CN113045617A - Preparation method of 3, 5-estradiene-3, 17 beta-diacetate - Google Patents
Preparation method of 3, 5-estradiene-3, 17 beta-diacetate Download PDFInfo
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- CN113045617A CN113045617A CN202110334603.5A CN202110334603A CN113045617A CN 113045617 A CN113045617 A CN 113045617A CN 202110334603 A CN202110334603 A CN 202110334603A CN 113045617 A CN113045617 A CN 113045617A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims description 57
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- 238000007259 addition reaction Methods 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000003379 elimination reaction Methods 0.000 claims description 19
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 19
- 238000002156 mixing Methods 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- NPAGDVCDWIYMMC-IZPLOLCNSA-N nandrolone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 NPAGDVCDWIYMMC-IZPLOLCNSA-N 0.000 claims description 12
- 229960004719 nandrolone Drugs 0.000 claims description 12
- 229910052759 nickel Inorganic materials 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 9
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 abstract description 21
- 238000006640 acetylation reaction Methods 0.000 abstract description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 239000003814 drug Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 7
- 230000008030 elimination Effects 0.000 description 5
- 150000003431 steroids Chemical class 0.000 description 5
- 230000001476 alcoholic effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 102000009151 Luteinizing Hormone Human genes 0.000 description 2
- 108010073521 Luteinizing Hormone Proteins 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 229940040129 luteinizing hormone Drugs 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- WZDGZWOAQTVYBX-XOINTXKNSA-N tibolone Chemical compound C([C@@H]12)C[C@]3(C)[C@@](C#C)(O)CC[C@H]3[C@@H]1[C@H](C)CC1=C2CCC(=O)C1 WZDGZWOAQTVYBX-XOINTXKNSA-N 0.000 description 2
- 229960001023 tibolone Drugs 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 1
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 1
- 206010027304 Menopausal symptoms Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229940028334 follicle stimulating hormone Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000003652 hormone inhibitor Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 231100000546 inhibition of ovulation Toxicity 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
- C07J1/0074—Esters
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention belongs to the technical field of organic synthesis. The invention provides a preparation method of 3, 5-estradiene-3, 17 beta-diacetate, which adopts a preparation method of step reaction and a gas pressurization method to protect double bonds so as to carry out the acetylation reaction of carbonyl in the next step. The preparation method provided by the invention has low requirements on reaction raw materials and process conditions, but the yield of the 3, 5-estradiene-3, 17 beta-diacetate is greatly improved, so that the preparation method is suitable for industrial large-scale production and reduces the industrial cost.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 3, 5-estradiene-3, 17 beta-diacetate.
Background
The steroid drugs play an important role in preventing and treating diseases, including medicines, veterinary medicines and pesticides, and are mainly characterized in that the steroid drugs have complex reaction, obvious group remote effect, low yield and difficult separation and purification. Many steroid drugs, especially those with high technical content, are in urgent need of research and development.
The steroid medicament tibolone is used for treating osteoporosis. Because of its weak estrogenic, progestogen-like activity. It can stabilize hypothalamus and pituitary system of climacteric women, and can obviously inhibit the level of follicle-stimulating hormone in blood plasma. The luteinizing hormone inhibitor has a low inhibition degree on luteinizing hormone, does not influence prolactin, has an ovulation inhibition effect on women of childbearing age, is used for relieving postmenopausal climacteric symptoms of women, and becomes a first-choice medicament for improving the life quality of the menopausal women. 3, 5-estradiene-3, 17 beta-diacetate is an important prodrug of the steroid drug tibolone, and the synthesis of the drug is a key step. In the prior art, nandrolone is taken as a substrate to perform carbonyl and hydroxyl acetylation protection to synthesize the 3, 5-estradiene-3, 17 beta-diacetate by a one-pot method, the method is simple and convenient, but has low yield, has high requirements on the purity of reactants and is not suitable for large-scale production.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a preparation method of 3, 5-estradiene-3, 17 beta-diacetate.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of 3, 5-estradiene-3, 17 beta-diacetate, which comprises the following steps:
(1) mixing nandrolone and chlorine for addition reaction to obtain a compound a;
(2) mixing the compound a, hydrogen and nickel, and then carrying out addition reaction to obtain a compound b;
(3) mixing the compound b, acetic acid and concentrated sulfuric acid, and then carrying out substitution reaction to obtain a compound c;
(4) and mixing the compound c, sodium hydroxide and an alcohol solution, and then carrying out elimination reaction to obtain the 3, 5-estradiene-3, 17 beta-diacetate.
Preferably, the molar ratio of nandrolone to chlorine in the step (1) is 1: 2 to 3.
Preferably, the time of the addition reaction in the step (1) is 1-2 h, and the pressure of the addition reaction is 0.3-0.7 MPa.
Preferably, the molar ratio of the compound a to hydrogen in the step (2) is 1: 1.5-2.5, wherein the molar ratio of the hydrogen to the nickel is 1: 0.5 to 0.8.
Preferably, the temperature of the addition reaction in the step (2) is 70-80 ℃, the time of the addition reaction is 2-3 h, and the pressure of the addition reaction is 0.5-0.8 MPa.
Preferably, the molar ratio of the compound b to acetic acid in the step (3) is 1: 2.5-3.5, wherein the molar ratio of the acetic acid to the concentrated sulfuric acid is 1: 0.5-1.5, wherein the mass concentration of the concentrated sulfuric acid is 45-65%.
Preferably, the temperature of the substitution reaction in the step (3) is 100-150 ℃, and the time of the substitution reaction is 1-2 h.
Preferably, the molar ratio of the compound c to the sodium hydroxide in the step (4) is 1: 3 to 4.
Preferably, the alcoholic solution in the step (4) is a methanol solution, an ethanol solution or a propanol solution, the mass concentration of the alcoholic solution is 60-75%, and the mass ratio of the sodium hydroxide to the alcoholic solution is 1: 5 to 6.
Preferably, the temperature of the elimination reaction in the step (4) is 200-300 ℃, and the time of the elimination reaction is 2-3 h.
The invention provides a preparation method of 3, 5-estradiene-3, 17 beta-diacetate, which adopts a preparation method of step reaction and a gas pressurization method to protect double bonds so as to carry out the acetylation reaction of carbonyl in the next step. The preparation method provided by the invention has low requirements on reaction raw materials and process conditions, but the yield of the 3, 5-estradiene-3, 17 beta-diacetate is greatly improved, so that the preparation method is suitable for industrial large-scale production and reduces the industrial cost.
Detailed Description
The invention provides a preparation method of 3, 5-estradiene-3, 17 beta-diacetate, which comprises the following steps:
(1) mixing nandrolone and chlorine for addition reaction to obtain a compound a;
(2) mixing the compound a, hydrogen and nickel, and then carrying out addition reaction to obtain a compound b;
(3) mixing the compound b, acetic acid and concentrated sulfuric acid, and then carrying out substitution reaction to obtain a compound c;
(4) and mixing the compound c, sodium hydroxide and an alcohol solution, and then carrying out elimination reaction to obtain the 3, 5-estradiene-3, 17 beta-diacetate.
In the present invention, the molar ratio of nandrolone to chlorine gas in the step (1) is preferably 1: 2-3, more preferably 1: 2.2 to 2.8, more preferably 1: 2.4 to 2.6.
In the invention, the time of the addition reaction in the step (1) is preferably 1-2 h, more preferably 1.2-1.8 h, and even more preferably 1.4-1.6 h; the pressure of the addition reaction is preferably 0.3 to 0.7MPa, more preferably 0.4 to 0.6MPa, and even more preferably 0.45 to 0.55 MPa.
In the present invention, the reaction of step (1) is as follows:
in the present invention, the molar ratio of the compound a to hydrogen in the step (2) is preferably 1: 1.5 to 2.5, and more preferably 1: 1.6-2.4, more preferably 1: 1.8-2.2; the molar ratio of hydrogen to nickel is preferably 1: 0.5 to 0.8, more preferably 1: 0.6 to 0.7.
In the invention, the temperature of the addition reaction in the step (2) is preferably 70-80 ℃, more preferably 72-78 ℃, and more preferably 74-76 ℃; the time of the addition reaction is preferably 2-3 h, more preferably 2.2-2.8 h, and even more preferably 2.4-2.6 h; the pressure of the addition reaction is preferably 0.5 to 0.8MPa, and more preferably 0.6 to 0.7 MPa.
In the present invention, the reaction of step (2) is as follows:
in the present invention, the molar ratio of compound b and acetic acid in said step (3) is preferably 1: 2.5 to 3.5, and more preferably 1: 2.6-3.4, more preferably 1: 2.8 to 3.2; the molar ratio of acetic acid to concentrated sulfuric acid is preferably 1: 0.5 to 1.5, and more preferably 1: 0.6 to 1.4, more preferably 1: 0.9 to 1.1; the mass concentration of the concentrated sulfuric acid is preferably 45-65%, more preferably 50-60%, and even more preferably 53-57%.
In the invention, the temperature of the substitution reaction in the step (3) is preferably 100-150 ℃, more preferably 110-140 ℃, and more preferably 120-130 ℃; the time of the substitution reaction is preferably 1 to 2 hours, more preferably 1.2 to 1.8 hours, and even more preferably 1.4 to 1.6 hours.
In the present invention, the reaction of step (3) is as follows:
in the present invention, the molar ratio of the compound c and the sodium hydroxide in the step (4) is preferably 1: 3-4, and more preferably 1: 3.2 to 3.8, more preferably 1: 3.4 to 3.6.
In the present invention, the alcohol solution in the step (4) is preferably a methanol solution, an ethanol solution or a propanol solution; the mass concentration of the alcoholic solution is preferably 60-75%, and more preferably 65-70%; the mass ratio of the sodium hydroxide to the alcohol solution is preferably 1: 5-6, and more preferably 1: 5.2-5.8, more preferably 1: 5.4 to 5.6.
In the invention, the temperature of the elimination reaction in the step (4) is preferably 200-300 ℃, more preferably 220-280 ℃, and more preferably 240-260 ℃; the time of the elimination reaction is preferably 2 to 3 hours, more preferably 2.2 to 2.8 hours, and even more preferably 2.4 to 2.6 hours.
In the present invention, the reaction of the step (4) is as follows:
the technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
Mixing 10mol of nandrolone and 30mol of chlorine for 2h under the pressure of 0.5MPa to carry out addition reaction to obtain a compound a; taking 10mol of the compound a, 20mol of hydrogen and 10mol of nickel to react for 3h at 0.8MPa and 75 ℃ to obtain a compound b; taking 10mol of the compound b, 30mol of acetic acid and 15mol of concentrated sulfuric acid to react, wherein the mass concentration of the concentrated sulfuric acid is 60%, the reaction temperature is 130 ℃, and reacting for 1.5h to obtain a compound c; 10mol of the compound c, 30mol of sodium hydroxide and 6.6kg of methanol solution are taken to react, wherein the mass concentration of the methanol solution is 60 percent, the elimination temperature is 250 ℃, and the time of the elimination reaction is 2.5 h. After the reaction is finished, filtering the obtained system, and fully washing and drying the system by using isopropanol to obtain the 3, 5-estradiene-3, 17 beta-diacetate.
The nuclear magnetic resonance hydrogen spectrum of the synthesized product in this example is 1H NMR (400MHz, CDCl3): δ 0.82(s,3H),0.90 to 0.99(m,1H),1.07 to 1.16(m,1H),1.18 to 1.28(m,3H),1.31 to 1.38(m,1H),1.43 to 1.56(m,2H),1.60 to 1.73(m,2H),1.76 to 1.78(m,1H),1.86 to 1.92(m,2H),2.04(s,3H),2.07 to 2.11(m,1H),2.13(s,3H),2.15 to 2.22(m,3H),2.43 to 2.49(m,1H),4.62(t, J ═ 8.44, 1H),5.47(s,1H), 5.77 to 5.77(m, 1H); the product was identified as 3, 5-estradiene-3, 17 β -diacetate in a yield of 96% in accordance with the literature.
Example 2
Mixing 0.5mol of nandrolone and 1.5mol of chlorine for 1 hour under the pressure of 0.4MPa to carry out addition reaction to obtain a compound a; taking 0.5mol of the compound a, 0.75mol of hydrogen and 0.6mol of nickel to react for 2 hours at the temperature of 80 ℃ under the pressure of 0.7MPa to obtain a compound b; taking 0.5mol of the compound b, 1.25mol of acetic acid and 1.8mol of concentrated sulfuric acid to react, wherein the mass concentration of the concentrated sulfuric acid is 50%, the reaction temperature is 110 ℃, and reacting for 1.2h to obtain a compound c; 0.5mol of the compound c, 2mol of sodium hydroxide and 400g of ethanol solution are taken to react, wherein the mass concentration of the ethanol solution is 65%, the elimination temperature is 230 ℃, and the time of the elimination reaction is 2.8 h. After the reaction is finished, the obtained system is filtered, and then is fully washed and dried by using isopropanol, so that the 3, 5-estradiene-3, 17 beta-diacetate is obtained, and the yield reaches 93%.
Example 3
Mixing 1mol of nandrolone and 2.3mol of chlorine for 1.5h under the pressure of 0.6MPa to carry out addition reaction to obtain a compound a; taking 1mol of the compound a, 2.3mol of hydrogen and 1.3mol of nickel to react for 2.2h at the temperature of 72 ℃ under the pressure of 0.6MPa to obtain a compound b; taking 1mol of the compound b, 2.6mol of acetic acid and 1.3mol of concentrated sulfuric acid for reaction, wherein the mass concentration of the concentrated sulfuric acid is 55%, the reaction temperature is 120 ℃, and reacting for 1h to obtain a compound c; 1mol of the compound c, 3.5mol of sodium hydroxide and 770g of methanol solution are taken to react, wherein the mass concentration of the methanol solution is 75 percent, the elimination temperature is 300 ℃, and the time of the elimination reaction is 2.8 h. After the reaction is finished, the obtained system is filtered, and then is fully washed and dried by using isopropanol to obtain the 3, 5-estradiene-3, 17 beta-diacetate, wherein the yield reaches 95%.
Example 4
Mixing 2mol of nandrolone and 5mol of chlorine for 1.8h under the pressure of 0.65MPa to carry out addition reaction to obtain a compound a; taking 2mol of the compound a, 3mol of hydrogen and 1.5mol of nickel to react for 2.65h at the temperature of 70 ℃ under the pressure of 0.5MPa to obtain a compound b; taking 2mol of the compound b, 6mol of acetic acid and 3mol of concentrated sulfuric acid to react, wherein the mass concentration of the concentrated sulfuric acid is 60%, the reaction temperature is 110 ℃, and reacting for 1h to obtain a compound c; taking 2mol of the compound c, 6mol of sodium hydroxide and 1.3kg of propanol solution for reaction, wherein the mass concentration of the propanol solution is 75%, the elimination temperature is 230 ℃, and the time of the elimination reaction is 2.8 h. After the reaction is finished, the obtained system is filtered, and then is fully washed and dried by using isopropanol to obtain the 3, 5-estradiene-3, 17 beta-diacetate, wherein the yield reaches 94%.
Example 5
Mixing 0.1mol of nandrolone and 0.3mol of chlorine for 1.4h under the pressure of 0.4MPa to carry out addition reaction to obtain a compound a; taking 0.1mol of the compound a, 0.2mol of hydrogen and 0.1mol of nickel to react for 2.7h at the temperature of 70 ℃ under the pressure of 0.5MPa to obtain a compound b; taking 0.1mol of the compound b, 3.5mol of acetic acid and 3mol of concentrated sulfuric acid to react, wherein the mass concentration of the concentrated sulfuric acid is 50%, the reaction temperature is 125 ℃, and reacting for 1.8h to obtain a compound c; 0.1mol of the compound c, 0.4mol of sodium hydroxide and 92g of ethanol solution are taken to react, wherein the mass concentration of the ethanol solution is 70 percent, the elimination temperature is 300 ℃, and the time of the elimination reaction is 3 hours. After the reaction is finished, the obtained system is filtered, and then is fully washed and dried by using isopropanol to obtain the 3, 5-estradiene-3, 17 beta-diacetate, wherein the yield reaches 95%.
The above embodiments show that the preparation method of 3, 5-estradiene-3, 17 β -diacetate provided by the invention does not have high requirements on the purity of raw materials, the process conditions are reduced, and the process energy consumption is reduced.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A method for preparing 3, 5-estradiene-3, 17 β -diacetate, comprising the steps of:
(1) mixing nandrolone and chlorine for addition reaction to obtain a compound a;
(2) mixing the compound a, hydrogen and nickel, and then carrying out addition reaction to obtain a compound b;
(3) mixing the compound b, acetic acid and concentrated sulfuric acid, and then carrying out substitution reaction to obtain a compound c;
(4) and mixing the compound c, sodium hydroxide and an alcohol solution, and then carrying out elimination reaction to obtain the 3, 5-estradiene-3, 17 beta-diacetate.
2. The method of claim 1, wherein the molar ratio of nandrolone to chlorine in step (1) is 1: 2 to 3.
3. The method according to claim 1 or 2, wherein the time of the addition reaction in the step (1) is 1 to 2 hours, and the pressure of the addition reaction is 0.3 to 0.7 MPa.
4. The method according to claim 3, wherein the molar ratio of the compound a to hydrogen in the step (2) is 1: 1.5-2.5, wherein the molar ratio of the hydrogen to the nickel is 1: 0.5 to 0.8.
5. The method according to claim 1 or 4, wherein the temperature of the addition reaction in the step (2) is 70 to 80 ℃, the time of the addition reaction is 2 to 3 hours, and the pressure of the addition reaction is 0.5 to 0.8 MPa.
6. The method according to claim 5, wherein the molar ratio of compound b to acetic acid in step (3) is 1: 2.5-3.5, wherein the molar ratio of the acetic acid to the concentrated sulfuric acid is 1: 0.5-1.5, wherein the mass concentration of the concentrated sulfuric acid is 45-65%.
7. The method according to claim 2 or 6, wherein the temperature of the substitution reaction in the step (3) is 100 to 150 ℃ and the time of the substitution reaction is 1 to 2 hours.
8. The method according to claim 7, wherein the molar ratio of the compound c to the sodium hydroxide in the step (4) is 1: 3 to 4.
9. The preparation method according to claim 4 or 8, wherein the alcohol solution in the step (4) is a methanol solution, an ethanol solution or a propanol solution, the mass concentration of the alcohol solution is 60-75%, and the mass ratio of the sodium hydroxide to the alcohol solution is 1: 5 to 6.
10. The method according to claim 1, 2, 4, 6 or 8, wherein the temperature of the elimination reaction in the step (4) is 200 to 300 ℃, and the time of the elimination reaction is 2 to 3 hours.
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