Preparation method of 2-(piperidine-2-yl)-2-(p-tolyl) methyl acetate hydrochloride

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 2-(piperidine-2-yl)-2-(p-tolyl) methyl acetate hydrochloride. According to the method, p-methyl benzyl cyanide, 2-bromopyridine and HCl are used as raw materials, and a final product is prepared through a three-step reaction. By optimizing the adding state of the alkali reagent in the step 1 and the adding state of the hydrogen chloride in the step 2, the reaction yield is increased, and the yield of each step of reaction is close to 90%. The method has the advantages that the cost is low, the raw materials are easy to obtain, the reaction process is simple, special equipment such as low-temperature equipment is not needed, the technological operation is convenient and safe, the yield is high, commercial production of the 2-(piperidine-2-yl)-2-(p-methylphenyl) methyl acetate hydrochloride is promoted, and the application prospect is wide.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing 2-(piperidin-2-yl)-2-(p-tolyl) methyl acetate hydrochloride. Background Art

[0002] Methylphenidate hydrochloride is a psychostimulant, which is mainly used clinically to treat various depressions, mild brain dysfunction (such as ADHD), narcolepsy, etc. Its structural formula is as follows:

[0003]

[0004] 2-(Piperidin-2-yl)-2-(p-tolyl) methyl acetate hydrochloride is its analogue, and it has the same clinical efficacy. At present, there are few reports on the existing methods for synthesizing 2-(piperidin-2-yl)-2-(p-tolyl) methyl acetate hydrochloride. For example, the patent with International Publication No. WO2022029151A1 discloses a method for synthesizing 2-(piperidin-2-yl)-2-(p-tolyl) methyl acetate hydrochloride and its analogues. However, the prior art has the problems of long synthesis steps, low yield, reaction conditions involving low temperature of -78°C or expensive raw materials.

[0005] Therefore, the prior art cannot achieve safe, simple, low-cost and high-yield synthesis of 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride, which greatly limits the large-scale production of 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride. Summary of the invention

[0006] In view of the problems of the prior art, the present invention provides a method for preparing 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride, and aims to prepare 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride safely, simply and efficiently.

[0007] The present invention provides a method for preparing a 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride intermediate, which comprises the following reaction 1:

[0008]

[0009] p-Tolueneacetonitrile, 2-bromopyridine and NaNH 2 Reaction, that's it.

[0010] Preferably, the reaction temperature of the reaction 1 is 20-50° C.; and / or the reaction time of the reaction 1 is 2-5 h.

[0011] The present invention provides a method for preparing a 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride intermediate, which comprises the following reaction 2:

[0012]

[0013] Hydrogen chloride gas is passed into a methanol solution of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile, and water is added after the reaction to obtain the product.

[0014] Preferably, the reaction temperature of reaction 2 is 20-40°C; and / or the reaction time of reaction 2 is 5-10h; and / or the reaction is further reacted for 1-3h after adding water; and / or the mass concentration of the methanol solution of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile is 6.2%-16.7%; and / or the molar ratio of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile to hydrogen chloride is 1:5-15.

[0015] Preferably, the 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile is prepared according to the following reaction 1:

[0016]

[0017] p-Tolueneacetonitrile, 2-bromopyridine and NaNH 2 Reaction, that's it.

[0018] Preferably, the reaction temperature of the reaction 1 is 20-50° C.; and / or the reaction time of the reaction 1 is 2-5 h.

[0019] The present invention provides a method for preparing 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride, which comprises the following reaction 3:

[0020]

[0021] 2-(pyridin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride reacts with a reducing agent to obtain;

[0022] The 2-(pyridin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride is prepared by any of the above-mentioned methods for preparing the 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride intermediate.

[0023] Preferably, the reducing agent is hydrogen, and the reaction 3 is carried out under 5-10% palladium-carbon catalyst.

[0024] Preferably, the pressure of the hydrogen is 1-2 MPa; and / or the mass ratio of the 2-(pyridin-2-yl)-2-(p-tolyl)acetate methyl hydrochloride to palladium carbon is 1:0.01-0.1.

[0025] Preferably, the reaction temperature of the reaction 3 is 30-60° C.; and / or the reaction time of the reaction 3 is 4-10 h.

[0026] The invention provides a method for preparing 2-(piperidin-2-yl)-2-(p-tolyl) methyl acetate hydrochloride. The method uses p-methylbenzene acetonitrile, 2-bromopyridine and HCl as raw materials, and prepares the final product through three-step reaction. The alkaline reagent in step 1 is preferably sodium amide, and the added state of hydrogen chloride in step 2 is preferably gaseous, so as to improve the reaction yield and make the yield of each step of the reaction close to 90%. The method has the advantages of low cost, easy availability of raw materials, simple reaction process, no need to use special equipment such as low temperature, convenient and safe process operation, and high yield, and promotes the commercial production of 2-(piperidin-2-yl)-2-(p-tolyl) methyl acetate hydrochloride, and has broad application prospects.

[0027] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0028] The following is a further detailed description of the above contents of the present invention through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies implemented based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The H NMR spectrum of 2-(piperidin-2-yl)-2-(p-tolyl)acetate methyl ester hydrochloride ( 1 HNMR) graph. DETAILED DESCRIPTION

[0030] In the following examples and experimental examples, reagents and raw materials not specifically described are all commercially available products.

[0031] The structure of the compound is 1 Determined by H NMR. 1 H NMR was measured using a 400 MHz nuclear magnetic spectrometer, and the measurement solvent was deuterated dimethyl sulfoxide (DMSO-d6).

[0032] Example 1 A method for preparing 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride

[0033] The present embodiment provides a method for preparing 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride, which comprises the following steps:

[0034]

[0035] (1) Compound 2: Synthesis of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile

[0036] Dissolve p-methylbenzeneacetonitrile (50g, 1.0eq) in toluene (500g), add 2-bromopyridine (78.3g, 1.3eq) to a three-necked flask, and add sodium amide (22.3g, 1.5eq) at a temperature of 40°C. After the addition is completed, the system is reacted at 40°C for 4h. The reaction of the raw material in the middle control is completed, and water is added to quench, concentrate, add n-heptane (250g), crystallize, and filter to obtain.

[0037] The yield of the product was 88%.

[0038] Product 1 The H NMR data are as follows:

[0039] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),5.06(s,1H),2.19(s,3H).

[0040] (2) Compound 3: Synthesis of methyl 2-(pyridin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0041] Dissolve compound 2 (50 g, 1.0 eq) in methanol (500 g), control the temperature at 35°C, slowly introduce hydrogen chloride gas (87.6 g, 10 eq), react for 9 h, then add water (0.86 g, 2 eq), react for 2 h, concentrate the organic phase until there is no fraction, add methyl tert-butyl ether (250 g), crystallize, and filter to obtain the product.

[0042] The yield of the product was 86%.

[0043] Product 1 The H NMR data are as follows:

[0044] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),4.89(s,1H),3.66(s,3H),2.18(s,3H).

[0045] (3) Compound 4: Synthesis of methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0046] Compound 3 (50 g, 1.0 eq) was dissolved in anhydrous methanol (500 g), the temperature was raised to 55°C, 5% palladium carbon (5 g) was added, hydrogen was introduced at 1 MPa, the reaction was maintained for 9 h, and after the reaction was completed, the organic phase was concentrated to no fraction, methyl tert-butyl ether (250 g) was added, crystallized, and filtered to obtain the product.

[0047] The yield of the product was 90%.

[0048] Product 1 H NMR Figure 1 The specific data are as follows:

[0049] δ7.12(d,2H),6.93(d,2H),3.75(t,1H),3.62(s,3H),3.46(t,1H),2.79(t,2H),2.19(s,3H),1.45-1.56(t,6H).

[0050] Example 2 A method for preparing 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride

[0051] The present embodiment provides a method for preparing 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride, which comprises the following steps:

[0052] (1) Compound 2: Synthesis of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile

[0053] Dissolve p-methylbenzeneacetonitrile (50g, 1.0eq) in toluene (500g), add 2-bromopyridine (66.3g, 1.1eq) to a three-necked flask, and add sodium amide (17.8g, 1.2eq) at a temperature of 40°C. After the addition is completed, the system is reacted at 40°C for 4h. The reaction of the raw material in the middle control is completed, quenched, concentrated, and n-heptane (250g) is added. Crystallization and filtration are performed to obtain the product.

[0054] The yield of the product was 78%.

[0055] Product 1 The H NMR data are as follows:

[0056] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),5.06(s,1H),2.19(s,3H).

[0057] (2) Compound 3: Synthesis of methyl 2-(pyridin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0058] Dissolve compound 2 (50 g, 1.0 eq) in methanol (500 g), control the temperature at 35°C, slowly introduce hydrogen chloride gas (43.8 g, 5 eq), react for 9 h, then add water (0.86 g, 2 eq), react for 2 h, concentrate the organic phase until there is no fraction, add methyl tert-butyl ether (250 g), crystallize, and filter to obtain the product.

[0059] The yield of the product was 78%.

[0060] Product 1 The H NMR data are as follows:

[0061] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),4.89(s,1H),3.66(s,3H),2.18(s,3H).

[0062] (3) Compound 4: Synthesis of methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0063] Dissolve compound 3 in anhydrous methanol (500 g), heat to 55° C., add 5% palladium carbon (3 g), introduce hydrogen at 1 MPa, and keep reacting for 9 h. After the reaction is completed, concentrate the organic phase until there is no fraction, add methyl tert-butyl ether (250 g), crystallize, and filter to obtain the product.

[0064] The yield of the product was 83%.

[0065] Product 1 The H NMR data are as follows:

[0066] δ7.12(d,2H),6.93(d,2H),3.75(t,1H),3.62(s,3H),3.46(t,1H),2.79(t,2H),2.19(s,3H),1.45-1.56(t,6H).

[0067] Example 3 Preparation method of 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride

[0068] The present embodiment provides a method for preparing 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride, which comprises the following steps:

[0069] (1) Compound 2: Synthesis of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile

[0070] Dissolve p-methylbenzeneacetonitrile (50g, 1.0eq) in toluene (500g), add 2-bromopyridine (78.3g, 1.3eq) to a three-necked flask, and add sodium amide (17.8g, 1.2eq) at a temperature of 40°C. After the addition is completed, the system is reacted at 25°C for 4h. The reaction of the raw material in the middle control is completed, quenched, concentrated, and n-heptane (250g) is added. Crystallization and filtration are performed to obtain the product.

[0071] The yield of the product was 81%.

[0072] Product 1 The H NMR data are as follows:

[0073] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),5.06(s,1H),2.19(s,3H).

[0074] (2) Compound 3: Synthesis of methyl 2-(pyridin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0075] Compound 2 (50 g, 1.0 eq) was dissolved in methanol (500 g), the temperature was controlled at 25°C, hydrogen chloride gas (87.6 g, 10 eq) was slowly introduced, the reaction was continued for 9 h, water (0.86 g, 2 eq) was added, the reaction was continued for 2 h, the organic phase was concentrated until there was no fraction, methyl tert-butyl ether (250 g) was added, crystallized, and filtered to obtain the product.

[0076] The yield of the product was 80%.

[0077] Product 1 The H NMR data are as follows:

[0078] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),4.89(s,1H),3.66(s,3H),2.18(s,3H).

[0079] (3) Compound 4: Synthesis of methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0080] Dissolve compound 3 in anhydrous methanol (500 g), heat to 35° C., add 5% palladium carbon (5 g), introduce hydrogen at 1 MPa, and keep reacting for 9 hours. After the reaction is completed, concentrate the organic phase until there is no fraction, add methyl tert-butyl ether (250 g), crystallize, and filter to obtain the product.

[0081] The yield of the product was 86%.

[0082] Product 1 The H NMR data are as follows:

[0083] δ7.12(d,2H),6.93(d,2H),3.75(t,1H),3.62(s,3H),3.46(t,1H),2.79(t,2H),2.19(s,3H),1.45-1.56(t,6H).

[0084] Example 4 Preparation method of 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride

[0085] The present embodiment provides a method for preparing 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride, which comprises the following steps:

[0086] (1) Compound 2: Synthesis of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile

[0087] Dissolve p-methylbenzeneacetonitrile (50g, 1.0eq) in toluene (500g), add 2-bromopyridine (78.3g, 1.3eq) to a three-necked flask, and add sodium amide (22.3g, 1.5eq) at a temperature of 40°C. After the addition is completed, the system is reacted at 40°C for 2h, and the reaction of the raw material in the middle control is completed, quench, concentrate, add n-heptane (250g), crystallize, and filter to obtain.

[0088] The yield of the product was 83%.

[0089] Product 1 The H NMR data are as follows:

[0090] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),5.06(s,1H),2.19(s,3H).

[0091] (2) Compound 3: Synthesis of methyl 2-(pyridin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0092] Dissolve compound 2 (50 g, 1.0 eq) in methanol (500 g), control the temperature at 35°C, slowly introduce hydrogen chloride gas (87.6 g, 10 eq), react for 5 h, then add water (0.86 g, 2 eq), react for 1 h, concentrate the organic phase until there is no fraction, add methyl tert-butyl ether (250 g), crystallize, and filter to obtain the product.

[0093] The yield of the product was 75%.

[0094] Product 1 The H NMR data are as follows:

[0095] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),4.89(s,1H),3.66(s,3H),2.18(s,3H).

[0096] (3) Compound 4: Synthesis of methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0097] Compound 3 (50 g, 1.0 eq) was dissolved in anhydrous methanol (500 g), the temperature was raised to 55°C, 5% palladium carbon (5 g) was added, hydrogen was introduced at 1 MPa, the reaction was maintained for 5 h, and after the reaction was completed, the organic phase was concentrated to no fraction, methyl tert-butyl ether (250 g) was added, crystallized, and filtered to obtain the product.

[0098] The yield of the product was 79%.

[0099] Product 1 The H NMR data are as follows:

[0100] δ7.12(d,2H),6.93(d,2H),3.75(t,1H),3.62(s,3H),3.46(t,1H),2.79(t,2H),2.19(s,3H),1.45-1.56(t,6H).

[0101] Example 5 A method for preparing 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride

[0102] The present embodiment provides a method for preparing 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride, which comprises the following steps:

[0103]

[0104] (1) Compound 2: Synthesis of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile

[0105] Dissolve p-methylbenzeneacetonitrile (50g, 1.0eq) in toluene (500g), add 2-bromopyridine (78.3g, 1.3eq) to a three-necked flask, and add sodium hydride (22.5g, 1.5eq) at a temperature of 40°C. After the addition is completed, the system is reacted at 40°C for 4h, and the reaction of the raw material is completed, quenched, concentrated, and n-heptane (250g) is added. Crystallization and filtration are performed to obtain the product.

[0106] The yield of the product was 65%.

[0107] Product 1 The H NMR data are as follows:

[0108] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),5.06(s,1H),2.19(s,3H).

[0109] (2) Compound 3: Synthesis of methyl 2-(pyridin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0110] Dissolve compound 2 (50 g, 1.0 eq) in methanol (500 g), control the temperature at 35°C, add concentrated hydrochloric acid (243.3 g, 10 eq), react for 9 h, then add water (0.86 g, 2 eq), react for 2 h, concentrate the organic phase until there is no fraction, add methyl tert-butyl ether (250 g), crystallize, and filter to obtain.

[0111] The yield of the product was 66%.

[0112] Product 1 The H NMR data are as follows:

[0113] δ8.45(d,1H),7.6(d,1H),7.38(d,1H),7.05-7.13(d,5H),4.89(s,1H),3.66(s,3H),2.18(s,3H).

[0114] (3) Compound 4: Synthesis of methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride

[0115] Compound 3 (50 g, 1.0 eq) was dissolved in anhydrous ethanol (500 g), the temperature was raised to 55°C, 5% palladium carbon (5 g) was added, hydrogen was introduced at 1 MPa, the reaction was maintained for 9 h, and after the reaction was completed, the organic phase was concentrated to no fraction, methyl tert-butyl ether (250 g) was added, crystallized, and filtered to obtain the product.

[0116] The yield of the product was 88%.

[0117] Product 1 The H NMR data are as follows:

[0118] δ7.12(d,2H),6.93(d,2H),3.75(t,1H),3.62(s,3H),3.46(t,1H),2.79(t,2H),2.19(s,3H),1.45-1.56(t,6H).

[0119] The relationship between the change of experimental conditions and the yield in the above examples is shown in Table 1-3:

[0120] Table 1 Relationship between experimental conditions and yield in step (1)

[0121]

[0122] Table 2 Relationship between experimental conditions and yield in step (2)

[0123]

[0124]

[0125] Table 3 Relationship between experimental conditions and yield in step (3)

[0126]

[0127] The above results show that the type of base in step (1) has a great influence on the product yield, and sodium amide is the preferred base reagent for step (1) of the present invention; the state of hydrogen chloride introduced in step (2) has a great influence on the product yield, and when hydrogen chloride gas is directly introduced into the reaction solution, the yield is significantly improved.

[0128] It can be seen from the above examples that the present invention provides a method for preparing 2-(piperidin-2-yl)-2-(p-tolyl) methyl acetate hydrochloride, which uses p-methylbenzene acetonitrile, 2-bromopyridine and HCl as raw materials, and prepares the final product through three-step reaction. The alkaline reagent of the preferred step 1 is sodium amide, and the addition state of the hydrogen chloride of the preferred step 2 is gaseous, so as to improve the reaction yield and make the yield of each step reaction close to 90%. The method has the advantages of low cost, easy availability of raw materials, simple reaction process, no need to use special equipment such as low temperature, convenient process operation, safety and high yield, and promotes the commercial production of 2-(piperidin-2-yl)-2-(p-tolyl) methyl acetate hydrochloride, and has broad application prospects.

Claims

1. A method for preparing a 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride intermediate, characterized in that: Including the following reaction 1: Tolueneacetonitrile, 2-bromopyridine and NaNH2 are reacted to obtain the product.

2. The preparation method according to claim 1, characterized in that: The reaction temperature of the reaction 1 is 20-50° C.; and / or the reaction time of the reaction 1 is 2-5 h.

3. A method for preparing a 2-(piperidin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride intermediate, characterized in that: Including the following reaction 2: Hydrogen chloride gas is passed into a methanol solution of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile, and water is added after the reaction to obtain the product.

4. The preparation method according to claim 3, characterized in that: The reaction temperature of reaction 2 is 20-40°C; and / or, the reaction time of reaction 2 is 5-10h; and / or, the reaction is continued for 1-3h after adding water; and / or, the mass concentration of the methanol solution of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile is 6.2%-16.7%; and / or, the molar ratio of 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile to hydrogen chloride is 1:5-15.

5. The preparation method according to claim 3, characterized in that: The 2-(pyridin-2-yl)-2-(p-tolyl)acetonitrile is prepared according to the following reaction 1: Tolueneacetonitrile, 2-bromopyridine and NaNH2 are reacted to obtain the product.

6. The preparation method according to claim 5, characterized in that: The reaction temperature of the reaction 1 is 20-50° C.; and / or the reaction time of the reaction 1 is 2-5 h.

7. A method for preparing methyl 2-(piperidin-2-yl)-2-(p-tolyl)acetate hydrochloride, characterized in that: Including the following reaction 3: 2-(pyridin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride reacts with a reducing agent to obtain; The 2-(pyridin-2-yl)-2-(p-tolyl)acetic acid methyl ester hydrochloride is prepared by the preparation method according to any one of claims 3 to 6.

8. The preparation method according to claim 7, characterized in that: The reducing agent is hydrogen, and the reaction 3 is carried out under 5-10% palladium carbon catalyst.

9. The preparation method according to claim 8, characterized in that: The pressure of the hydrogen is 1-2 MPa; and / or the mass ratio of the 2-(pyridin-2-yl)-2-(p-tolyl)acetate methyl hydrochloride to palladium carbon is 1:0.01-0.

1.

10. The preparation method according to claim 7, characterized in that: The reaction temperature of the reaction 3 is 30-60° C.; and / or the reaction time of the reaction 3 is 4-10 h.

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