CN116606216B

CN116606216B - Preparation method of gabapentin

Info

Publication number: CN116606216B
Application number: CN202310370916.5A
Authority: CN
Inventors: 彭家荣; 何匡; 朱银龙; 袁晓虎; 吴依阳; 黄凯
Original assignee: Zhejiang Shouxin Pharmaceutical Co ltd
Current assignee: Zhejiang Shouxin Pharmaceutical Co ltd
Priority date: 2023-04-10
Filing date: 2023-04-10
Publication date: 2024-06-14
Anticipated expiration: 2043-04-10
Also published as: CN116606216A

Abstract

The invention discloses a preparation method of a compound shown in a formula I, and relates to the field of drug synthesis. The preparation method takes cyclohexyl chloride as a raw material, and products are produced through cyanidation, substitution and hydrogenation reactions. The preparation method for preparing the gabapentin has the advantages of simple raw materials, relatively simplified steps, no need of intermediate process of the gabapentin hydrochloride, direct synthesis of the gabapentin with high purity, shortened production period, remarkably improved product yield and capability of solving the defect that the traditional process is not easy for industrial production. The structure of the formula I is as follows:

Description

Preparation method of gabapentin

Technical Field

The invention relates to the field of medicine synthesis, in particular to a preparation method of barpentadine.

Background

Gabapentin, known under the chemical name 1- (aminomethyl) cyclohexane acetic acid, also known as 1- (methylamino) cyclohexane acetic acid, has a molecular formula of C ₉H₁₇NO₂, and was the first antiepileptic developed by the company Warner-Lanbert in the United states, and was first marketed in the United kingdom in 1993.

The structural formula is shown as follows.

Gabapentin is a derivative of gamma-aminobutyric acid (GABA) with a pharmacological effect different from that of existing antiepileptic drugs, and recent studies have shown that the effect of gabapentin is produced by altering GABA metabolism. It has the advantages of good tolerance and slight side effect. Gabapentin showed an epileptic effect in various animal models, and in addition, also in animal spasticity, analgesia, and amyotrophic lateral sclerosis models. Gabapentin has a high affinity for novel binding sites of brain tissue, and it can cross some barriers in vivo via amino acid transfer bodies, with less behavioral and cardiovascular side effects than other anticonvulsants. Additional treatments for epileptic patients with localized seizures that are not satisfactorily controlled or tolerated by conventional antiepileptic drugs, and epileptic patients with localized seizures and subsequent generalization.

The existing preparation method of gabapentin comprises the following steps:

Route one:

The method for synthesizing gabapentin disclosed in patent 2015107555. X comprises the steps of adding cyclohexanone and ethyl cyanoacetate into anhydrous isopropanol solution of liquid ammonia to form a ring reaction; performing hydrolysis reaction on 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile ammonium salt in high-temperature liquid water by taking H2SO4 as a catalyst; adding phosphorus pentoxide into 1, 1-cyclohexyl diacid to carry out dehydration reaction in dichloroethane solvent; carrying out ammonolysis reaction on 1, 1-cyclohexyl diacetic anhydride in ammonia water; carrying out hofmann degradation reaction on 1, 1-cyclohexyl oxalic acid acetamide. The intermediate of the cyclohexyl diacetic acid is needed to be synthesized firstly, then the cyclohexyl diacetic acid monoamide is synthesized by reaction, the steps are complicated, and the yield of the product obtained by the preparation method is only 48.2-51.1%.

Route two:

As disclosed in patent 20150105806.4, a method for synthesizing gabapentin is disclosed, wherein cyclohexanone and diethyl malonate are subjected to addition elimination reaction in an aprotic solvent at-5 to 5 ℃ by using zirconium tetrachloride as a catalyst; carrying out Michael addition on the product obtained in the first step in an alcohol solvent; carrying out hydrogenation reaction on the product obtained in the second step and hydrogen by taking Pd as a catalyst; carrying out hydrolysis reaction on the product obtained in the third step under the condition of hydrochloric acid; and (3) carrying out ion exchange on the product obtained in the fourth step. But the yield of the product is only 43.2% -46.3%.

There is therefore a great need in the industry to improve these problems in order to achieve the industrialization of gabapentin. The gabapentin provided by the invention has the advantages of simple and cheap preparation raw materials, simple method operation, high yield and high purity of the prepared product, and is suitable for large-scale popularization.

Disclosure of Invention

The invention aims at the problems and provides a high-yield and high-purity gabapentin preparation method.

In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:

The preparation method of the gabapentin is characterized in that cyclohexyl chloride is used as a raw material, and products are generated through cyanidation, substitution and hydrogenation reactions, wherein the synthetic route is as follows:

The preparation method comprises the following steps:

1) Adding a solvent into cyclohexyl chloride, mixing with tetrabutylammonium cyanide, adding a catalyst for cyanide reaction, extracting, and concentrating to obtain a compound 2;

2) Dissolving the compound 2 in a solvent, cooling, adding lithium diisopropylamide, reacting for a period of time, dropwise adding bromoacetic acid tert-butyl, extracting, concentrating, and purifying to obtain a compound 3;

3) Adding hydrochloric acid-dioxane into the compound 3 for dissolution, and reacting to obtain a compound 4;

4) And adding a catalyst and an auxiliary agent into the compound 4, introducing hydrogen, and reacting to obtain a product I.

Preferably, the solvent of step 1) is selected from any one of acetonitrile or dimethylsulfoxide; further preferably, the solvent of step 1) is acetonitrile.

Preferably, the catalyst in step 1) is at least one selected from CuI, cuCl, cuBr, TBAI; further preferably, the catalysts described in step 1) are CuI and TBAI.

Preferably, the temperature of the cyanation reaction in the step 1) is 20-30 ℃ and the reaction time is 10-24 hours; further preferably, the cyanation reaction in step 1) is carried out at a temperature of 25℃for a reaction time of 18 hours.

Preferably, the molar ratio of cyclohexyl chloride to tetrabutylammonium cyanide described in step 1) is 1:1.5-2; further preferably, the molar ratio of cyclohexyl chloride to tetrabutylammonium cyanide is 1:1.8.

Preferably, the mole ratio of TBAI to tetrabutylammonium cyanide is 1:15-40; further preferably, the molar ratio of TBAI to tetrabutylammonium cyanide is 1:20-25 parts of a base; most preferably, 1:22.5.

12. The preparation method according to claim 2, wherein the solvent in step 2) is selected from any one of tetrahydrofuran, dichloromethane, acetone, acetonitrile, and dimethylsulfoxide; most preferably, the solvent of step 2) is tetrahydrofuran.

Preferably, the molar ratio of lithium diisopropylamide, tert-butyl bromoacetate and compound 2 in step 2) is 1-2:1-1.5:1, a step of; further preferably, the molar ratio of lithium diisopropylamide, tert-butyl bromoacetate to compound 2 is 1.5:1.2:1.

Preferably, the temperature of the step 2) is reduced to-80 to-75 ℃, and further preferably, is-78 ℃.

Preferably, the catalyst in the step 4) is at least one selected from palladium carbon, raney nickel or rhodium carbon; further preferably, the catalyst of step 4) is selected from palladium on carbon.

Preferably, the auxiliary agent in the step 4) is at least one of organic acid, inorganic acid, organic base or inorganic base; further preferably, the auxiliary agent in the step 4) is at least one selected from sodium hydroxide, formic acid, acetic acid and triethylamine.

Preferably, the mass percentage of the sodium hydroxide is 40-60%.

Preferably, the specific conditions for the reaction described in step 4) are: the pressure is 0.9-1.2Mpa, the time is 4-12h, and the temperature is 30-60 ℃; further preferably, the specific conditions of the reaction described in step 4) are: the pressure was 1Mpa, the time was 8 hours, and the temperature was 50 ℃.

Compared with the prior art, the invention has the beneficial technical effects that:

The preparation method for preparing the gabapentin has the advantages of simple raw materials, relatively simplified steps, no need of intermediate process of the gabapentin hydrochloride, direct synthesis of the gabapentin with high purity, shortened production period, remarkably improved product yield and capability of solving the defect that the traditional process is not easy for industrial production.

Detailed Description

In order to make the technical means, the creation features, the achievement of the purpose and the effect of the present invention easy to understand, the present invention will be further elucidated with reference to the specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all of them. Based on the examples in the embodiments, those skilled in the art can obtain other examples without making any inventive effort, which fall within the scope of the invention. It is to be noted that the raw materials used in the present invention are all common commercial products, and the sources thereof are not particularly limited. Technical and scientific terms used in the examples have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The technical terms and abbreviations involved in this patent are explained as follows:

TBAI: tetrabutylammonium iodide

TBACN: tetrabutylammonium cyanide

MeCN: acetonitrile

CuI: copper iodide

CuCl: copper chloride

CuBr: copper bromide

THF: tetrahydrofuran (THF)

DMSO: dimethyl sulfoxide

LDA: lithium diisopropylamide

LiHMDS: lithium bis (trimethylsilyl) amide

Example 1.

1) In a 500mL three-necked flask, 110mL of acetonitrile was added, tetrabutylammonium cyanide (48.3 g,1.8 eq) was added after complete dissolution, and TBAI (2.95 g,0.08 eq) and CuI (1.5 g,0.08 eq) were then added for cyanation reaction at room temperature for 18h; extraction with DCM, washing the aqueous phase 3 times with DCM, drying the organic phase over anhydrous Na ₂SO₄, concentrating to give compound 2, cyclohexanecarbonitrile (11 g,98% year);

2) Dissolving the compound 2 obtained in the step 1) in THF (110 mL), cooling to-78 ℃ by using an ethanol dry ice bath, slowly dropwise adding lithium diisopropylamide (75 mL,1.5 eq), controlling the reaction temperature to be lower than 0 ℃, stirring for 15min, cooling to-78 ℃ again, slowly dropwise adding bromoacetic acid tert-butyl (23.4 g,1.2 eq), removing the dry ice ethanol bath after the dropwise adding is completed, reacting for 12h, adding water for quenching reaction, extracting by using DCM, washing an aqueous phase by using DCM for 3 times, drying an organic phase by using anhydrous Na ₂SO₄, concentrating, and purifying by column chromatography to obtain a compound 3 (19.1 g, 85%yeild);

3) Adding HCl-dioxane (20 mL) into the compound 3 obtained in the step 2) for dissolution, reacting for 3 hours at room temperature, and concentrating to obtain a compound 4 (14.2 g, 100%);

4) The compound 4 obtained in step 4) was put in a reaction vessel, pd/C (1 g, pd mass loading 10%) and 50% aqueous NaOH solution (3.7 g,1.1 eq) were added, hydrogen gas (pressure 1 MPa) was introduced, and the reaction was carried out at 50℃for 18 hours, the catalyst was filtered, and then methanol and water were used for 5:3 (13.05 g,90.1% yeild, 99.2% HPLC purity).

¹HNMR(400MHz,CDCl₃)δ9.03(s,1H),2.49(s,4H),1.54-1.43(m,10H)。

Example 2.

1) Cyclohexylchloride (11.8 g,1 eq) was taken in a 500mL three-necked flask, 110mL of acetonitrile was added, tetrabutylammonium cyanide (53.7 g,2.0 eq) was added after complete dissolution, and then TBAI (1.84 g,0.05 eq) and CuI (1.5 g,0.08 eq) were added for cyanation reaction at room temperature for 18h; extraction with DCM, washing the aqueous phase 3 times with DCM, drying the organic phase over anhydrous Na ₂SO₄, concentrating to give compound 2, cyclohexanecarbonitrile (10.6 g,95% year);

2) Dissolving the compound 2 obtained in the step 1) in THF (110 mL), cooling to-78 ℃ by using an ethanol dry ice bath, slowly dropwise adding lithium diisopropylamide (9 mL,1.8 eq), controlling the reaction temperature to be lower than 0 ℃, stirring for 15min, cooling to-78 ℃ again, slowly dropwise adding bromoacetic acid tert-butyl (29.2 g,1.5 eq), removing the dry ice ethanol bath after the dropwise adding is completed, reacting for 12h, adding water for quenching reaction, extracting by using DCM, washing an aqueous phase by using DCM for 3 times, drying an organic phase by using anhydrous Na ₂SO₄, concentrating, and purifying by column chromatography to obtain a compound 3 (19.1 g, 85%yeild);

3) Adding HCl-dioxane (20 mL) into the compound 3 obtained in the step 2) for dissolution, reacting for 3 hours at room temperature, and concentrating to obtain a compound 4 (13.5 g, 99%);

4) The compound 4 obtained in step 4) was put in a reaction vessel, pd/C (1 g, pd mass loading 10%) and formic acid (5 g,1.1 eq) were added, hydrogen gas (pressure 1 MPa) was introduced, reacted at 50℃for 18 hours, the catalyst was filtered, and then methanol and water 5:3 (12.7 g,88% yeild, 99.2% HPLC purity).

Example 3.

In comparison with example 1, only the catalyst in step 1) was changed from TBAI and CuI to CuI, the equivalent weight being unchanged.

1) Taking cyclohexyl chloride (11.8 g,1 eq) in a 500mL three-necked flask, adding 110mL acetonitrile, adding tetrabutylammonium cyanide (48.3 g,1.8 eq) after full dissolution, then adding CuI (1.5 g,0.08 eq), and carrying out cyanidation reaction at room temperature for 18h; extraction with DCM, washing the aqueous phase 3 times with DCM, drying the organic phase over anhydrous Na ₂SO₄, concentrating to give compound 2, cyclohexanecarbonitrile (9.5 g,85% year);

2) Dissolving the compound 2 obtained in the step 1) in THF (110 mL), cooling to-78 ℃ by using an ethanol dry ice bath, slowly dropwise adding lithium diisopropylamide (65 mL,1.5 eq), controlling the reaction temperature to be lower than 0 ℃, stirring for 15min, cooling to-78 ℃ again, slowly dropwise adding bromoacetic acid tert-butyl (16.6 g,1.2 eq), removing the dry ice ethanol bath after the dropwise adding is completed, reacting for 12h, adding water for quenching reaction, extracting by using DCM, washing an aqueous phase by using DCM for 3 times, drying an organic phase by using anhydrous Na ₂SO₄, concentrating, and purifying by column chromatography to obtain a compound 3 (16.23 g, 72.2%yeild);

3) Adding HCl-dioxane (16 mL) into the compound 3 obtained in the step 2) for dissolution, reacting for 3 hours at room temperature, and concentrating to obtain a compound 4 (11.9 g, 100%);

4) The compound 4 obtained in step 4) was put in a reaction vessel, pd/C (1 g, pd mass loading 10%) and 50% aqueous NaOH solution (3.1 g,1.1 eq) were added, hydrogen gas (pressure 1 MPa) was introduced, and the reaction was carried out at 50℃for 18 hours, the catalyst was filtered, and then methanol and water were used for 5:3 to give the product I (8.4 g,80.2% yeild, 99.1% HPLC purity).

Example 4.

1) In a 500mL three-necked flask, 110mL of acetonitrile was added, tetrabutylammonium cyanide (48.3 g,1.8 eq) was added after complete dissolution, and TBAI (2.95 g,0.08 eq) and CuI (1.5 g,0.08 eq) were then added for cyanation reaction at room temperature for 18h; extraction with DCM, washing the aqueous phase 3 times with DCM, drying the organic phase over anhydrous Na ₂SO₄, concentrating to give compound 2, cyclohexanecarbonitrile (10.8 g,97% year);

2) Dissolving the compound 2 obtained in the step 1) in THF (110 mL), cooling to-78 ℃ by using an ethanol dry ice bath, slowly dropwise adding lithium diisopropylamide (90 mL,1.8 eq), controlling the reaction temperature to be lower than 0 ℃, stirring for 15min, cooling to-78 ℃ again, slowly dropwise adding bromoacetic acid tert-butyl (28.9 g,1.5 eq), removing the dry ice ethanol bath after the dropwise adding is completed, reacting for 12h, adding water for quenching reaction, extracting by using DCM, washing an aqueous phase by using DCM for 3 times, drying an organic phase by using anhydrous Na ₂SO₄, concentrating, and purifying by column chromatography to obtain a compound 3 (18.5 g, 84%yeild);

3) Adding HCl-dioxane (20 mL) into the compound 3 obtained in the step 2) for dissolution, reacting for 3 hours at room temperature, and concentrating to obtain a compound 4 (13.3 g, 98%);

4) The compound 4 obtained in the step 4) was put in a reaction vessel, pd/C (1 g, pd mass loading 10%) and triethylamine (8.8 g,1.1 eq) were added, hydrogen gas (pressure 1 MPa) was introduced, reacted at 50℃for 18 hours, the catalyst was filtered, and then methanol and water were used for 5:3 (11.6 g,85% yeild, 99.5% HPLC purity).

Other examples the nuclear magnetism of the final product was essentially the same as in example 1.

Comparative example 1.

In contrast to example 1, step 1) does not use a catalyst.

1) Taking cyclohexyl chloride (11.8 g,1 eq) in a 500mL three-necked flask, adding 110mL acetonitrile, adding tetrabutylammonium cyanide (48.3 g,1.8 eq) after full dissolution, and carrying out cyanidation reaction at room temperature for 18h; extraction with DCM, washing the aqueous phase 3 times with DCM, drying the organic phase over anhydrous Na ₂SO₄ and concentrating to give compound 2, cyclohexanecarbonitrile (7.15 g,65% year).

Comparative example 2.

1) In a 500mL three-necked flask, 110mL of acetonitrile was added, tetrabutylammonium cyanide (26.8 g,1.0 eq) was added after complete dissolution, and TBAI (7.4 g,0.2 eq) and CuI (3.75 g,0.2 eq) were added to carry out cyanation reaction at room temperature for 18h; extraction with DCM, washing the aqueous phase 3 times with DCM, drying the organic phase over anhydrous Na ₂SO₄, concentrating to give Compound 2, cyclohexanecarbonitrile (7.8 g,71% year);

2) Dissolving the compound 2 obtained in the step 1) in THF (110 mL), cooling to-78 ℃ by using an ethanol dry ice bath, slowly dropwise adding lithium diisopropylamide (36 mL,1.0 eq), controlling the reaction temperature to be lower than 0 ℃, stirring for 15min, cooling to-78 ℃ again, slowly dropwise adding bromoacetic acid tert-butyl (25.3 g,1.8 eq), removing the dry ice ethanol bath after the dropwise adding is completed, reacting for 12h, adding water for quenching reaction, extracting by using DCM, washing an aqueous phase by using DCM for 3 times, drying an organic phase by using anhydrous Na ₂SO₄, concentrating, and purifying by column chromatography to obtain a compound 3 (12.7 g, 79%yeild);

3) Adding HCl-dioxane (13 mL) into the compound 3 obtained in the step 2) for dissolution, reacting for 3 hours at room temperature, and concentrating to obtain a compound 4 (9.35 g, 99%);

4) The compound 4 obtained in step 4) was put in a reaction vessel, pd/C (1 g, pd mass loading 10%) and 50% aqueous NaOH solution (2.1 g,1.1 eq) were added, hydrogen gas (pressure 1 MPa) was introduced, and the reaction was carried out at 50℃for 18 hours, the catalyst was filtered, and then methanol and water were used for 5:3 (7.2 g,75% yeild, 99.2% HPLC purity).

Comparative example 3.

In comparison with example 1, the only difference is that step 1) is to replace the catalyst with Cu ₂ O (1.14 g,0.08 eq)

1) Taking cyclohexyl chloride (11.8 g,1 eq) in a 500mL three-necked flask, adding 110mL acetonitrile, adding tetrabutylammonium cyanide (48.3 g,1.8 eq) after full dissolution, then adding Cu ₂ O (1.14 g,0.08 eq), and carrying out cyanidation reaction at room temperature for 18h; extraction with DCM, washing the aqueous phase 3 times with DCM, drying the organic phase over anhydrous Na ₂SO₄ and concentrating to give the compound 2 cyclohexanecarbonitrile (5.7 g,52% year).

Comparative example 4.

In comparison with example 1, the only difference is that step 1) is to replace the catalyst with CuCl ₂ (1.1 g,0.08 eq)

1) Adding cyclohexyl chloride (11.8 g,1 eq) into a 500mL three-necked flask, adding 110mL acetonitrile, adding tetrabutylammonium cyanide (48.3 g,1.8 eq) after complete dissolution, then adding CuCl ₂ (1.1 g,0.08 eq), and carrying out cyanidation reaction at room temperature for 18h; extraction with DCM, washing the aqueous phase 3 times with DCM, drying the organic phase over anhydrous Na ₂SO₄ and concentrating to give the compound 2 cyclohexanecarbonitrile (5.9 g,54% year).

Comparative example 5.

Compared with example 1, the only difference is that step 2) changes LDA to LiHMDS (25.05 g,1.5 eq)

1) In a 500mL three-necked flask, 110mL of acetonitrile was added, tetrabutylammonium cyanide (48.3 g,1.8 eq) was added after complete dissolution, and TBAI (2.95 g,0.08 eq) and CuI (1.5 g,0.08 eq) were then added for cyanation reaction at room temperature for 18h; extraction with DCM, washing the aqueous phase 3 times with DCM, drying the organic phase over anhydrous Na ₂SO₄, concentrating to give compound 2, cyclohexanecarbonitrile (10.8 g,96% year);

2) Dissolving the compound 2 obtained in the step 1) in THF (110 mL), cooling to-78 ℃ by using an ethanol dry ice bath, slowly adding 1M LiHMDS (150 mL,1.5 eq), controlling the reaction temperature to be lower than 0 ℃, stirring for 15min, cooling to-78 ℃ again, slowly dropwise adding bromoacetic acid tert-butyl (23.4 g,1.2 eq), removing the dry ice ethanol bath after the dropwise addition is completed, reacting for 12h, adding water to quench the reaction, extracting with DCM, washing an aqueous phase with DCM for 3 times, drying an organic phase with anhydrous Na ₂SO₄, concentrating and purifying by column chromatography to obtain the compound 3 (13.9 g,62% yeild).

Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.

Claims

1. A preparation method of gabapentin is characterized in that cyclohexyl chloride is used as a raw material, and products are generated through cyanidation, substitution and hydrogenation reactions, and the synthetic route is shown as follows:

The method comprises the following steps:

1) Adding a solvent into cyclohexyl chloride, mixing with tetrabutylammonium cyanide, adding a catalyst for cyanide reaction, extracting, and concentrating to obtain a compound 2; the molar ratio of the cyclohexyl chloride to the tetrabutylammonium cyanide is 1:1.8 or 1:2.0; the catalyst is CuI and TBAI; the mol ratio of TBAI to tetrabutylammonium cyanide is 1:15-40; the temperature of the cyanidation reaction is 20-30 ℃ and the reaction time is 10-24h;

2) Dissolving the compound 2 in a solvent, cooling, adding lithium diisopropylamide, reacting for a period of time, dropwise adding tert-butyl bromoacetate, extracting, concentrating, and purifying to obtain a compound 3; the molar ratio of the lithium diisopropylamide, the tert-butyl bromoacetate and the compound 2 is 1-2:1-1.5:1, a step of;

4) Adding a catalyst and an auxiliary agent into the compound 4, introducing hydrogen, and reacting to obtain a product I, wherein methanol and water 5 are used for: 3, recrystallizing the mixed solution; the catalyst is palladium carbon, and the auxiliary agent is at least one selected from sodium hydroxide, formic acid, acetic acid and triethylamine.

2. The method according to claim 1, wherein the solvent of step 1) is selected from any one of acetonitrile or dimethylsulfoxide.

3. The method of claim 2, wherein the solvent of step 1) is acetonitrile.

4. The process of claim 1, wherein the molar ratio of cyclohexyl chloride to tetrabutylammonium cyanide in step 1) is 1:1.8.

5. The process of claim 1, wherein the molar ratio of TBAI to tetrabutylammonium cyanide in step 1) is 1:20-25.

6. The method according to claim 1, wherein the solvent in step 2) is selected from any one of tetrahydrofuran, dichloromethane, acetone, acetonitrile, and dimethylsulfoxide.

7. The method according to claim 6, wherein the solvent in step 2) is tetrahydrofuran.

8. The method according to claim 1, wherein the molar ratio of lithium diisopropylamide, tert-butyl bromoacetate to compound 2 in step 2) is 1.5:1.2:1.

9. The method according to claim 1, wherein the temperature of the step 2) is reduced to-80 to-75 ℃.

10. The preparation method of claim 1, wherein the mass percentage of the sodium hydroxide is 40-60%.

11. The method according to claim 1, wherein the specific conditions of the reaction in step 4) are: the pressure is 0.9-1.2Mpa, the time is 4-12h, and the temperature is 30-60 ℃.