CN116854674A - Preparation method of terazosin hydrochloride and intermediate thereof - Google Patents
Preparation method of terazosin hydrochloride and intermediate thereof Download PDFInfo
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- CN116854674A CN116854674A CN202310796585.1A CN202310796585A CN116854674A CN 116854674 A CN116854674 A CN 116854674A CN 202310796585 A CN202310796585 A CN 202310796585A CN 116854674 A CN116854674 A CN 116854674A
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- terazosin
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- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229960001909 terazosin hydrochloride Drugs 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- -1 tetrahydrofurfuryl Chemical group 0.000 claims abstract description 14
- HJVAVGOPTDJYOJ-UHFFFAOYSA-N 2-amino-4,5-dimethoxybenzoic acid Chemical compound COC1=CC(N)=C(C(O)=O)C=C1OC HJVAVGOPTDJYOJ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 11
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 229960001693 terazosin Drugs 0.000 claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003651 drinking water Substances 0.000 claims description 3
- 235000020188 drinking water Nutrition 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 238000004321 preservation Methods 0.000 claims 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 5
- DJDBLBBSUAQYAA-UHFFFAOYSA-N piperazine-1-carbonitrile Chemical compound N#CN1CCNCC1 DJDBLBBSUAQYAA-UHFFFAOYSA-N 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 230000020477 pH reduction Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 24
- 238000000034 method Methods 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 229940125782 compound 2 Drugs 0.000 description 6
- 239000012535 impurity Substances 0.000 description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 3
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 3
- 238000007664 blowing Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- DGHKCBSVAZXEPP-UHFFFAOYSA-N 2,4-dichloro-6,7-dimethoxyquinazoline Chemical compound ClC1=NC(Cl)=C2C=C(OC)C(OC)=CC2=N1 DGHKCBSVAZXEPP-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- WJUFSDZVCOTFON-UHFFFAOYSA-N veratraldehyde Chemical compound COC1=CC=C(C=O)C=C1OC WJUFSDZVCOTFON-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DBOAGRILJPETJN-UHFFFAOYSA-N 2-chloro-6,7-dimethoxy-1h-quinazolin-4-one Chemical compound N1=C(Cl)NC(=O)C2=C1C=C(OC)C(OC)=C2 DBOAGRILJPETJN-UHFFFAOYSA-N 0.000 description 1
- KWNQIIMVPSMYEM-UHFFFAOYSA-N 6,7-dimethoxy-1h-quinazoline-2,4-dione Chemical compound N1C(=O)NC(=O)C2=C1C=C(OC)C(OC)=C2 KWNQIIMVPSMYEM-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- NZMOFYDMGFQZLS-UHFFFAOYSA-N terazosin hydrochloride dihydrate Chemical compound [H+].O.O.[Cl-].N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 NZMOFYDMGFQZLS-UHFFFAOYSA-N 0.000 description 1
- HFFLGKNGCAIQMO-UHFFFAOYSA-N trichloroacetaldehyde Chemical compound ClC(Cl)(Cl)C=O HFFLGKNGCAIQMO-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/20—Oxygen atoms
Abstract
The invention discloses a novel preparation method of terazosin hydrochloride, belonging to the field of drug synthesis. According to the invention, the cyano piperazine and the tetrahydrofurfuryl acid are condensed, then the cyano piperazine and the tetrahydrofurfuryl acid are combined with the 6-amino veratric acid to construct a quinazoline ring, and the terazosin hydrochloride is obtained through chlorination, ammoniation and acidification.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a preparation method of a medicine terazosin hydrochloride for treating hypertension and benign prostatic hyperplasia and an intermediate thereof.
Background
Terazosin hydrochloride as novel long-acting selectivity alpha 1 The noradrenal receptor blocker can reduce peripheral vascular resistance, and is a novel long-acting antihypertensive drug for treating benign prostatic hyperplasia. It has found wide clinical application in developed countries and regions such as the united states, europe, and japan, and is also a first-line drug recommended by the international BPH consultation committee for the treatment of benign prostatic hyperplasia. At present, terazosin hydrochloride is listed in the basic medicine catalogue of China, and the national public charge medical reimbursement variety is listed. In recent years, the terazosin hydrochloride preparation has fast market sales growth, and the demands of raw materials are continuously increased, so that the terazosin hydrochloride preparation has wide market prospect. In order to meet the requirement of the terazosin hydrochloride bulk drugThe market demand, the guarantee supply and important social and economic values for the process research of the terazosin hydrochloride key intermediate are provided, and the method has great market prospect.
Terazosin hydrochloride has the chemical name of 1- (4-amino-6, 7-dimethoxy-2-quinazolinyl) -4- [ (tetrahydrofuranyl) carbonyl ] piperazine hydrochloride dihydrate, and has the structural formula of
Patent US6015819 reports a synthetic method of terazosin hydrochloride. The method takes veratraldehyde as a raw material, and is subjected to nitration, oxidation and reduction to obtain 2-amino-4, 5-dimethoxy benzoic acid, then cyclization is carried out to obtain 2, 4-dihydroxy-6, 7-dimethoxy quinazoline, then chlorine substitution and ammoniation are carried out to obtain 4-amino-2-chlorine-6, 7-dimethoxy quinazoline, then the 4-amino-2-chlorine-6, 7-dimethoxy quinazoline reacts with anhydrous piperazine and tetrahydrofurfuryl acid to generate terazosin, and finally salt formation is carried out to obtain terazosin hydrochloride, wherein the specific synthetic route is shown as follows.
The synthetic steps of the route are longer, and the total yield is less than 20%. The synthetic quinazoline ring has low yield which is lower than 55%, high reaction temperature, and the use of sodium cyanate as a reagent, and the safety and environmental protection problems of wastewater treatment and the like are outstanding. In addition, under the process condition, 2, 4-dichloro-6, 7-dimethoxy quinazoline is unstable and is easy to hydrolyze, so that the difficulty coefficient of work operation is high, the product quality is uncontrollable, and the industrial application of the process is limited.
Patent (CN 108358828) reports a synthetic method of terazosin hydrochloride, which is improved on the basis of the route of patent US6015819, and 6-amino veratric acid is obtained by a method of obtaining amino and carboxyl by chloral and hydroxylamine hydrochloride, and the subsequent reaction steps are completely consistent, and the route is shown below.
The synthetic route only improves the synthetic method of 6-amino veratric acid, and does not greatly improve the quinazoline ring of the mother nucleus of terazosin hydrochloride.
Generally, the existing technology comprises the steps of constructing quinazoline ring, then chloridizing and ammoniating, and then condensing with piperazine and tetrahydrofurfuryl acid in sequence to obtain terazosin hydrochloride, and has the following problems:
1) The intermediate 2, 4-dichloro-6, 7-dimethoxy quinazoline of the process method is unstable, and other intermediates are easy to generate impurities. The impurities all have quinazoline ring structures, are very similar to terazosin, and are very difficult to remove in the later steps of raw material medicine production, so that the product needs to be refined for many times to meet pharmacopoeia requirements, and the product yield is low and the productivity is low.
2) Two nitrogen atoms which can be acylated exist in the molecular structure of the 4-amino-6, 7-dimethyl-2-piperazinyl-4-quinazoline, so the reaction selectivity is not high, the product has more impurities, the separation is difficult, the yield is low, and the quality is difficult to control.
3) The existing process steps are longer, the operation difficulty of industrial production is higher, the three wastes are difficult to treat, the key reaction yield is lower, and the route cost is still higher, so that a method for synthesizing the terazosin hydrochloride, which has the advantages of simple process route, low cost and suitability for industrial production, is still needed to be found.
Disclosure of Invention
The invention aims to: in order to solve the technical problems, the invention provides a preparation method of terazosin hydrochloride, which has the advantages of stable intermediate, short steps and high yield.
In order to achieve the aim, one of the purposes of the invention provides an intermediate compound 2 for preparing terazosin hydrochloride and a synthesis method thereof, wherein the structural formula of the compound 2 is as follows:
the synthesis method of the intermediate compound 2 of the terazosin hydrochloride is that the intermediate compound 1 reacts with tetrahydrofurfuryl acid to obtain the compound formula 2.
The second purpose of the invention is to provide an intermediate compound 4 for preparing terazosin hydrochloride and a synthesis method thereof, wherein the structural formula of the compound 4 is as follows:
the synthesis method of the terazosin hydrochloride intermediate compound 4 comprises the steps of cyclizing an intermediate compound 2 and 6-amino veratric acid, and then carrying out chlorination reaction to obtain the compound formula 4.
The invention relates to a preparation method of terazosin hydrochloride, which comprises the steps of condensing cyano piperazine with tetrahydrofurfuryl acid, then constructing a quinazoline ring, greatly improving the stability of the quinazoline ring, greatly reducing process impurities, reducing the refining times of intermediates and finished products, and improving the reaction yield. And by constructing a new intermediate compound 2 and a new intermediate compound 4, experimental conditions are optimized, and the yield of each reaction step and the separation purity of the intermediate are improved. These improvements greatly increase the efficiency of the route, further reduce the cost of the process, reduce the formation of by-products and facilitate the improvement of the purity of the final product. The process route has the advantages of less steps, simple operation, higher yield, higher purity of the obtained product, suitability for industrial production, and the reaction route is shown as follows:
the first step: intermediate 1 and tetrahydrofurfuryl acid produce intermediate 2;
and a second step of: intermediate 2 and 6-amino veratric acid are cyclized to obtain intermediate 3;
and a third step of: intermediate 3 is subjected to chlorination to obtain intermediate 4;
fourth step: and (3) ammonifying the intermediate 4 to obtain terazosin, and acidifying with hydrochloric acid to obtain a final product.
The beneficial effects are that: the invention provides a preparation method of terazosin hydrochloride, which has the following advantages compared with the prior art: the stability of the quinazoline ring is improved by changing the ring closing mode, the process impurities are greatly reduced, the intermediate of the preparation method is easy to purify, the reaction condition is mild, the post-treatment operation is simple and convenient, the total yield can reach more than 35%, and the preparation method is more suitable for large-scale industrial production.
Detailed Description
The principles and features of the present invention are described below with examples of implementation for further explanation of the invention, but without limiting the scope of the invention.
Example 1 4- (tetrahydrofuran-2-carbonyl) piperazine-1-carbonitrile (Compound 2)
Cyanopiperazine (55.57 g,0.50 mol) was added to toluene (277.87 g), warmed to 40-50 ℃, 2-tetrahydrofurfuryl acid toluene solution (58.02 g,0.50mol, dissolved in 55.57g toluene) was added dropwise, and reacted for 1.0-2.0h, after the addition, warmed to reflux (115-120 ℃) for 5.5h. After the reaction was completed, toluene was distilled off under reduced pressure until no distillate was present, and the product was a pale yellow to brown oil. The yield is 83.2%, and the purity (GC) is more than or equal to 98.5%.
Example 2 1- (4-hydroxy-6, 7-dimethoxy-2-quinazolinyl) -4- [ (tetrahydrofuranyl) carbonyl ] piperazine (Compound 3)
4- (tetrahydrofuran-2-carbonyl) piperazine-1-carbonitrile (115.02 g,0.55 mol), 6-aminoveratric acid (98.59 g,0.50 mol), toluene (266.19 g), drinking water (29.58 g), naOH (20.00 g,0.50 mol) were added to a 1L autoclave, the autoclave was closed, and the temperature was raised to 140-160℃and stirred for 6 hours. After the reaction is finished, the feed liquid is cooled and transferred into a 1L reaction bottle, cooled and crystallized, and filtered. The filter cake is dried by blowing at 80 ℃ to obtain white solid with yield: 86.9 percent and the purity (HPLC) is more than or equal to 99.0 percent.
Example 3 1- (4-chloro-6, 7-dimethoxy-2-quinazolinyl) -4- [ (tetrahydrofuranyl) carbonyl ] piperazine (Compound 4)
Compound 3 (194.08 g,0.50 mol), phosphorus oxychloride (579 ml), DMF (32.00 g) was charged into a 2L reactor, heated and reacted at a temperature of 90-100℃for 10h. After the completion of the reaction, excess phosphorus oxychloride was distilled off under reduced pressure, and ice water (400.00 g) was added dropwise to the residue, followed by extraction with dichloromethane 2 times, each with 600ml of dichloromethane. The methylene chloride phases were combined, methylene chloride was distilled off under reduced pressure, toluene (610.29 g) was added to the residue, and crystallization was carried out by cooling. Filtering, drying the filter cake by blowing to obtain white powder, and obtaining the yield: 87.2 percent and the purity (HPLC) is more than or equal to 99.0 percent.
EXAMPLE 4 terazosin
2-chloro-4-hydroxy-6, 7-dimethoxy quinazoline (203.43 g,0.50 mol) and DMF (1017.15 g) are added into a 2L reaction bottle and stirred, after all the solid is dissolved, ammonia gas is introduced at room temperature for 8 hours, and after the ammonia gas introduction is stopped, stirring reaction is continued for 2 hours. DMF was distilled under reduced pressure, about half of the DMF was distilled off, ice water (1017.15 g) was added under ice bath cooling, and a solid was precipitated. Filtering, washing the filter cake twice with ice water, and drying by blowing to obtain 183.92g of light yellow crystals, yield: 95.1 percent and the purity (HPLC) is more than or equal to 99.0 percent.
EXAMPLE 5 terazosin hydrochloride
Terazosin (69.7 g,0.18 mol), absolute ethyl alcohol (766.70 g) and purified water (83.00 g) are added into a reaction bottle, stirred and heated to 70-75 ℃, 6M hydrochloric acid is added dropwise, pH is regulated to 2.49, after addition, stirring is performed for 0.5h while maintaining the temperature, cooling is performed to 40-50 ℃, stirring is performed for 1h, cooling is performed to 0-5 ℃, stirring is performed for 2h while maintaining the temperature, suction filtration is performed, and air blast drying is performed to obtain white solid, wherein the yield is 93.8%, and the purity (HPLC) is more than or equal to 99.5%).
Claims (7)
1. The preparation method of the terazosin hydrochloride is characterized by comprising the following steps:
the first step: intermediate 1 and tetrahydrofurfuryl acid produce intermediate 2;
and a second step of: intermediate 2 and 6-amino veratric acid are cyclized to obtain intermediate 3;
and a third step of: intermediate 3 is subjected to chlorination to obtain intermediate 4;
fourth step: the intermediate 4 is aminated to obtain terazosin, and the terazosin is acidified by hydrochloric acid to obtain the final product
2. The preparation method according to claim 1, wherein in the first step, a toluene solution of 2-tetrahydrofurfuryl acid is added dropwise to a reaction flask containing intermediate 1 and toluene, and the mixture is subjected to reflux reaction at a temperature.
3. The preparation method according to claim 1, wherein in the second step, the intermediate 2, 6-amino veratric acid, toluene, drinking water and sodium hydroxide are added into a reaction kettle, and the temperature is raised to 140-160 ℃ for reaction.
4. The preparation method according to claim 1, wherein in the third step, the intermediate 3, phosphorus oxychloride and DMF are added into a reaction bottle to perform reflux reaction.
5. The preparation method of claim 1, wherein the intermediate 4 is dissolved in DMF, ammonia gas is introduced at room temperature for stirring reaction to obtain terazosin, then intermediate 5, ethanol and drinking water are added into a reaction bottle, stirring and heating are carried out at 70-75 ℃, hydrochloric acid is added dropwise to adjust pH to about 2.49, stirring and cooling are carried out at 40-50 ℃, stirring and cooling are carried out at 0-5 ℃, heat preservation and stirring are carried out, and suction filtration is carried out.
6. The preparation method according to claim 2, wherein the ratio of the feeding amount of the intermediate 1 to the feeding amount of the 2-tetrahydrofurfuryl acid is 1:1, the temperature is raised, the reflux reaction is carried out for 5.5 hours, and the reduced pressure distillation is carried out after the completion.
7. The preparation method according to claim 3, wherein the addition amount ratio of the intermediate 2, 6-amino veratric acid and sodium hydroxide is 1-1.1:1:1-1.2.
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