CN114249703B - Preparation method of medical intermediate suitable for industrial amplification - Google Patents
Preparation method of medical intermediate suitable for industrial amplification Download PDFInfo
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- CN114249703B CN114249703B CN202011023802.6A CN202011023802A CN114249703B CN 114249703 B CN114249703 B CN 114249703B CN 202011023802 A CN202011023802 A CN 202011023802A CN 114249703 B CN114249703 B CN 114249703B
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- C07—ORGANIC CHEMISTRY
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- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/14—Thiadiazoles; Hydrogenated thiadiazoles condensed with carbocyclic rings or ring systems
Abstract
The invention discloses a preparation method of a medical intermediate suitable for industrial amplification, in particular to a preparation method of 5-chloro-4-amino-2, 1, 3-benzothiadiazole, which comprises the following steps: 5-chloro-4-nitro-2, 1, 3-benzothiadiazole is used as a raw material, and is subjected to nitroreduction reaction in the presence of a metal reducing agent, electrolyte, active carbon and a solvent to prepare the 5-chloro-4-amino-2, 1, 3-benzothiadiazole. The method has higher yield and purity, is simple and convenient to operate, has high production efficiency and safety, and is suitable for industrial mass production.
Description
Technical Field
The invention relates to a preparation method of a medical intermediate suitable for industrial amplification. In particular to a preparation method of an intermediate 5-chloro-4-amino-2, 1, 3-benzothiadiazole of tizanidine hydrochloride serving as a muscle relaxant.
Background
Tizanidine hydrochloride (Tizanidine) is a central skeletal muscle relaxant with an imidazoline structure, and is first developed by the company of North China, switzerland, and is marketed in Danish and Switzerland for the first time in 1988, and then subsequently obtained in more than 20 countries such as Europe, the United states, japan, etc., and is the only novel central skeletal muscle relaxant and central alpha 2 adrenergic receptor agonist with gastrointestinal tract protection effect on the market at present. As a novel central alpha 2 adrenergic receptor agonist, tizanidine hydrochloride has the effects of sedation, analgesia and anxiolytic, has small influence on respiratory and cardiovascular systems, can provide stable hemodynamics, has small side effect and good safety. Has wide application prospect in aspects of anti-spasmodic, curing various pains and anesthesia.
Tizanidine hydrochloride has a chemical name of 5-chloro-N- (4, 5-dihydro-1H-imidazol-2-yl) -2,1, 3-benzothiadiazole-4-amine hydrochloride, and a specific structure is shown in a formula I.
At present, a plurality of synthetic routes for preparing tizanidine hydrochloride are reported, wherein 5-chloro-4-amino-2, 1, 3-benzothiadiazole is an important intermediate, and the specific structure of the synthetic routes is shown as a formula (II).
Document 1 (chemical reagent, 2003,25 (2), 115-117) reports a method for synthesizing 5-chloro-4-amino-2, 1, 3-benzothiadiazole: 5-chloro-4-nitro-2, 1, 3-benzothiadiazole is taken as a raw material, and an iron/hydrochloric acid system is adopted to reduce nitro, so that 5-chloro-4-amino-2, 1, 3-benzothiadiazole is obtained.
The following preparation methods are reported in document 2 (journal of Chinese New medicine, vol.15, 8, 621-623), document 3 (journal of Chinese medical industry 2005,36 (10), 593-595): the nitro is reduced by adopting an iron powder/acetic acid system to obtain the 5-chloro-4-amino-2, 1, 3-benzothiadiazole.
Indian patent (Indian Pat,2008MU 01713) reports the following preparation methods: and adopting an iron powder, ferric chloride and toluene system to reduce nitro, so as to prepare the 5-chloro-4-amino-2, 1, 3-benzothiadiazole.
Chinese patent application (CN 102140095 a) reports a preparation method: the 5-chloro-4-amino-2, 1, 3-benzothiadiazole is prepared by adopting a catalytic hydrogenation reduction method.
In the existing nitro preparation process, different problems exist. The iron powder reduction method is thorough in reaction, but can produce more iron mud, the iron mud is very thin and difficult to remove by a conventional filtering mode, and the filtering time is long, so that the method is not beneficial to industrial production. In addition, the iron sludge also wraps the product, and the product and the iron sludge are difficult to separate, so that the product yield is low. In order to reduce the packing of the iron sludge into the product as much as possible, a large amount of solvent is generally used to repeatedly wash the iron sludge, thereby increasing the production cost, and the reduction products packed with the iron sludge belong to hazardous waste, increasing the risk of environmental pollution during storage, transportation and handling.
The catalytic hydrogenation reaction has the advantages of environmental protection, but in practical application, a pressure reaction kettle is required, and the requirements on laboratory and factory equipment are severe; the hydrogen used in the reaction belongs to inflammable and explosive gas, the gaseous hydrogen is difficult to control and operate and easy to leak, and great potential safety hazards exist; in addition, the hydrogenation reaction system usually uses palladium-carbon catalyst or Raney nickel catalyst, which are inflammable substances, and spontaneous combustion is easy to occur when the catalyst is exposed to the air, so that the risk of industrial production is increased. In addition, catalytic hydrogenation reactions are long, typically up to 24 hours.
Therefore, there is a need to develop a safe, economical, high-purity and high-yield preparation method of tizanidine intermediate 5-chloro-4-amino-2, 1, 3-benzothiadiazole.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of tizanidine intermediate 5-chloro-4-amino-2, 1, 3-benzothiadiazole, which comprises the following steps:
5-chloro-4-nitro-2, 1, 3-benzothiadiazole is used as a raw material, and is subjected to nitroreduction reaction in the presence of a metal reducing agent, electrolyte, active carbon and a solvent to prepare the 5-chloro-4-amino-2, 1, 3-benzothiadiazole.
Further, the metal reducing agent is selected from any one of zinc powder, iron powder and tin powder.
Further, the electrolyte is selected from any one of ammonium chloride, ammonium sulfate, ammonium acetate, ferric chloride, hydrochloric acid, acetic acid, and formic acid.
Further, the solvent is selected from water or a mixed solvent composed of water and an organic solvent, wherein the organic solvent is selected from any one of methanol, ethanol, isopropanol, ethylene glycol, acetone, tetrahydrofuran and acetonitrile or a combination thereof.
Further, the molar ratio of the metal reducing agent to the 5-chloro-4-nitro-2, 1, 3-benzothiadiazole is 2.0:1 to 4.0:1mol/mol, preferably 2.4:1 to 3.6:1mol/mol.
Further, the molar ratio of the electrolyte to 5-chloro-4-nitro-2, 1, 3-benzothiadiazole is 1.2:1 to 5.0:1mol/mol, preferably 1.5:1 to 3.0:1mol/mol.
Further, the mass ratio of the activated carbon to the 5-chloro-4-nitro-2, 1, 3-benzothiadiazole is 0.1:1-0.6:1 g/g, preferably 0.16:1-0.4:1 g/g.
Further, the volume to mass ratio of the solvent to the 5-chloro-4-nitro-2, 1, 3-benzothiadiazole is 3:1 to 10:1mL/g, preferably 4:1 to 7.5:1mL/g.
Further, the temperature of the nitroreduction reaction is 60-120 ℃, preferably 70-100 ℃; the reaction time is 0.5-3 hours.
Further, the preparation method of the medical intermediate comprises the following specific steps:
weighing electrolyte, adding the electrolyte into a solvent, adding active carbon, a metal reducing agent and 5-chloro-4-nitro-2, 1, 3-benzothiadiazole into the electrolyte solution, stirring and heating to react completely, adjusting pH, adding an organic solvent, stirring, filtering, separating liquid, and concentrating an organic phase under reduced pressure until the organic phase is dried to obtain 5-chloro-4-amino-2, 1, 3-benzothiadiazole;
preferably, the reduced pressure concentration of this step may further comprise a step of recrystallization, the solvent of which is selected from 75% methanol, 75% acetonitrile, dichloromethane or isopropanol.
Compared with the prior art, the method has the advantages that:
1) The method of the invention improves the yield and ensures the high purity of the product. The yield of the 5-chloro-4-amino-2, 1, 3-benzothiadiazole prepared by the method can reach more than 95 percent, and the purity can reach more than 99.3 percent. The purity intermediate can participate in the next reaction without further purification, and the purity of the prepared tizanidine hydrochloride product meets the requirement of medicinal quality.
2) The color of the 5-chloro-4-amino-2, 1, 3-benzothiadiazole obtained by the preparation method is yellow, and compared with the brown yellow of the product prepared by the prior art, the color of the product is greatly improved, and the product is favorable for finally preparing white tizanidine hydrochloride.
3) The method solves the technical problem that iron mud and products are difficult to separate caused by reduction of iron powder in the prior art. The invention adopts a system of active carbon and iron powder, prevents the precipitation of the iron powder in the reaction, quickens the reaction speed, prevents the formation of iron mud in the reaction system, solves the problem of difficult filtration caused by the iron mud, and reduces the residue of iron ions in the reduction product.
4) The invention reduces the consumption of iron powder. The iron powder is used in the prior art in an amount of at least about 4.7 equivalents, and even up to 20 equivalents, of 5-chloro-4-nitro-2, 1, 3-benzothiadiazole. The invention adopts the combination of the iron powder and the activated carbon, and unexpectedly, the reduction reaction of the nitro can be completed by reducing the dosage of the iron powder, and the reaction is faster.
5) The method is suitable for industrial mass production. The method can replace the catalytic hydrogenation reduction with high price and high risk in the prior art. In addition, the method of the invention also prevents the abrasion of equipment in the common iron powder reduction process, and reduces the damage of the equipment. The method disclosed by the invention is simple to operate, has no special requirement on equipment, is economical and safe, meets the requirements of large-scale industrial production, greatly saves materials and reduces the industrial production cost.
Drawings
FIG. 1 is a chart showing the hydrogen nuclear magnetic resonance spectrum of 5-chloro-4-amino-2, 1, 3-benzothiadiazole in example 1 of the present invention;
FIG. 2 is a chart showing the nuclear magnetic resonance of 5-chloro-4-amino-2, 1, 3-benzothiadiazole in example 1 of the present invention.
Detailed Description
The raw material 5-chloro-4-nitro-2, 1, 3-benzothiadiazole used in the examples of the present invention may be obtained commercially or may be prepared according to a method reported in the literature, for example, literature: journal of new Chinese medicine, volume 15, 8, 621-623; journal of new medicine in China, volume 15, 8, 621-623. Other reagents for use in the present invention are commercially available.
Example 15 preparation of chloro-4-amino-2, 1, 3-benzothiadiazole
2.5g of ammonium chloride is weighed, added into 35mL of water, then 0.8g of active carbon, 3.1g of iron powder and 5.0g of 5-chloro-4-nitro-2, 1, 3-benzothiadiazole are added into the ammonium chloride aqueous solution, and the mixture is stirred and heated to 75+/-5 ℃ for reaction for 0.5 hour. The reaction was completed and the pH was adjusted to 7.5 to 9 with a 10% sodium carbonate solution. Ethyl acetate was added thereto, stirred well and filtered. The filtrate was separated and the organic phase was collected. The organic phase was concentrated to dryness under reduced pressure to give 4.1g of a yellow 5-chloro-4-amino-2, 1, 3-benzothiadiazole concentrate. The yield was 95.3% and the HPLC purity was 99.35%.
The resulting concentrate was further recrystallized from isopropanol to give 3.9g of 5-chloro-4-amino-2, 1, 3-benzothiadiazole as a bright yellow powder. The yield was 95.1% and the HPLC purity was 99.90%.
The 5-chloro-4-amino-2, 1, 3-benzothiadiazole obtained in example 1 was analyzed by nuclear magnetic resonance spectroscopy to obtain nuclear magnetic resonance hydrogen spectrum and carbon spectrum, and the results were as follows:
1 H NMR(400MHz，DMSO)，δ＝6.391(s，2H)；7.158～7.181(d，1H)；7.476～7.499(d，1H)。
13 C NMR(100MHz，DMSO)，δ＝153.964，146.845，136.645，132.262，109.326，107.140。
example 25 preparation of chloro-4-amino-2, 1, 3-benzothiadiazole
76.6g of ammonium sulfate is weighed, 250mL of water is added, 20.0g of active carbon, 38.8g of iron powder and 50.0g of 5-chloro-4-nitro-2, 1, 3-benzothiadiazole are added into the ammonium sulfate aqueous solution, and the mixture is stirred and heated to 85+/-5 ℃ for reaction for 1 hour. The reaction was completed and the pH was adjusted to 7.5 to 9 with a 10% sodium carbonate solution. Ethyl acetate was added thereto, stirred well and filtered. The filtrate was separated and the organic phase was collected. The organic phase was concentrated to dryness under reduced pressure to give 40.9g of a yellow 5-chloro-4-amino-2, 1, 3-benzothiadiazole concentrate. The yield was 95.0% and the HPLC purity was 99.46%.
The resulting concentrate was further recrystallized from isopropanol to give 37.6g of 5-chloro-4-amino-2, 1, 3-benzothiadiazole as a bright yellow powder. Yield 91.9% and HPLC purity 99.95%.
The 5-chloro-4-amino-2, 1, 3-benzothiadiazole obtained in example 2 was analyzed by nuclear magnetic resonance spectroscopy, which was similar to the result of example 1, confirming that the obtained target product was obtained.
Example 35 preparation of chloro-4-amino-2, 1, 3-benzothiadiazole
26.8g of ammonium acetate was weighed, added to 167mL of water and 33mL of isopropyl alcohol, 15.0g of activated carbon, 46.6g of iron powder and 50.0g of 5-chloro-4-nitro-2, 1, 3-benzothiadiazole were added to the ammonium acetate aqueous solution, and the mixture was stirred and heated to 90.+ -. 5 ℃ to react for 1 hour. The reaction was completed and the pH was adjusted to 7.5 to 9 with a 10% sodium carbonate solution. Dichloromethane was added, stirred well, filtered, the filtrate was separated and the organic phase was collected. The organic phase was concentrated to dryness under reduced pressure to give 41.1g of a yellow 5-chloro-4-amino-2, 1, 3-benzothiadiazole concentrate, yield 95.5% and HPLC purity 99.54%.
The resulting concentrate was further recrystallized from methylene chloride to give 39.0g of 5-chloro-4-amino-2, 1, 3-benzothiadiazole as a bright yellow powder. The yield was 94.9% and the HPLC purity was 99.93%.
The 5-chloro-4-amino-2, 1, 3-benzothiadiazole obtained in example 3 was analyzed by nuclear magnetic resonance spectroscopy, which was similar to the result of example 1, confirming that the obtained target product was obtained.
Example 45 preparation of chloro-4-amino-2, 1, 3-benzothiadiazole
112.8g of ferric chloride is weighed, 273mL of water and 27mL of propylene glycol are added, 10.0g of active carbon, 45.3g of iron powder and 50.0g of 5-chloro-4-nitro-2, 1, 3-benzothiadiazole are added into the ferric chloride aqueous solution, and the mixture is stirred and heated to 90+/-5 ℃ for reaction for 1 hour. The reaction was completed and the pH was adjusted to 7.5 to 9 with a 10% sodium carbonate solution. Ethyl acetate was added thereto, and the mixture was stirred well, filtered, and the filtrate was separated to collect an organic phase. The organic phase was concentrated to dryness under reduced pressure to give 41.9g of a yellow 5-chloro-4-amino-2, 1, 3-benzothiadiazole concentrate in 97.3% yield and 99.85% purity by HPLC.
The resulting concentrate was further recrystallized from 75% methanol to give 38.0g of 5-chloro-4-amino-2, 1, 3-benzothiadiazole as a bright yellow powder. The yield was 90.7% and the HPLC purity was 99.97%.
The 5-chloro-4-amino-2, 1, 3-benzothiadiazole obtained in example 4 was analyzed by nuclear magnetic resonance spectroscopy, which was similar to the result of example 1, confirming that the obtained target product was obtained.
Example 55 preparation of chloro-4-amino-2, 1, 3-benzothiadiazole
63.3g of ammonium chloride is weighed, 1125mL of water is added, 30.0g of active carbon, 100.9g of iron powder and 150.0g of 5-chloro-4-nitro-2, 1, 3-benzothiadiazole are added into the ammonium chloride aqueous solution, and the mixture is stirred and heated to 95+/-5 ℃ for reaction for 2.5 hours. The reaction was completed and the pH was adjusted to 7.5 to 9 with a 10% sodium carbonate solution. Ethyl acetate was added thereto, and the mixture was stirred well, filtered, and the filtrate was separated to collect an organic phase. The organic phase was concentrated to dryness under reduced pressure to give 123.7g of a yellow 5-chloro-4-amino-2, 1, 3-benzothiadiazole concentrate, yield 95.8% and HPLC purity 99.55%.
The resulting concentrate was further recrystallized from 75% acetonitrile to give 118.0g of 5-chloro-4-amino-2, 1, 3-benzothiadiazole as a bright yellow powder. The yield was 95.4% and the HPLC purity was 99.94%.
Analysis of 5-chloro-4-amino-2, 1, 3-benzothiadiazole obtained in example 5 was performed by nuclear magnetic resonance spectroscopy, which was similar to the result of example 1, confirming that the obtained target product was obtained.
Example 65 preparation of chloro-4-amino-2, 1, 3-benzothiadiazole
0.84kg of ammonium chloride is weighed, added into 15L of water, then 0.40kg of active carbon, 1.35kg of iron powder and 2.00kg of 5-chloro-4-nitro-2, 1, 3-benzothiadiazole are added into the ammonium chloride aqueous solution, and the mixture is stirred and heated to 95+/-5 ℃ for reaction for 3 hours. The reaction was completed and the pH was adjusted to 7.5 to 9 with a 10% sodium carbonate solution. Adding ethyl acetate, stirring thoroughly, and filtering. The filtrate was separated and the organic phase was collected. The organic phase was concentrated to dryness under reduced pressure to give 1.64kg of yellow 5-chloro-4-amino-2, 1, 3-benzothiadiazole concentrate with a yield of 95.3% and an HPLC purity of 99.78%.
The resulting concentrate was further recrystallized from 75% acetonitrile to give 1.52kg of 5-chloro-4-amino-2, 1, 3-benzothiadiazole as a yellow powder. Yield 92.7% and HPLC purity 99.96%.
The 5-chloro-4-amino-2, 1, 3-benzothiadiazole obtained in example 6 was analyzed by nuclear magnetic resonance spectroscopy, which was similar to the result of example 1, confirming that the obtained target product was obtained.
Comparative example 1 (cf. The prior art: chemical Agents, 2003,25 (2), 115-117)
To a 250mL three-necked flask equipped with a sealed mechanical stirrer and a reflux condenser, 78mL of water was added, the pH was adjusted to 3 to 4 with dilute hydrochloric acid, 3.12g (0.014 mol) of 5-chloro-4-nitro-2, 1, 3-benzothiadiazole was added, heated to 50 to 55 ℃ in a water bath, 15.6g (0.279 mo 1) of reduced iron powder was added in portions with stirring, 6 to 7g each, stirring was continued for 1 hour after the addition was completed, cooled, methylene chloride (70 ml×2) was added, filtration was performed, a methylene chloride layer was separated, and the solvent was recovered under reduced pressure to obtain 2.48g of a dark yellow solid. Yield 92.3% HPLC purity 98.27%. Recrystallisation from 75% methanol gives 2.23g of yellow crystals. The yield was 90.0% and the HPLC purity was 99.05%.
Comparative example 2 (cf. The existing literature: magazine of New Chinese medicine, vol.15, 8, 621-623, 2006)
40.0g (0.72 mol) of reduced iron powder and 200mL of 36% acetic acid aqueous solution are added into a reaction flask, after the temperature is raised to 50 ℃, the mixture is kept at a temperature and stirred for 15min, 32.8g (0.15 mol) of solid 5-chloro-4-nitro-2, 1, 3-benzothiadiazole is added in batches, and then the mixture is kept at a temperature of 90-95 ℃ and stirred for 30min for reaction. After the reaction was completed, the mixture was filtered while it was still hot, and the cake was washed with a small amount of hot acetic acid, and the filtrate was left at room temperature overnight and filtered to give 27.0g of a dark yellow solid. Yield 95.6%, HPLC purity 98.09%.
70ml of isopropanol is used for recrystallization to obtain deep yellow powder crystal of 24.5g of 5-chloro-4-amino-2, 1, 3-benzothiadiazole. The yield was 90.7% and the HPLC purity was 99.10%.
Comparative example 3 (cf. The prior art: indian Pat,2008MU 01713)
10g of 5-chloro-4-nitro-2, 1, 3-benzothiadiazole was added to 100mL of toluene, heated to 60-65℃with stirring, and 20g of iron powder was added to form a black suspension. FeCl is added into the black suspension at 70-75 DEG C 3 (20g) (50 mL) and the reaction mixture was stirred at 85-90℃for 2 hours. After the reaction was completed, the reaction mixture was filtered under hot conditions and washed with hot toluene (10 ml). The organic layer was separated and concentrated under reduced pressure to give a total of 8.20g of 5-chloro-4-amino-2, 1, 3-benzothiadiazole with a yield of 95.3% and an HPLC purity of 99.72%.
Comparative example 4
2.5g of ammonium chloride is weighed, 35mL of water is added, 3.1g of iron powder and 5.0g of 5-chloro-4-nitro-2, 1, 3-benzothiadiazole are added into the ammonium chloride aqueous solution, and the mixture is stirred and heated to 75+/-5 ℃ for reaction for 0.5 hour. The reaction was checked by TLC, and starting material remained. The reaction was continued for 5 hours, and the reaction was checked by TLC, with a small amount of starting material remaining. The pH was adjusted to 7.5-9 with 10% sodium carbonate solution. Ethyl acetate was added thereto, and the mixture was stirred well, filtered, and the filtrate was separated to collect an organic phase. The organic phase was concentrated to dryness under reduced pressure to give 4.0g of a dark yellow 5-chloro-4-amino-2, 1, 3-benzothiadiazole concentrate. Yield 93.0% and HPLC purity 85.84%.
The resulting concentrate was further recrystallized from isopropanol to give 3.4g of 5-chloro-4-amino-2, 1, 3-benzothiadiazole as a dark yellow powder. Yield 85.0% and HPLC purity 92.50%.
The amount, yield, purity, stirring state during the reaction, and filtration after the reaction of the iron powder of each example are shown below:
* The iron powder amount refers to the molar ratio (mol/mol) of the iron powder to the raw material 5-chloro-4-nitro-2, 1, 3-benzothiadiazole.
As can be seen from the table, the preparation method successfully solves the technical problem that iron mud and products are difficult to separate after the reduction reaction of iron powder in the prior art, and the condition that filtration is difficult does not exist in the amplification test of the method (example 6) in the invention, which proves that the preparation process is suitable for industrial mass production. In the reduction reaction of the iron powder in the prior art (comparative examples 1 to 4), the problem of difficult filtration exists in the separation process of the product and the iron mud, so that a large amount of time is required for the step, and the industrial mass production is very unfavorable. Furthermore, the present invention unexpectedly found that when activated carbon is used in combination with iron powder, the amount of iron powder used (examples 1-6) can be reduced while improving the efficiency of the reaction and increasing the yield and purity of the product, which was not taught in the prior art. The amount of iron powder is simply reduced (comparative example 4), the nitroreduction reaction is incomplete in the same reaction time, and the reaction is always incomplete due to factors such as iron powder precipitation, encapsulation and the like which obstruct mass transfer. Moreover, the purity of the product obtained by this scheme is significantly reduced compared with the reaction system (example 1) to which activated carbon is added, which is disadvantageous for the subsequent process reactions.
In conclusion, the method has higher yield and purity, is simple and convenient to operate, has high production efficiency and safety, and is suitable for industrial mass production.
Claims (6)
1. A preparation method of a medical intermediate, which is 5-chloro-4-amino-2, 1, 3-benzothiadiazole, is characterized in that: 5-chloro-4-nitro-2, 1, 3-benzothiadiazole is used as a raw material, and is subjected to nitroreduction reaction in the presence of a metal reducing agent, an electrolyte, active carbon and a solvent, wherein the metal reducing agent is selected from iron powder, the electrolyte is selected from any one of ammonium chloride, ammonium sulfate, ammonium acetate and ferric chloride, the solvent is selected from water or a mixed solvent composed of water and an organic solvent, wherein the organic solvent is selected from any one of methanol, ethanol, isopropanol, ethylene glycol, acetone, tetrahydrofuran and acetonitrile or a combination thereof, the molar ratio of the metal reducing agent to the 5-chloro-4-nitro-2, 1, 3-benzothiadiazole is 2.4:1-3.6:1 mol/mol, and the mass ratio of the active carbon to the 5-chloro-4-nitro-2, 1, 3-benzothiadiazole is 0.16:1-0.4:1 g/mol.
2. The process for producing a pharmaceutical intermediate according to claim 1, wherein: the mole ratio of the electrolyte to the 5-chloro-4-nitro-2, 1, 3-benzothiadiazole is 1.5:1-3.0:1 mol/mol.
3. The process for producing a pharmaceutical intermediate according to claim 1, wherein: the volume mass ratio of the solvent to the 5-chloro-4-nitro-2, 1, 3-benzothiadiazole is 4:1-7.5:1 mL/g.
4. The process for producing a pharmaceutical intermediate according to claim 1, wherein: the temperature of the nitroreduction reaction is 70-100 ℃; the reaction time is 0.5-3 hours.
5. The method for preparing a pharmaceutical intermediate according to claim 1, comprising the specific steps of:
weighing electrolyte, adding the electrolyte into a solvent, adding active carbon, a metal reducing agent and 5-chloro-4-nitro-2, 1, 3-benzothiadiazole into the electrolyte solution, stirring and heating to react completely, adjusting pH, adding an organic solvent, stirring, filtering, separating liquid, and concentrating an organic phase under reduced pressure until the organic phase is dried to obtain the 5-chloro-4-amino-2, 1, 3-benzothiadiazole.
6. The method for preparing a pharmaceutical intermediate according to claim 5, further comprising a step of recrystallizing after concentrating under reduced pressure, wherein the solvent for recrystallization is selected from 75% methanol, 75% acetonitrile, dichloromethane or isopropanol.
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