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DESCRIPTION CN106336366

The technical problem to be solved by the present invention is to provide a method for synthesizing 4-(2-
aminoethyl)benzenesulfonamide, which comprises β-phenylethylamine as a raw material, through acetylation
reaction, chlorosulfonation reaction and ammoniation reaction. , hydrolysis reaction and purification to obtain 4
- (2 - aminoethyl) benzene sulfonamide finished product. The method of the invention has the advantages of
easy availability of raw materials, low cost, less chlorosulfonic acid used in the chlorosulfonation reaction, less
waste water, high product yield, reusable by-products, and convenient application. The product prepared by the
method of the invention can be used in the synthetic production of sulfonylurea hypoglycemic drugs glipizide,
glimepiride, gliclazone, glibenclamide and the like. The method of the invention adopts cheap chemical raw
materials, the reaction is simple and easy to operate, overcomes the problems of expensive raw materials at home
and abroad, difficulty in operating the reaction conditions, etc., reduces production cost and is easy to
industrialize.

Method for synthesizing 4-(2-aminoethyl)benzenesulfonamide

Technical field

The invention belongs to the technical field of preparation of sulfonylurea drug intermediates, and relates to a
hypoglycemic drug intermediate of type II diabetes, in particular to a method for synthesizing 4-(2-
aminoethyl)benzenesulfonamide.

Background technique

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Diabetes is a common and frequently-occurring disease, which can lead to heart disease, cerebrovascular disease,
gastric failure, blindness, and so on. It is the leading cause of death and disability, and it has not been cured so far.
Sulfonylurea hypoglycemic agents are currently the most effective and widely used class of oral hypoglycemic
agents. 4-(2-Aminoethyl)benzenesulfonamide, widely used in the treatment of type 2 diabetes drugs, such as
glipizide, glimepiride, gliclazone, glibenclamide, etc. In synthetic production, it is used to regulate the deficiency
of endogenous insulin in type 2 diabetic patients, which can achieve a reasonable index of blood glucose in more
than 70% of patients.

In order to maximize the profit of 4-(2-aminoethyl)benzenesulfonamide production, it is necessary to consider

not only the production cost, but also the post-treatment process, taking into account economic benefits, and
the social benefits are aimed at optimizing the interests of the social human body. Its comprehensive benefits are
optimized.

4 -(2-Aminoethyl)benzenesulfonamide is a key intermediate for a class of hypoglycemic drugs, and its synthesis
method has also been studied by many people at home and abroad. As a single product, it is also isolated as a by-
product. For example, as early as 1940, American scientists used n-acetanilide as a raw material to obtain 4-(2-
aminoethyl)benzenesulfonamide through a three-step reaction. The raw materials were rare and the yield was
low. 1979In the United States, a patent us4153710 separated 4-(2-aminoethyl)benzenesulfonamide as one of the
products, and the cost was high. 2012，The fifth phase of "Chemical Intermediates" Feng Chengjun, Xu Feifei 4-
(2-aminoethyl)benzenesulfonamide synthesis process, introduced the experimental preparation method, and the
chlorosulfonation reaction in the experiment, using "one pot" The main disadvantage of this method is that the
amount of chlorosulfonic acid is large, and the chlorosulfonic acid process is not recovered, resulting in low
utilization of chlorosulfonic acid in the production process. Excessive acid is extremely corrosive to equipment,
greatly reducing equipment life and shortening equipment. Use cycles to increase equipment investment costs. In
addition, the method of post-treatment water washing requires a large amount of water to be washed due to a
large excess of chlorosulfonic acid, thereby producing more waste acid. With the increasing environmental
problems, the importance of environmental protection is deepening under the common requirements at home
and abroad, especially the treatment of “three wastes” is the top priority of environmental protection.

Summary of the invention

The technical problem to be solved by the present invention is to provide a method for synthesizing 4-(2-
aminoethyl)benzenesulfonamide, which uses chlorinating agent instead of excess chlorosulfonic acid for
chlorosulfonation, and the amount of chlorosulfonic acid is small, and the production The cost is low, the waste
acid is reduced, the wastewater load is small, and the product yield is high.

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In order to solve the above technical problem, the technical solution of the present invention is:

A method for synthesizing 4-(2-aminoethyl)benzenesulfonamide, the specific steps are as follows:

Step 1) Acetylation:

Using β-phenethylamine and an acylating agent as raw materials, the acylating agent is acetic acid or acetic
anhydride, and the weight ratio of β-phenethylamine to acylating agent is 1:1~1:1.25, and the acylating agent is
put into the reaction vessel. Add β-phenylethylamine by stirring, mix well, then heat up, reflux and keep the
reaction for 3~5 hours, the reaction is finished, dilute acetic acid is distilled off, the normal pressure is in the early
stage, the decompression is carried out in the later stage, the dilute acetic acid is distilled off, the distillation is
finished, and the temperature is lowered. Obtaining acetylate, adding solvent, the weight ratio of β-
phenethylamine to solvent is 1:0.6~1:0.8, stirring and mixing to form a mixed solution for use;

Step 2) Chlorosulfonation reaction:

The weight ratio of acetylate to chlorosulfonic acid is 1:1.42~1:3.6, chlorosulfonic acid is added to the reaction
vessel, and the step 1) is stirred and added to obtain the mixed solution into chlorosulfonic acid, and the
dropping rate is controlled to control the reaction temperature at 50°. Below C, the temperature is raised to 50-
60 ° C, and then the reaction is carried out at 60-70 ° C for 2 to 4 hours. The reaction is added to the reaction
vessel to add a dry auxiliary agent and stirred for 5 to 30 minutes. Acetate and help The weight ratio of the agent is
1:0.033~1:0.19, the chlorinating agent is added to the reaction vessel or the mixture of the chlorinating agent and
the solvent is added dropwise, and the weight ratio of the acetylated compound and the chlorinating agent is
1:1.01 to 1:1.66, and the addition is completed. The temperature is maintained at 60~75 °C for 2~4 hours. After
the reaction is completed, the reaction liquid is cooled to be used;

Drop the reaction material into the ice water reaction vessel containing 0~5 °C, control the drop rate, and add
crushed ice to the reaction vessel in time to control the temperature not exceeding 20 °C, drip, stir 0.5~1 In the
hour, the crystallization is completed, the material is discharged, the filtration is filtered, the filtrate is recovered,
the solvent is treated, the solution is applied, the acid water is concentrated and recovered to prepare the
inorganic acid solution containing phosphorus, the filter cake is washed by centrifugation, washed with cold
water at 10 ° C for three times, and washed to Congo. The red test paper is not discolored, and the
chlorosulfonate wet product is obtained for use;

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Step 3) Amination reaction:

Adding solvent to the reaction vessel, the weight ratio of chlorosulfonate wet product to solvent is 1:0.5~1:1.2,
stirring the chlorosulfonate wet product obtained in step 2), stirring into a paste mixture, adding 20% by mass.
~27% ammonia water, the weight ratio of chlorosulfonate wet product to ammonia water is 1:2.0~1:3.0, the drip
acceleration is controlled so that the temperature is below 50 °C, and the reaction is stirred at a temperature of
22~28 °C. 6 hours, discharge filtration, centrifugation, filtrate recovery, solvent treatment, apply, filter cake
washed with cold water at 10 ° C three times, washed to near neutral or neutral, centrifuged dry to receive, to
obtain ammonia wet product for use ;

Step 4) Hydrolysis reaction:

Adding a mass percent concentration of 18~30% sodium hydroxide lye into the reaction vessel, the ammoniated
wet product is dried and the lye weight ratio is 1:2~1:4, and the ammoniated wet product obtained in step 3) is
stirred, Heating to 105~115 °C and refluxing for 3.5~6.0 hours, cooling to 80~90 °C, adding medicinal
activated carbon, keeping for 0.5~1 hour, the ratio of ammoniated wet product to medicinal activated carbon is
1:0.06 ~1:0.08, hot filtration or pressure filtration, the filtrate is pumped into another reaction vessel, after
filtration, the filtrate is stirred and cooled to 25~30 ° C and kept for 0.5 hour, and the mass concentration of 28-
31 is added to the filtrate. % hydrochloric acid, control the dropping rate so that the temperature is below 50 °
C, adjust the pH of the filtrate to 10 or close to 10, and the wet weight of the ammoniated product and the weight
ratio of hydrochloric acid are 1: 1.0~1:1.2, which has a large amount of white or Light yellow crystals
precipitated, stirred for 1 hour, cooled and crystallized. When the temperature is 10 °C, the material is
centrifuged, and the filter cake is washed three times with cold water of 5~10 °C, washed to near neutral or
neutral, and dried. Obtaining crude 4-(2-aminoethyl)benzenesulfonamide;

Step 5) Refining process:

Adding solvent to the reaction vessel, the crude 4-(2-aminoethyl)benzenesulfonamide is dried and the solvent
weight ratio is 1:2.5~1:5.5, and the step 4-) is stirred to obtain 4-(2-aminoethyl). The crude benzenesulfonamide
is dissolved by heating, and the medicinal activated carbon is added. The crude 4-(2-
aminoethyl)benzenesulfonamide is dried and the weight ratio of the medicinal activated carbon is 1:0.05~1:0.10,
stirring, heating and refluxing 0.5 ~1.0 hours, hot filtration or pressure filtration, the filtrate is pumped into
another reaction vessel, stirred and cooled, and cooled to 10 ° C, crystallization for 0.5 to 1 hour, a large
amount of white or light yellow crystals are precipitated, the discharge is centrifuged, and the filter cake It was
washed with a cold solvent and dried to obtain a 4-(2-aminoethyl)benzenesulfonamide product.

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The above method for synthesizing 4-(2-aminoethyl)benzenesulfonamide, step 1) in the acetylation reaction, the
solvent is dichloromethane, chloroform, carbon tetrachloride or dichloroethane.

The above method for synthesizing 4-(2-aminoethyl)benzenesulfonamide, step 2) in the chlorosulfonation

reaction, the auxiliary agent is sodium chloride or ammonium chloride, and the chlorinating agent is phosphorus
pentachloride and phosphorus oxychloride. Or the solvent in the sulfoxide, chlorinating agent and solvent
mixture is dichloromethane, chloroform, carbon tetrachloride or dichloroethane.

The above method for synthesizing 4-(2-aminoethyl)benzenesulfonamide, step 3) in the amination reaction, the
solvent is dichloromethane, chloroform, carbon tetrachloride or dichloroethane.

In the above method for synthesizing 4-(2-aminoethyl)benzenesulfonamide, in step 4), the centrifugal mother
liquor is recovered in the hydrolysis reaction, and the inorganic salt is concentrated and filtered, and then
crystallized to recover a part of the crude sulfonamide.

In the above method for synthesizing 4-(2-aminoethyl)benzenesulfonamide, in the step 5), the solvent is
methanol, ethanol, water or a mixture thereof.

The method for synthesizing 4-(2-aminoethyl)benzenesulfonamide of the invention comprises β-

phenylethylamine as a raw material, and is obtained by acetylation reaction, chlorosulfonation reaction,
amination reaction, hydrolysis reaction and refining to obtain 4-( 2-aminoethyl)benzenesulfonamide finished
product. The method of the invention has the advantages of easy availability of raw materials, low cost, less
chlorosulfonic acid used in the chlorosulfonation reaction, less waste water, high product yield, reusable by-
products, and convenient application. The product prepared by the method of the invention can be used in the
synthetic production of sulfonylurea hypoglycemic drugs glipizide, glimepiride, gliclazone, glibenclamide and
the like. The method of the invention adopts cheap chemical raw materials, the reaction is simple and easy to
operate, overcomes the problems of expensive raw materials at home and abroad, difficulty in operating the
reaction conditions, etc., reduces production cost and is easy to industrialize.

detailed description

Example 1:

09-08-2018 5
A method for synthesizing 4-(2-aminoethyl)benzenesulfonamide, the specific steps are as follows:

Step 1) Acetylation

Using β-phenylethylamine and acetic acid as raw materials, 300 kg of acetic acid was poured into a clean 1000 L
reaction kettle (with full reflux device), and 300 kg of β-phenylethylamine was added thereto with stirring, and
the temperature was raised and refluxed for 4 hours. The reaction was completed and distilled. Dilute acetic acid,
pre-pressure, late decompression, try to dilute acetic acid, cool, and collect acetylated (ie N-acetyl
phenethylamine) 390.5kg. 180 kg of the solvent was added to the reaction liquid, stirred and mixed until the
mixture was ready for use. The solvent was selected from chloroform, and the acetylated product (i.e., N-
acetylphenethylamine) was obtained in a weight yield of 130%. The solvent may be selected from
dichloromethane, chloroform, carbon tetrachloride or dichloroethane, preferably chloroform.

Step 2) Chlorosulfonation reaction:

554.5 kg of chlorosulfonic acid was put into a dry 1000 L reaction kettle, and a mixture of 390.5 kg of acetylated
compound (ie, N-acetylphenethylamine) and a solvent obtained in the step 1) was stirred and added to control
the dropping rate to keep the reaction temperature not exceeding. 50 ° C. After the dropwise addition, the
temperature is raised to 50-60 ° C, and the temperature is maintained at 60-70 ° C for 2.0 hours. During the
period, the tail gas can be absorbed to recover the hydrogen chloride system hydrochloric acid, and the reaction
is completed.

Add 12.89kg of dry auxiliary ammonium chloride, select ammonium chloride as auxiliary, add, stir for 30
minutes, add 495.9kg of chlorinating agent, and choose phosphorus pentachloride by chlorinating agent. Adding
a chlorinating agent to the reaction vessel, or using a dropping method, selecting a solvent and a mixture of
chlorinating agents, selecting a solvent for the chloroform, adding the temperature, controlling the temperature
to 60-70 ° C, maintaining the temperature for 3 hours, and cooling to 10 ° C. , the reaction liquid is obtained
for use. The auxiliary can be selected from ammonium chloride or sodium chloride. The chlorinating agent is
selected from phosphorus pentachloride, thionyl chloride or phosphorus oxychloride, preferably phosphorus
pentachloride. The solvent is a halogenated alkane, optionally dichloromethane, chloroform, carbon
tetrachloride or dichloroethane, preferably chloroform,

The reaction material was dropped into a 3000 L reaction kettle stirred with ice water to control the dropping rate
so that the temperature did not exceed 20 ° C. During the dropping process, the crushed ice pieces were

09-08-2018 6
replenished in time and dripped. Stir for 1 hour, draining and filtering, draining the filtrate, treating the solvent,
applying it, collecting the acid water to recover the water containing phosphoric acid, centrifuging the filter cake,
filtering it, and washing it with cold water at 10 ° C for three times, washing until Congo red test paper does not
change color. Up to now, 666 kg of chlorosulfonate (ie 4-[2-(acetylamino)ethyl]benzenesulfonyl chloride) wet
product was obtained, and the weight yield of chlorosulfonate wet product was 170%.

Step 3) Amination reaction:

332kg of solvent was pumped into the 3000L kettle, the solvent was selected to be chloroform, and the step 2) was
stirred and stirred to obtain 666 kg of chlorosulfonate (ie 4-[2-(acetylamino)ethyl]benzenesulfonyl chloride) wet
product, which was stirred into a paste. 1328kg of ammonia water is added dropwise, and the mass concentration
of ammonia water is 25%. When the ammonia water is added, the dropping rate is controlled, and the
temperature is not more than 50 ° C. After the dropwise addition, the reaction is stirred for 3 to 6 hours,
preferably 5 hours. The temperature is controlled at 25 ± 3 °C. After the reaction, the mixture was cooled to 10
° C, centrifuged, and filtered. The filtrate was recovered from the filtrate and applied after treatment. The filter
cake was washed three times with cold water at 10 ° C, and dried to obtain a white ammonia-based wet product
(ie (4-[2-(acetylamino)ethyl)benzenesulfonamide)) 480 kg, dried dry 400 kg, white-like The dry weight yield of
the amide was 60%. The solvent is selected from halogenated alkanes, optionally dichloromethane, chloroform,
carbon tetrachloride, dichloroethane, preferably chloroform.

Step 4) Hydrolysis reaction:

Put the mass percentage concentration into 20% sodium hydroxide lye 800kg, put it into the 1500L reaction
kettle, and dilute the ammonia product wet product, the weight and alkali liquid weight ratio is 1:2~1:4, stir, add
the ammoniat wet product 240kg (Dry dry product is 200kg), heat up to 105~115 °C, reflux, and reflux for 5
hours. After refluxing, reduce the temperature to 80~90 °C, add 16kg of medicinal activated carbon, stir and
keep for 0.5~1 hour, pressurize or filter by hot press, pump or pump into the other 2000L reactor, filter, filtrate
Stir, cool to 30 ° C, add 28-31% hydrochloric acid by weight, control the drop rate, so that the temperature
does not exceed 50 ° C, the weight ratio of ammonia wet product to hydrochloric acid is 1:1~1:1.2, Adjusting
PH=10 or close to 10, a large amount of white or light yellow crystals are precipitated, stirred for 1 hour, cooled
and crystallized, and the pH value is unchanged. Cool down to 10 ° C, centrifuge the centrifuge, filter, filter
cake with 10 ° C cold water, dry to obtain a crude 4- (2-aminoethyl) benzenesulfonamide wet weight 200kg
(dry 160 kg), The above-mentioned timing is refluxed for 3.5 to 6.0 hours, preferably for 5 hours.

Ammonia wet product (i.e., (4-[2-(acetylamino)ethyl)benzenesulfonamide)) 480 kg (dry dry product 400 kg),
hydrolyzed in two portions, one half hydrolysis at a time.

09-08-2018 7
Step 5) Refining process:

800 kg of solvent was put into a 1500 L reaction vessel, the solvent was selected to be water, stirred, and the crude
4-(2-aminoethyl)benzenesulfonamide wet weight was added to 200 kg (160 kg), heated to heat, dissolved, and
medicinal activated carbon 10 kg, 80 was added. The temperature was kept at ~90 ° C for 1 hour, hot filtered or
pressure filtered, and the filtrate was placed in another 1500 L reactor. After press filtration, the filtrate was stirred,
cooled and crystallized, and the temperature was kept at 10 ° C for 1 hour. The material was discharged,
centrifuged and filtered, and the filter cake was washed three times with 10 ° C cold water, and dried to obtain
4-(2-aminoethyl)benzenesulfonate. The wet weight of the amide product was 204kg, 170kg, and the finished
product yield of 4-(2-aminoethyl)benzenesulfonamide was 85%. The solvent may be selected from methanol,
ethanol, water or a mixture thereof. Preference is given to a mixture of ethanol and water (weight ratio of ethanol
to water = 1:3)

Example 2:

Step 1) Acetylation:

The acetic acid was changed to acetic anhydride in a ratio of β-phenethylamine: acetic anhydride = 1:1 (weight
ratio), and other conditions were the same as in Example 1. The reaction yield was 95% by weight.

Step 2) Chlorosulfonation reaction:

390.5kg of acetylate (N-acetyl phenethylamine), 936kg of chlorosulfonic acid, 390.5kg of chlorinating agent
(selective phosphorus pentachloride), other conditions as in Example 1, reaction, weight yield It is 130%.

Step 3) Amination reaction:

The mass percentage concentration was 25% ammonia water and the amount was 1660 kg. Other conditions
were the same as those in Example 1, and the weight yield was 55%.

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Step 4) Hydrolysis reaction:

The sodium hydroxide lye concentration was 25%, and other conditions were the same as in Example 1, and the
weight yield was 75%.

Step 5) Refining process:

The solvent was selected as a mixture of ethanol and water. The weight ratio of ethanol to water was 1:3. Other
conditions were the same as in Example 1, and the weight yield was 83%.

Example 3:

Step 1) Acetylation:

The reaction was carried out by selecting β-phenethylamine and acetic acid, but the solvent was carbon
tetrachloride, and other conditions were the same as in Example 1, and the weight yield was 128%.

Step 2) Chlorosulfonation reaction:

The reaction conditions were the same as in Example 1, and the solvent was selected to be carbon tetrachloride in
a weight yield of 150%.

Step 3) Amination reaction:

The reaction conditions were the same as in Example 1, and the solvent was selected to be carbon tetrachloride in
a weight yield of 55%.

Step 4) Hydrolysis reaction:

09-08-2018 9
The reaction conditions were the same as in Example 1, and the reaction weight yield was 80%.

Step 5) Refining process:

The purification conditions were the same as in Example 1, and the reaction weight yield was 85%.

Example 4:

Step 1) Acetylation:

The reaction conditions were the same as in Example 1.

Step 2) Chlorosulfonation reaction:

The reaction conditions were the same as in Example 1. The chlorinating agent was selected from thionyl
chloride, and the reaction weight yield was 120%.

Step 3) Amination reaction:

The reaction conditions were the same as in Example 1, and the reaction weight yield was 60%.

Step 4) Hydrolysis reaction:

The reaction conditions were the same as in Example 1, and the temperature was raised to 105 to 107 ° C by
heating, refluxed, and refluxed for 5 hours, and the reaction weight yield was 75%.

Step 5) Refining process:

09-08-2018 10
The purification conditions were the same as in Example 1, and the reaction weight yield was 85%.

Example 5:

Step 1) Acetylation:

β-Phenylethylamine: acetic acid = 1:1.25 (weight ratio), and other conditions were the same as in Example 1.
The reaction yield was 125% (weight yield).

Step 2) Chlorosulfonation reaction:

390.5kg of acetylate (N-acetyl phenethylamine), 554.5kg of chlorosulfonic acid, 648.2kg of chlorinating agent
(selective phosphorus pentachloride), other conditions are the same as in Example 1, the reaction is completed,
and the weight is collected. The rate is 120%.

Step 3) Amination reaction:

The chlorosulfonated wet product weighs 468.6kg, the ammonia water (25% by mass) dosage is 1405.8kg, and
the solvent (optional chloroform) dosage is 562.3kg. Other conditions are the same as in Example 1, the reaction
is complete, and the weight yield is 55. %.

Step 4) Hydrolysis reaction:

The reaction conditions were the same as those in Example 1. The weight ratio of the amide (dry) dry product to
the medicinal activated carbon was 1:0.06, and the reaction weight yield was 80%.

Step 5) Refining process:

Solvent was selected as a mixture of methanol and water (weight ratio 1:3), crude product (dry basis) and solvent
weight ratio = 1:5, and other conditions were the same as in Example 1, and the weight yield was 80%.

09-08-2018 11
Example 6

Step 1) Acetylation:

β-Phenylethylamine: acetic anhydride = 1:1.25 (weight ratio), and other conditions were the same as in
Example 1, and the weight yield was 120%.

Step 2) Chlorosulfonation reaction:

390.5kg of acetylate (N-acetylphenethylamine), 781kg of chlorosulfonic acid, 585.8kg of chlorinating agent

(selective phosphorus pentachloride), 12.89kg of sodium chloride for auxiliary agent, other conditions In the
same manner as in Example 1, the reaction was completed, and the weight yield was 150%.

Step 3) Amination reaction:

The amount of ammonia water (25% by mass) was 1463.38 kg, and the amount of solvent (option of
chloroform) was 585.75 kg. Other conditions were the same as those in Example 1, and the weight yield was 55%.

Step 4) Hydrolysis reaction:

The weight ratio of the ammoniated wet product (dried dry) and sodium hydroxide lye is 1:3, (mass percent
concentration) is 18% sodium hydroxide lye, and other conditions are the same as in Example 1, the reaction is
completed, and the weight yield is 70%.

Step 5) Refining process:

The crude product (dry basis) and the solvent weight ratio = 1:5, the solvent is selected as water, the crude
product (dried dry) dry product and the medicinal activated carbon weight ratio is 1:0.10, other conditions are

09-08-2018 12
the same as in the first embodiment, the reaction is completed, and the weight yield is 75%.

Example 7

Step 1) Acetylation:

β-Phenylethylamine: acetic acid = 1:1.25 (weight ratio), solvent (selected dichloroethane), β-phenethylamine
and solvent weight ratio was 1:0.8, and other conditions were the same as in Example 1. The reaction yield was
120% (weight yield).

Step 2) Chlorosulfonation reaction:

390.5kg of acetylate (N-acetyl phenethylamine), 1171.5kg of chlorosulfonic acid, 394.4kg of chlorinating agent
(selective phosphorus pentachloride), 39.05kg of sodium chloride for adjuvant, solvent (Selected
dichloroethane), other conditions were the same as in Example 1, and the weight yield was 150%.

Step 3) Amination reaction:

The amount of ammonia water (27% by mass) was 1640.1 kg, and the amount of solvent (selected
dichloroethane) was 468.6 kg. Other conditions were the same as in Example 1, and the weight yield was 55%.

Step 4) Hydrolysis reaction:

The weight ratio of the ammoniated wet product (dried dry) and sodium hydroxide lye is 1:3, (mass percent
concentration) is 30% sodium hydroxide lye, and other conditions are the same as in Example 1, the reaction is
completed, and the weight yield is 70%.

Step 5) Refining process:

The solvent was selected as a mixture of ethanol and water (weight ratio 1:3), crude product (dry basis) and

09-08-2018 13
solvent weight ratio = 1:5.5, and other conditions were the same as in Example 1, and the weight yield was 80%.

Example 8

Step 1) Acetylation:

Β-phenethylamine: acetic anhydride = 1:1.1 (weight ratio), solvent (selective dichloromethane), β-

phenethylamine and solvent weight ratio of 1:0.8, other conditions are the same as in Example 1, the weight yield
is 115%.

Step 2) Chlorosulfonation reaction:

390.5kg of acetylate (N-acetyl phenethylamine), 1405.8kg of chlorosulfonic acid, 394.4kg of chlorinating agent
(selected thionyl chloride), 74.2kg of ammonium chloride for auxiliary agent, solvent (Methylene chloride was
selected), and other conditions were the same as in Example 1, and the weight yield was 150%.

Step 3) Amination reaction:

The chlorosulfonated wet product weighs 585.75kg, the ammonia water (27% by mass) dosage is 1288.65kg, and
the solvent (selective dichloromethane) dosage is 585.75kg. Other conditions are the same as in Example 1, the
reaction is complete, and the weight yield is 55. %.

Step 4) Hydrolysis reaction:

The weight ratio of the ammoniated wet product (dried dry) and sodium hydroxide lye is 1:4, (mass percent
concentration) is 30% sodium hydroxide lye, other conditions are the same as in the first embodiment, the
reaction is completed, and the weight yield is 70%.

Step 5) Refining process:

09-08-2018 14
Ethanol was selected as solvent, and the crude product (dry basis) and solvent weight ratio = 1:5.5. Other
conditions were the same as in Example 1, and the weight yield was 75%.

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