CN113045617B - 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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- CN113045617B CN113045617B CN202110334603.5A CN202110334603A CN113045617B CN 113045617 B CN113045617 B CN 113045617B CN 202110334603 A CN202110334603 A CN 202110334603A CN 113045617 B CN113045617 B CN 113045617B
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- 238000002360 preparation method Methods 0.000 title abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims description 60
- 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 238000007259 addition reaction Methods 0.000 claims description 26
- 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
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 19
- 238000003379 elimination reaction Methods 0.000 claims description 17
- 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 13
- 229960004719 nandrolone Drugs 0.000 claims description 13
- 229910052759 nickel Inorganic materials 0.000 claims description 11
- 238000006467 substitution reaction Methods 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 5
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 abstract description 33
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 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
- 238000003541 multi-stage reaction Methods 0.000 abstract description 3
- 239000002994 raw material Substances 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 7
- 229940079593 drug Drugs 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 5
- 150000003431 steroids Chemical class 0.000 description 5
- 230000008030 elimination Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000694 effects Effects 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
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 1
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 1
- 102000009151 Luteinizing Hormone Human genes 0.000 description 1
- 108010073521 Luteinizing 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
- 230000006978 adaptation 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
- 238000005265 energy consumption Methods 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 229940028334 follicle stimulating hormone Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940040129 luteinizing hormone Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000016087 ovulation Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000001817 pituitary effect Effects 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
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
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 stepwise reaction and adopts a gas pressurizing method to protect double bonds so as to carry out the next step of acetylation reaction of carbonyl. The preparation method provided by the invention has low requirements on reaction raw materials and process conditions, but greatly improves the yield of the 3, 5-estradiene-3, 17 beta-diacetate, 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
Steroid drugs play an important role in preventing and treating diseases, including medicines, veterinary medicines and pesticides, and are mainly characterized by complex reactions of the steroid drugs, obvious remote effects of groups, low yield and difficult separation and purification. Many steroid drugs, especially those with high technical content, are in urgent need for research and development.
The steroid drug tibolone is used for treating osteoporosis. Because of its weak estrogenic, progestogenic-like activity. It can stabilize hypothalamic pituitary system of climacteric woman and inhibit the level of follicle stimulating hormone. The luteinizing hormone has a light inhibition degree, does not influence the prolactin, has the function of inhibiting ovulation of women of childbearing age, is used for relieving postmenopausal symptoms of women, and becomes a first-choice medicament for improving the life quality of the women of childbearing age. 3, 5-estradiene-3, 17 beta-diacetate is an important prodrug of the steroid tibolone, the synthesis of which is a key step. In the prior art, the synthesis of 3, 5-estradiene-3, 17 beta-diacetate by using a one-pot method with nandrolone as a substrate for carbonyl and hydroxyl acetylation protection is simple and convenient, but the yield is not high, and the method 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 with chlorine gas, and performing addition reaction to obtain a compound a;
(2) Mixing the compound a, hydrogen and nickel, and then carrying out an 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 performing elimination reaction to obtain the 3, 5-estradiene-3, 17 beta-diacetate.
Preferably, in the step (1), the molar ratio of the nandrolone to the chlorine is 1:2 to 3.
Preferably, 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 0.7MPa.
Preferably, the molar ratio of the compound a to the hydrogen in the step (2) is 1:1.5 to 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 hours, and the pressure of the addition reaction is 0.5-0.8 MPa.
Preferably, the molar ratio of compound b to acetic acid in step (3) is 1:2.5 to 3.5, wherein the molar ratio of the acetic acid to the concentrated sulfuric acid is 1:0.5 to 1.5 percent, and the mass concentration of the concentrated sulfuric acid is 45 to 65 percent.
Preferably, 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.
Preferably, the molar ratio of compound c to sodium hydroxide in step (4) is 1:3 to 4.
Preferably, 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.
Preferably, 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.
The invention provides a preparation method of 3, 5-estradiene-3, 17 beta-diacetate, which adopts a preparation method of stepwise reaction and adopts a gas pressurizing method to protect double bonds so as to carry out the next step of acetylation reaction of carbonyl. The preparation method provided by the invention has low requirements on reaction raw materials and process conditions, but greatly improves the yield of the 3, 5-estradiene-3, 17 beta-diacetate, 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 with chlorine gas, and performing addition reaction to obtain a compound a;
(2) Mixing the compound a, hydrogen and nickel, and then carrying out an 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 performing elimination reaction to obtain the 3, 5-estradiene-3, 17 beta-diacetate.
In the present invention, the molar ratio of the nandrolone to the chlorine gas in the step (1) is preferably 1:2 to 3, more preferably 1:2.2 to 2.8, more preferably 1:2.4 to 2.6.
In the present invention, the time of the addition reaction in the step (1) is preferably 1 to 2 hours, more preferably 1.2 to 1.8 hours, still more preferably 1.4 to 1.6 hours; the pressure of the addition reaction is preferably 0.3 to 0.7MPa, more preferably 0.4 to 0.6MPa, and still more preferably 0.45 to 0.55MPa.
In the present invention, the reaction of the 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, more preferably 1:1.6 to 2.4, more preferably 1:1.8 to 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 present invention, the temperature of the addition reaction in the step (2) is preferably 70 to 80 ℃, more preferably 72 to 78 ℃, still more preferably 74 to 76 ℃; the time of the addition reaction is preferably 2 to 3 hours, more preferably 2.2 to 2.8 hours, and still more preferably 2.4 to 2.6 hours; the pressure of the addition reaction is preferably 0.5 to 0.8MPa, more preferably 0.6 to 0.7MPa.
In the present invention, the reaction of the step (2) is as follows:
in the present invention, the molar ratio of the compound b to acetic acid in the step (3) is preferably 1:2.5 to 3.5, more preferably 1:2.6 to 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, 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 to 65%, more preferably 50 to 60%, and even more preferably 53 to 57%.
In the present invention, the temperature of the substitution reaction in the step (3) is preferably 100 to 150 ℃, more preferably 110 to 140 ℃, still more preferably 120 to 130 ℃; the time for the substitution reaction is preferably 1 to 2 hours, more preferably 1.2 to 1.8 hours, and still more preferably 1.4 to 1.6 hours.
In the present invention, the reaction of the step (3) is as follows:
in the present invention, the molar ratio of the compound c to sodium hydroxide in the step (4) is preferably 1:3 to 4, 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 alcohol solution is preferably 60-75%, more preferably 65-70%; the mass ratio of the sodium hydroxide to the alcohol solution is preferably 1:5 to 6, more preferably 1:5.2 to 5.8, more preferably 1:5.4 to 5.6.
In the present invention, the temperature of the elimination reaction in the step (4) is preferably 200 to 300 ℃, more preferably 220 to 280 ℃, and even more preferably 240 to 260 ℃; the time for the elimination reaction is preferably 2 to 3 hours, more preferably 2.2 to 2.8 hours, and still 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 with 30mol of chlorine at the pressure of 0.5MPa for 2 hours to perform addition reaction to obtain a compound a; taking 10mol of compound a, 20mol of hydrogen and 10mol of nickel, and reacting for 3 hours at the temperature of 75 ℃ under the pressure of 0.8MPa to obtain a compound b; taking 10mol of compound b, 30mol of acetic acid and 15mol of concentrated sulfuric acid for reaction, wherein the mass concentration of the concentrated sulfuric acid is 60%, the reaction temperature is 130 ℃, and the reaction is carried out for 1.5 hours to obtain a compound c; 10mol of compound c, 30mol of sodium hydroxide and 6.6kg of methanol solution were taken for reaction, wherein the mass concentration of the methanol solution was 60%, the elimination temperature was 250℃and the elimination reaction time was 2.5 hours. After the reaction is finished, the obtained system is filtered, and then is fully washed and dried by isopropanol, so that the 3, 5-estradiene-3, 17 beta-diacetate is obtained.
The synthesized product in this example had a nuclear magnetic resonance hydrogen spectrum of 1H NMR (400 MHz, CDCl 3): delta 0.82 (s, 3H), 0.90-0.99 (m, 1H), 1.07-1.16 (m, 1H), 1.18-1.28 (m, 3H), 1.31-1.38 (m, 1H), 1.43-1.56 (m, 2H), 1.60-1.73 (m, 2H), 1.76-1.78 (m, 1H), 1.86-1.92 (m, 2H), 2.04 (s, 3H), 2.07-2.11 (m, 1H), 2.13 (s, 3H), 2.15-2.22 (m, 3H), 2.43-2.49 (m, 1H), 4.62 (t, J=8.44 Hz, 1H), 5.47 (s, 1H), 5.76-5.77 (m, 1H). The yield of the 3, 5-estradiene-3, 17 beta-diacetate is 96% according to the document.
Example 2
Mixing 0.5mol of nandrolone with 1.5mol of chlorine under the pressure of 0.4MPa for 1h to perform addition reaction to obtain a compound a; taking 0.5mol of compound a, 0.75mol of hydrogen and 0.6mol of nickel, and reacting for 2 hours at the temperature of 80 ℃ under the pressure of 0.7MPa to obtain a compound b; taking 0.5mol of compound b, 1.25mol of acetic acid and 1.8mol of concentrated sulfuric acid for reaction, wherein the mass concentration of the concentrated sulfuric acid is 50%, the reaction temperature is 110 ℃, and the reaction is carried out for 1.2h to obtain a compound c; 0.5mol of compound c, 2mol of sodium hydroxide and 400g of ethanol solution were taken for reaction, wherein the mass concentration of the ethanol solution was 65%, the elimination temperature was 230 ℃, and the elimination reaction time was 2.8h. After the reaction is finished, the obtained system is filtered, and then is fully washed and dried by isopropanol, so that the 3, 5-estradiene-3, 17 beta-diacetate is obtained, and the yield reaches 93%.
Example 3
Mixing 1mol of nandrolone with 2.3mol of chlorine at the pressure of 0.6MPa for 1.5h to perform addition reaction to obtain a compound a; taking 1mol of compound a, 2.3mol of hydrogen and 1.3mol of nickel, and reacting for 2.2 hours at the temperature of 72 ℃ under the pressure of 0.6MPa to obtain a compound b; taking 1mol of 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 the reaction is carried out for 1h to obtain a compound c; 1mol of compound c, 3.5mol of sodium hydroxide and 770g of methanol solution were taken for reaction, wherein the mass concentration of the methanol solution was 75%, the elimination temperature was 300℃and the elimination reaction time was 2.8 hours. After the reaction is finished, the obtained system is filtered, and then is fully washed and dried by isopropanol, so that the 3, 5-estradiene-3, 17 beta-diacetate is obtained, and the yield reaches 95%.
Example 4
Mixing 2mol of nandrolone with 5mol of chlorine at the pressure of 0.65MPa for 1.8h for addition reaction to obtain a compound a; taking 2mol of compound a, 3mol of hydrogen and 1.5mol of nickel, and reacting for 2.65 hours under the temperature of 70 ℃ under the pressure of 0.5MPa to obtain a compound b; 2mol of compound b, 6mol of acetic acid and 3mol of concentrated sulfuric acid are taken for reaction, wherein the mass concentration of the concentrated sulfuric acid is 60%, the reaction temperature is 110 ℃, and the reaction is carried out for 1h to obtain a compound c; 2mol of compound c, 6mol of sodium hydroxide and 1.3kg of propanol solution were taken for reaction, wherein the mass concentration of the propanol solution was 75%, the erasing temperature was 230℃and the erasing reaction time was 2.8 hours. After the reaction is finished, the obtained system is filtered, and then is fully washed and dried by isopropanol, so that the 3, 5-estradiene-3, 17 beta-diacetate is obtained, and the yield reaches 94%.
Example 5
Mixing 0.1mol of nandrolone with 0.3mol of chlorine at the pressure of 0.4MPa for 1.4h for addition reaction to obtain a compound a; taking 0.1mol of compound a, 0.2mol of hydrogen and 0.1mol of nickel, and reacting for 2.7 hours under the temperature of 70 ℃ under the pressure of 0.5MPa to obtain a compound b; taking 0.1mol of compound b, 3.5mol of acetic acid and 3mol of concentrated sulfuric acid for reaction, wherein the mass concentration of the concentrated sulfuric acid is 50%, the reaction temperature is 125 ℃, and the reaction is carried out for 1.8 hours to obtain a compound c; 0.1mol of compound c, 0.4mol of sodium hydroxide and 92g of ethanol solution were taken for reaction, wherein the mass concentration of the ethanol solution was 70%, the elimination temperature was 300℃and the elimination reaction time was 3 hours. After the reaction is finished, the obtained system is filtered, and then is fully washed and dried by isopropanol, so that the 3, 5-estradiene-3, 17 beta-diacetate is obtained, and the yield reaches 95%.
As can be seen from the above examples, the present invention provides a preparation method of 3, 5-estradiene-3, 17 beta-diacetate, which does not require high purity of raw materials, has reduced process conditions and reduced process energy consumption, and the present invention obtains 3, 5-estradiene-3, 17 beta-diacetate by sequential reaction of groups on nandrolone through multi-step reaction, and the yield reaches 96%, which is suitable for mass production.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (10)
1. A method for preparing 3, 5-estradiene-3, 17 beta-diacetate, which is characterized by comprising the following steps:
(1) Mixing nandrolone with chlorine gas, and performing addition reaction to obtain a compound a;
(2) Mixing the compound a, hydrogen and nickel, and then carrying out an 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) Mixing a compound c, sodium hydroxide and an alcohol solution, and then performing elimination reaction to obtain the 3, 5-estradiene-3, 17 beta-diacetate;
the compound a is
The compound b is
The compound c is
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 0.7MPa.
4. The process according to claim 3, wherein the molar ratio of compound a to hydrogen in step (2) is 1:1.5 to 2.5, wherein the molar ratio of the hydrogen to the nickel is 1:0.5 to 0.8.
5. The process 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 0.8MPa.
6. The process according to claim 5, wherein the molar ratio of compound b to acetic acid in step (3) is 1:2.5 to 3.5, wherein the molar ratio of the acetic acid to the concentrated sulfuric acid is 1:0.5 to 1.5 percent, and the mass concentration of the concentrated sulfuric acid is 45 to 65 percent.
7. The process 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 of claim 7, wherein the molar ratio of compound c to sodium hydroxide in step (4) is 1:3 to 4.
9. The 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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