis of aromatic brominated compounds mainly employs indirect and direct methods. Indirect methods primarily utilize the Sandmeyer reaction to achieve denitrification and bromination of aromatic amines via intermediate heavy nitrogen salts, or through functional group transformation (halogen exchange) to obtain brominated aromatics. Direct methods can be divided into four main categories: direct bromination via elemental bromine; bromination via N-bromosuccinimide (NBS); bromination via bromine molecules and halide adducts; and bromination via in-situ oxidation to zero-valent bromine. While numerous methods exist for the bromination of aromatic compounds, strict experimental conditions are required for the bromination of passivated aromatic compounds. The bromination reaction of passivated aromatic compounds has always attracted attention. Due to the presence of electron-withdrawing groups on the aromatic ring, the conditions for bromination of the aromatic ring in passivated aromatic compounds become quite demanding, and side reactions are also increased. For example, in the direct bromination of trifluoromethylbenzene, 15%-30% of the trifluoromethylbenzene is converted to m-bromobenzoic acid; the direct bromination of acetophenone requires prior reaction with excess aluminum trichloride, making the operation very cumbersome. Some researchers have worked on the direct bromination and passivation of aromatic compounds using bromine as a brominating agent. However, this often requires the addition of large amounts of concentrated sulfuric acid or the use of a mixture of Br2 / BrF3, Br2 / AgNO3 / H2SO4, Br2 / HgO / H2SO4, Br2 / Hg2O, HF, SbF5 / Br2 with benzoyl peroxide and lithium bromide. These reactions are subject to harsh conditions and often require metal catalysts. Rajesh et al. reported the bromination of aromatic compounds using NBS in concentrated H2SO4, with good yields at 60°C. NBS has long been used for the passivation of aromatic compounds (e.g., NBS / TFA / H2SO4, NBS / BF3-H2O, NBS / H2SO4 aqueous solution), but its high preparation cost limits its industrial applicability. Kumar et al. reported a method of bromide passivation of aromatic compounds by adding NaBr and NaIO4 to a concentrated sulfuric acid system. Although this avoids the use of NBS, the amount of concentrated sulfuric acid used is large, which is not conducive to the subsequent treatment of waste and increases the cost of waste treatment.

[0004] Therefore, there is an urgent need for a low-cost, simple-to-synthesize, mild-condition, highly applicable, and safe method for the bromination of passivating aromatic compounds. Summary of the Invention

[0005] The purpose of this invention is to overcome the problems of high raw material and waste treatment costs, complex processes, harsh reaction conditions, and low product yield in existing technologies, and to provide a bromination method for passivating aromatic compounds that has low raw material and waste treatment costs, simple synthesis, mild reaction conditions, high product yield and purity, high applicability, and safety.

[0006] According to a first aspect of the present invention, a method for passivating the bromination of aromatic compounds is provided, comprising the following steps:

[0007] In an acidic system containing sulfuric acid and liquid organic acid, the passivated aromatic compound of formula (I), bromine, and sodium periodate are brominated to obtain the aromatic bromide of formula (II).

[0008]

[0009] The passivation method for bromination of aromatic compounds provided by this invention is low-cost, simple, has mild reaction conditions, high product yield and purity, high applicability, and safe operation. This is presumably because, in the bromination system of passivated aromatic compounds, bromine, and sodium periodate of this invention, the liquid organic acid can increase the solubility of the raw materials and provide protons, promoting the bromination reaction; sodium periodate, as a catalyst, can improve the conversion rate and product selectivity.

[0010] Unlike this invention, existing technologies primarily use sulfuric acid as a liquid acid in large quantities, resulting in a dangerous post-treatment quenching process, high waste treatment costs, and the use of other liquid organic acids primarily as solvents. In contrast, the liquid organic acid used in this invention serves two purposes: it acts as a solvent to dissolve the raw materials, and it also provides protons to promote the reaction, thus reducing the amount of sulfuric acid required.

[0011] This invention targets the bromination of desensitized aromatic compounds, using bromine, which is cheaper and more readily available, as the brominating agent, and has a wider range of substrate adaptability. Attached Figure Description

[0012] Figure 1 This is a simplified diagram of the reaction apparatus;

[0013] Figure 2 The 1H NMR spectrum of 5-bromo-2-chlorobenzoic acid;

[0014] Figure 3 The carbon spectrum of 5-bromo-2-chlorobenzoic acid;

[0015] Figure 4 The 1H NMR spectrum of 3-bromobenzoic acid;

[0016] Figure 5 The carbon spectrum of 3-bromobenzoic acid;

[0017] Figure 6 The 1H NMR spectrum of 3-bromotrifluorotoluene;

[0018] Figure 7 The carbon spectrum of 3-bromotrifluorotoluene;

[0019] Figure 8 The 1H NMR spectrum of p-bromochlorobenzene;

[0020] Figure 9 The carbon spectrum of p-bromochlorobenzene;

[0021] Figure 10 The 1H NMR spectrum of 3-bromo-5-nitrobenzaldehyde;

[0022] Figure 11 The carbon spectrum of 3-bromo-5-nitrobenzaldehyde;

[0023] Figure 12 The 1H NMR spectrum of 3-bromobenzaldehyde;

[0024] Figure 13 The carbon spectrum of 3-bromobenzaldehyde;

[0025] Figure 14 This is a schematic diagram of the reaction process of this system. Detailed Implementation

[0026] The following provides a detailed description of specific embodiments of the present invention. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the invention. The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values; these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0027] This invention provides a method for passivating the bromination of aromatic compounds, comprising, as follows: Figure 14 The following steps are shown:

[0028] In an acidic system containing sulfuric acid and liquid organic acid, the passivated aromatic compound of formula (I), bromine, and sodium periodate are brominated to obtain the aromatic bromide of formula (II).

[0029]

[0030] The bromination method for passivated aromatic compounds, which includes the above-mentioned features, has the advantages of high reaction conversion rate, high product purity, mild reaction conditions, low cost, and simple operation.

[0031] In this invention, the molar ratio of the passivating aromatic compound, bromine, and sodium periodate shown in formula (I) can be selected over a wide range. The following is an illustrative description, but it does not limit the scope of the invention. According to a preferred embodiment of the invention, the molar ratio of the passivating aromatic compound, bromine, and sodium periodate is 1:0.5-1:0.25-1, preferably 1:0.5-1:0.3-1, and more preferably 1:0.5-1:0.5-0.7.

[0032] In this invention, the amount of liquid organic acid and water can be selected from a wide range, as illustrated below, but this does not limit the scope of the invention. According to a preferred embodiment of the invention, the molar ratio of the passivated aromatic compound, liquid organic acid and water shown in formula (I) is 1:7-11:22-34, preferably 1:8.5-10.5:27.5-33.3.

[0033] In this invention, the range of types of liquid organic acids that can be selected is relatively wide. The following is an illustrative description, but it does not limit the scope of this invention. According to a preferred embodiment of the invention, the liquid organic acid is one or more of acetic acid, formic acid, propionic acid, and lactic acid.

[0034] According to a preferred embodiment of the present invention, the organic acid is a mixture of formic acid and lactic acid, with a molar ratio of formic acid to lactic acid of 1:0.2-0.6 based on the liquid organic acid. The combined use of formic acid and lactic acid exhibits a synergistic effect, thereby ensuring a high yield with a relatively low amount of organic acid used.

[0035] In this invention, the amount of sulfuric acid used can be selected within a wide range. The following is an illustrative example, but it does not limit the scope of the invention. According to a preferred embodiment of the invention, the molar ratio of the passivating aromatic compound shown in formula (I) to sulfuric acid (based on H2SO4) is 1:0.01-15, preferably 1:1.9-11.3, and more preferably 1:7-10. Using the aforementioned preferred technical solution can further improve the selectivity of the bromination reaction of the passivating aromatic compound and reduce the generation of byproducts.

[0036] In this invention, the types of R1 and R2 in the passivated aromatic compound represented by formula (I) are relatively wide. The following is an illustrative description, but it does not limit the scope of the invention. According to a preferred embodiment of the invention, R1 and R2 are each independently selected from H and the passivating substituent group.

[0037] In this invention, the range of types of passivating substituents is relatively wide. The following examples illustrate this, but do not limit the scope of the invention. According to a preferred embodiment of the invention, the passivating substituent is an electron-withdrawing group, preferably one or more of a strong electron-withdrawing group, a moderate electron-withdrawing group, and a weak electron-withdrawing group.

[0038] In this invention, the strong electron-withdrawing group has no special requirements; any common strong electron-withdrawing group is applicable. According to a preferred embodiment of this invention, the strong electron-withdrawing group is selected from tertiary amine cations (-N... + One or more of R3, nitro (-NO2), and trihalomethyl (-CX3, for example, X is F and / or Cl).

[0039] In this invention, there are no special requirements for the electron-withdrawing group; any common electron-withdrawing group is applicable. According to a preferred embodiment of this invention, the electron-withdrawing group is selected from one or more of a cyano group (-CN) and a sulfonic acid group (-SO3H).

[0040] In this invention, there are no special requirements for the weak electron-withdrawing group; any common weak electron-withdrawing group is applicable. According to a preferred embodiment of this invention, the weak electron-withdrawing group is selected from one or more of the following: F atom, Cl atom, acyl group (-COR), and carboxyl group (-COOH).

[0041] In this invention, the position of R1 on the benzene ring is not particularly required. The following is an illustrative description, but it does not limit the scope of the invention. According to a preferred embodiment of the invention, H represents the position of benzene ring 1, and R1 is located at position 2, 3, 4, 5, or 6 of the benzene ring.

[0042] In this invention, the position of R2 on the benzene ring is not particularly required. The following is an illustrative description, but it does not limit the scope of the invention. According to a preferred embodiment of the invention, H represents the position of benzene ring 1, and R2 is located at position 2, 3, 4, 5, or 6 of the benzene ring.

[0043] In this invention, the range of passivating aromatic compounds represented by formula (I) is relatively wide. Any passivating aromatic compound that meets the aforementioned requirements can achieve the purpose of this invention. The following is an illustrative description, but it does not limit the scope of this invention. According to a preferred embodiment of this invention, the passivating aromatic compound is selected from one or more of 2-chlorobenzoic acid, benzoic acid, trifluorotoluene, chlorobenzene, m-nitrobenzaldehyde, and benzaldehyde.

[0044] In this invention, the contact temperature can be selected over a wide range, as illustrated below, but this does not limit the scope of the invention. According to a preferred embodiment of the invention, the contact temperature is 20-70°C, preferably 40-70°C.

[0045] In this invention, the contact time can be selected within a wide range, as illustrated below, but this does not limit the scope of the invention. According to a preferred embodiment of the invention, the contact time is 1-4 hours, preferably 2-4 hours.

[0046] In this invention, the contact reaction can be implemented in various reactors, such as... Figure 1 The experiment was conducted in a three-necked flask equipped with a magnet, thermometer, and raw material funnel, as shown.

[0047] In this invention, the purpose of the invention can be achieved by carrying out the bromination reaction system of this invention. There are no special requirements for the way each material is added. For example, liquid organic acid and water are generally mixed, then passivating aromatic compounds, bromine and sodium periodate are added, the temperature is raised to the temperature required for bromination, sulfuric acid is added, and then the reaction is carried out.

[0048] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various specific technical features in any suitable manner. To avoid unnecessary repetition, the present invention will not describe the various possible combinations separately. However, these simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

[0049] The present invention will be described in detail below through embodiments. It should be noted that the following embodiments are only used to further illustrate the present invention and should not be construed as limiting the scope of protection of the present invention. Those skilled in the art can make some non-essential improvements and adjustments to the present invention based on the above description.

[0050] For any experimental steps or conditions not specified in the examples and comparative examples, the procedures and conditions described in the literature in this field can be followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.

[0051] A. Source of raw materials for the example

[0052] The passivated aromatic compounds were all from Shanghai Bide Pharmaceutical Technology Co., Ltd., and their purity was ≥98%.

[0053] The bromine Br2 was sourced from Nanjing Wanqing Chemical Glassware Co., Ltd., with a purity of ≥99.5%.

[0054] Sodium periodate is sourced from Shanghai Bide Pharmaceutical Technology Co., Ltd., with a purity of ≥99%.

[0055] The liquid organic acids are all from Shanghai BIDE Pharmaceutical Technology Co., Ltd., with a purity of ≥99.0%.

[0056] The concentrated sulfuric acid was sourced from Nanjing Wanqing Chemical Glass Instrument Co., Ltd., with a purity of ≥98wt%.

[0057] B. Reaction apparatus

[0058] The reaction apparatus used in the embodiments is as follows: Figure 1 As shown.

[0059] C. Effectiveness Evaluation Methods

[0060] The instruments used for proton and carbon spectroscopy were NMR spectrometers, both from Bruker GmbH, Germany. Sample preparation method: 20-50 mg of the product was dissolved in deuterated chloroform, the dissolved product was transferred to an NMR tube, and placed in the NMR spectrometer. Automated analysis was performed according to the built-in detection method of the NMR spectrometer, and then NMR analysis was performed using MestReNova software.

[0061] The yield is calculated as follows:

[0062] Product yield = Actual product mass / Theoretical product mass × 100%.

[0063] Example 1

[0064] Add 5 mL (87.4 mmol) of acetic acid and 5 mL (277.8 mmol) of water to a 50 mL three-necked flask, start stirring, and add 1.56 g (10 mmol) of 2-chlorobenzoic acid, 0.80 g (5 mmol) of bromine, and 1.07 g (5 mmol) of sodium periodate. Heat to 50 °C, and slowly add 4 mL of concentrated sulfuric acid dropwise to the reaction flask. After the addition is complete, maintain the temperature for 3 hours to obtain 5-bromo-2-chlorobenzoic acid, with a yield of 90%. Figure 2 The 1H NMR spectrum of the obtained 5-bromo-2-chlorobenzoic acid; Figure 3 The carbon spectrum of the obtained 5-bromo-2-chlorobenzoic acid is shown.

[0065] Example 2

[0066] Add 5 mL (87.4 mmol) of acetic acid and 5 mL (277.8 mmol) of water to a 50 mL three-necked flask, start stirring, and add 1.22 g (10 mmol) of benzoic acid, 0.80 g (5 mmol) of bromine, and 1.07 g (5 mmol) of sodium periodate. Heat to 45 °C, and slowly add 4 mL of concentrated sulfuric acid dropwise to the reaction flask. Maintain the temperature for 3 hours after the addition is complete to obtain 3-bromobenzoic acid, with a yield of 93%. Figure 4 The 1H NMR spectrum of the obtained 3-bromobenzoic acid; Figure 5 The carbon spectrum of the obtained 3-bromobenzoic acid is shown.

[0067] Example 3

[0068] Add 5 mL (87.4 mmol) of acetic acid and 5 mL (277.8 mmol) of water to a 50 mL three-necked flask, start stirring, and add 1.46 g (10 mmol) of trifluorotoluene, 0.80 g (5 mmol) of bromine, and 1.07 g (5 mmol) of sodium periodate. Heat to 60 °C, and slowly add 4 mL of concentrated sulfuric acid dropwise to the reaction flask. Maintain the temperature for 4 hours after the addition is complete to obtain 3-bromotrifluorotoluene, with a yield of 83%. Figure 6 The 1H NMR spectrum of the obtained 3-bromotrifluorotoluene; Figure 7 The carbon spectrum of the obtained 3-bromotrifluorotoluene is shown.

[0069] Example 4

[0070] Add 5 mL (87.4 mmol) of acetic acid and 5 mL (277.8 mmol) of water to a 50 mL three-necked flask, start stirring, and add 1.12 g (10 mmol) of chlorobenzene, 0.80 g (5 mmol) of bromine, and 1.07 g (5 mmol) of sodium periodate. Heat to 40 °C, and slowly add 4 mL of concentrated sulfuric acid dropwise to the reaction flask. Maintain the temperature for 3 hours after the addition is complete to obtain p-bromochlorobenzene, with a yield of 62%. Figure 8 The hydrogen spectrum of the obtained p-bromochlorobenzene; Figure 9 The image shows the carbon spectrum of the obtained p-bromochlorobenzene.

[0071] Example 5

[0072] Add 5 mL (87.4 mmol) of acetic acid and 5 mL (277.8 mmol) of water to a 50 mL three-necked flask, start stirring, and add 1.51 g (10 mmol) of m-nitrobenzaldehyde, 0.80 g (5 mmol) of bromine, and 1.07 g (5 mmol) of sodium periodate. Heat to 60 °C, and slowly add 5 mL of concentrated sulfuric acid dropwise to the reaction flask. Maintain the temperature for 3.5 h after the addition is complete to obtain 3-bromo-5-nitrobenzaldehyde, with a yield of 81%. Figure 10 The 1H NMR spectrum of the obtained 3-bromo-5-nitrobenzaldehyde; Figure 11 The carbon spectrum of the obtained 3-bromo-5-nitrobenzaldehyde is shown.

[0073] Example 6

[0074] Add 5 mL (87.4 mmol) of acetic acid and 5 mL (277.8 mmol) of water to a 50 mL three-necked flask, start stirring, and add 1.06 g (10 mmol) of benzaldehyde, 0.80 g (5 mmol) of bromine, and 1.07 g (5 mmol) of sodium periodate. Heat to 50 °C, and slowly add 4 mL of concentrated sulfuric acid dropwise to the reaction flask. Maintain the temperature for 3 hours after the addition is complete to obtain 3-bromobenzaldehyde, with a yield of 81%. Figure 12 The 1H NMR spectrum of the obtained 3-bromobenzaldehyde; Figure 13 The carbon spectrum of the obtained 3-bromobenzaldehyde is shown.

[0075] Example 7

[0076] The method was followed in Example 1, except that bromine was added in an amount of 1.60 g (10 mmol) and sodium periodate in an amount of 0.53 g (2.5 mmol). The yield of the product 5-bromo-2-chlorobenzoic acid was 65%.

[0077] Example 8

[0078] The method was followed in Example 1, except that bromine was added in an amount of 1.20 g (7.5 mmol) and sodium periodate in an amount of 1.60 g (7.5 mmol). The yield of the product 5-bromo-2-chlorobenzoic acid was 74%.

[0079] Example 9

[0080] The method was followed in Example 1, except that 3 mL (79.5 mmol) of formic acid was added. The yield of the product, 5-bromo-2-chlorobenzoic acid, was 78%.

[0081] Example 10

[0082] The method was followed in Example 1, except that the added liquid organic acids were 3 mL (79.5 mmol) formic acid and 2 mL (26.7 mmol) propionic acid. The yield of the product 5-bromo-2-chlorobenzoic acid was 82%.

[0083] Example 11

[0084] The method was followed in Example 1, except that the added liquid organic acids were 1.5 mL (39.8 mmol) formic acid and 1.5 mL (20.0 mmol) lactic acid. The yield of the product 5-bromo-2-chlorobenzoic acid was 92%.

[0085] Example 12

[0086] The method was followed in Example 1, except that 2 mL (53.0 mmol) of formic acid and 1 mL (13.4 mmol) of lactic acid were added. The yield of the product, 5-bromo-2-chlorobenzoic acid, was 90%.

[0087] Comparative Example 1

[0088] Compared with Example 4, 56.3 g (0.5 mol) of chlorobenzene was added to a 250 mL three-necked flask. After purging with nitrogen three times, stirring was started, and the temperature was lowered to 0 °C. Then, a mixture of 5 mL (0.1 mol) BrF3 and 6.5 mL (0.12 mol) bromine was added dropwise to the 250 mL three-necked flask. The temperature was maintained between 0 and 10 °C, and the reaction was carried out for 1 hour. After simple post-treatment, p-bromochlorobenzene was obtained with a yield of 25%.

[0089] Comparative Example 2

[0090] Compared with Example 2, 70 mL of water, 12.3 g (0.1 mol) of benzoic acid, and 16.7 g (0.1 mol) of potassium bromate were added to a 250 mL three-necked flask equipped with a magnetic stirrer, dropping funnel, and thermometer. Stirring was started. The mixture was heated to 90 °C, and 80 mL of concentrated sulfuric acid was slowly added over 70 min. The mixture was then reacted at 90 °C for 2 h. After simple post-treatment, 3-bromobenzoic acid was obtained in a yield of 62%.

Claims

1. A method for passivating the bromination of aromatic compounds, characterized in that, Includes the following steps: In an acidic system containing sulfuric acid and liquid organic acid, the passivated aromatic compound of formula (I), bromine, and sodium periodate are brominated to obtain the aromatic bromide of formula (II).

2. The method according to claim 1, wherein, The molar ratio of the passivating aromatic compound, bromine and sodium periodate shown in formula (I) is 1:0.5-1:0.25-1, preferably 1:0.5-1:0.3-1, and more preferably 1:0.5-1:0.5-0.

7.

3. The method according to claim 1 or 2, wherein, The molar ratio of the passivated aromatic compound, liquid organic acid, and water shown in formula (I) is 1:7-11:22-34, preferably 1:8.5-10.5:27.5-33.3; and / or The liquid organic acid is one or more of acetic acid, formic acid, propionic acid, and lactic acid; Preferably, the organic acid is a mixture of formic acid and lactic acid, and the molar ratio of formic acid to lactic acid is 1:0.2-0.6, calculated as liquid organic acid.

4. The method according to any one of claims 1-3, wherein, The molar ratio of the passivating aromatic compound shown in formula (I) to sulfuric acid (calculated as H2SO4) is 1:0.01-15, preferably 1:1.9-11.3, and more preferably 1:7-10.

5. The method according to any one of claims 1-4, wherein, In the passivated aromatic compound shown in formula (I), R1 and R2 are each independently selected from H and the passivating substituent group.

6. The method according to claim 5, wherein, The passivating substituent is an electron-withdrawing group, including one or more of strong electron-withdrawing groups, medium electron-withdrawing groups, and weak electron-withdrawing groups.

7. The method according to claim 6, wherein, The strongly electron-withdrawing group is selected from one or more of tertiary amine cations, nitro groups, and trihalomethyl groups; preferably, the trihalomethyl group is -CX3, wherein X is F and / or Cl; and / or The electron-withdrawing group is selected from one or more of cyano and sulfonic acid groups; and / or The weak electron-withdrawing group is selected from one or more of F atoms, Cl atoms, acyl groups, and carboxyl groups.

8. The method according to any one of claims 1-7, wherein, H represents position 1 of the benzene ring, and R1 is located at position 2, 3, 4, 5, or 6 of the benzene ring.

9. The method according to any one of claims 1-8, wherein, H represents the position of benzene ring 1, and R2 is located at position 2, 3, 4, 5, or 6 of benzene ring.

10. The method according to any one of claims 1-9, wherein, The passivating aromatic compound is selected from one or more of 2-chlorobenzoic acid, benzoic acid, trifluorotoluene, chlorobenzene, m-nitrobenzaldehyde, and benzaldehyde; and / or The conditions for contact include: Temperature is 20-70℃; and / or The duration is 1-4 hours; Preferably, Temperature is 40-70℃; and / or The time is 2-4 hours.

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