阅读说明：本技术 一种伊维菌素的制备方法 (Preparation method of ivermectin ) 是由 方丽 王雪峰 熊加赵 蒋东栋 叶玉平 梅家祺 于 2020-11-27 设计创作，主要内容包括：本发明公开了一种伊维菌素的制备方法,包括如下步骤：将阿维菌素和催化剂溶于有机溶剂中,混合均匀得到物料通入微通道反应器,在氢气气氛下,在90～130℃条件下,反应停留80s～130s,得到伊维菌素。本发明通过微通道反应制备伊维菌素,反应过程时间短,反应安全性高,无需经过柱层析后处理过程,得到的产物收率高、选择性好、纯度高,副产物3,4,22,23-四氢阿维菌含量低。(The invention discloses a preparation method of ivermectin, which comprises the following steps: dissolving abamectin and a catalyst in an organic solvent, uniformly mixing to obtain a material, introducing the material into a microchannel reactor, and reacting and staying for 80-130 s at 90-130 ℃ in a hydrogen atmosphere to obtain the ivermectin. The method for preparing the ivermectin by the microchannel reaction has the advantages of short reaction process time, high reaction safety, no need of post-treatment process of column chromatography, high yield, good selectivity and high purity of the obtained product, and low content of the byproduct 3,4,22, 23-tetrahydroabamectin.)

1. A preparation method of ivermectin is characterized by comprising the following steps: the method comprises the following steps:

dissolving the abamectin and the catalyst in an organic solvent, uniformly mixing to obtain a material, introducing the material into a microchannel reactor, and reacting in a hydrogen atmosphere to obtain the ivermectin.

2. The method of claim 1, wherein: the catalyst is RhCl (PPh)₃)₃。

3. The method of claim 1, wherein: the mass ratio of the abamectin to the catalyst is 100: 1.0-3.0, preferably 50: 1.

4. The method of claim 1, wherein: the reaction temperature is 90-130 ℃, and preferably 110-120 ℃; the reaction residence time is from 80s to 130s, preferably from 85s to 95 s.

5. The method of claim 1, wherein: the flow rate of the material is 25-45 mL/min, preferably 40 mL/min.

6. The method of claim 1, wherein: the inlet pressure of the reaction hydrogen is 7-11.5 bar, preferably 9 bar.

7. The method of claim 1, wherein: the organic solvent is preferably isopropanol, DCM or THF, and is preferably isopropanol; the adding amount of the organic solvent is 5-15ml/g, preferably 10-13ml/g based on the mass of the abamectin.

8. The method of claim 1, wherein: and introducing the material into a microchannel reactor, performing nitrogen replacement, heating to 90-140 ℃, and switching to a hydrogen atmosphere.

9. The method of claim 1, wherein: the microchannel reactor is formed by connecting 1 or a plurality of reaction modules in series, and is preferably a corning G1-Hybrid reactor.

10. The method of claim 1, wherein: the method also comprises a post-processing process:

(1) concentrating the reaction solution obtained after the reaction, and dissolving a concentrated crude product in 75% ethanol;

(2) adding sodium diethyldithiocarbamate trihydrate, stirring at room temperature, and filtering; the mass ratio of the crude product to sodium diethyldithiocarbamate trihydrate is 1: 0.02-0.5;

(3) the filtrate is subjected to the operation of the step (2);

(4) adding 75% ethanol and formamide into the obtained filtrate, and adding purified water at room temperature to separate out a solid;

(5) filtering, and drying a filter cake in vacuum to obtain the ivermectin.

Technical Field

The invention relates to a preparation method of ivermectin.

Background

Avermectins (Avermectins) is a group of high-effective insecticidal sixteen-membered ring macrolide antibiotics produced by fermentation of Streptomyces avermitilis, and its natural product contains eight components (A)_1a，A_1b，A_2a，A_2b，B_1a，B_1b，B_2a，B_2b) (Natural Product Reports,1986, pp.87-121.), in which the B1 component has the strongest insecticidal activity against almost all agricultural nematodes and arthropods, and is widely used in agricultural production.

Ivermectin (Ivermectin) is prepared by hydrogenation reduction of abamectin B1 serving as a raw material at a C22-C23 position, achieves the aim of expelling parasites by inhibiting gamma-aminobutyric acid (GABA) receptors so as to block nerve conduction, and can prevent and treat parasites which have drug resistance to common medicaments. Compared with abamectin, ivermectin has less dosage and 2-3 times lower toxicity than abamectin, and is widely used as an insecticide, a miticide and the like for human bodies, animals and plants at present, so that ivermectin is one of biological pesticides with great development potential.

At present, the process for preparing ivermectin mainly uses the avermectin in hydrocarbon-soluble Wilkinson catalyst triphenylphosphine rhodium chloride (RhCl (PPh)₃)₃) The ivermectin is generated by hydrogenation under the action of the (A), certain safety risk exists in the amplification production of hydrogenation reaction, and the reaction mainly generates by-product 3,4,22, 23-tetrahydroabamectin, the structure and the product similarity of the reaction are extremely high, so that the problems of difficult separation and purification of the product, complex post-treatment and the like are caused.

The existing separation and purification method mainly adopts multiple cooling crystallization to purify, for example, Chinese patent CN101362786B, the reaction solution after post-treatment is naturally cooled to 40 ℃ from 54-56 ℃, then is cooled to 25 ℃ in water bath, and then is cooled to 0-5 ℃ by using ice brine, and the total time is 18 hours; if necessary, the obtained crystals can be subjected to secondary crystallization by the method, which shows that the method has low purity, more crystallization times and long time consumption, and further leads to the reduction of the yield of the final product of the process and the increase of the cost. US4429042 also mentions isolation and purification of ivermectin by means of column chromatography, which is solvent consuming, time consuming, and results in complex process operations and increased costs.

Therefore, it is necessary to develop a process for preparing ivermectin with high safety and low impurity content.

Disclosure of Invention

In order to overcome the defects in the prior art, the invention provides a preparation method of ivermectin.

In order to achieve the purpose, the method adopts the following technical scheme:

a preparation method of ivermectin comprises the following steps:

dissolving abamectin and a catalyst in an organic solvent, uniformly mixing to obtain a material, introducing the material into a microchannel reactor, and reacting and staying for 80-130 s at 90-130 ℃ in a hydrogen atmosphere to obtain the ivermectin.

Further, the catalyst is RhCl (PPh)₃)₃。

Further, the mass ratio of the abamectin to the catalyst is 100: 1.0-3.0, preferably 50: 1.

Further, the flow rate of the material A is 25-45 mL/min, and preferably 40 mL/min.

Further, the reaction temperature is preferably 110-120 ℃.

Further, the inlet pressure of the reaction hydrogen is 7-11.5 bar, preferably 9 bar.

Further, the residence time is preferably 85 to 95 seconds.

Further, the organic solvent is preferably isopropanol, DCM, THF, further preferably isopropanol; the adding amount of the organic solvent is 5-15ml/g, preferably 10-13ml/g based on the mass of the abamectin.

And further, introducing the material A into a microchannel reactor, performing nitrogen replacement, heating to 90-130 ℃, and switching to a hydrogen atmosphere.

Furthermore, the microchannel reactor is formed by connecting 1 or a plurality of reaction modules in series, and preferably is a corning G1-Hybrid reactor (namely, a corning G1-Hybrid reactor)-G1-Hybrid reactor).

Further, the method of the invention also comprises a post-treatment process:

(1) concentrating the reaction solution obtained after the reaction, and dissolving a concentrated crude product in 75% ethanol;

(2) adding sodium diethyldithiocarbamate trihydrate, stirring at room temperature, and filtering; the mass ratio of the crude product to sodium diethyldithiocarbamate trihydrate is 1: 0.02-0.5;

(3) the filtrate is subjected to the operation of the step (2);

(4) adding 75% ethanol and formamide into the obtained filtrate, and adding purified water at room temperature to separate out a solid;

(5) filtering, and drying a filter cake in vacuum to obtain the ivermectin.

Furthermore, in the step (1), the adding amount of the ethanol is 2-4 times of the volume of the crude product.

Furthermore, in the step (4), the volume ratio of the filtrate to the 75% ethanol, the formamide and the purified water is 1:8-10:1-3: 10-30.

Furthermore, in the step (5), the drying temperature is 70 ℃, and the drying time is 18-24 hours.

Further, more specifically, the post-processing process of the present invention is:

(1) concentrating the reaction solution, and dissolving a concentrated crude product in 75% ethanol with the volume 2-4 times that of the reaction solution;

(2) adding sodium diethyldithiocarbamate trihydrate, stirring for 1 hour at room temperature, and filtering; the mass ratio of the crude product to sodium diethyldithiocarbamate trihydrate is 1: 0.02-0.5;

(3) the filtrate is subjected to the operation of the step (2);

(4) supplementing 75% ethanol into the obtained filtrate to 8-10 times of volume, adding formamide with the volume of 1-3 times of volume, dropwise adding purified water with the volume of 10-30 times of volume at room temperature, finishing dropping within 30 minutes, separating out solid, and stirring at room temperature for 1 hour;

(5) filtering, and vacuum drying the filter cake at 70 ℃ for about 18-24 hours to obtain the ivermectin.

Compared with the prior art, the invention has the beneficial effects that: the method for preparing the ivermectin by the microchannel reaction has the advantages of short reaction process time, high reaction safety, no need of post-treatment process of column chromatography, high yield, good selectivity and high purity of the obtained product, and low content of the byproduct 3,4,22, 23-tetrahydroabamectin.

Drawings

FIG. 1 is a schematic diagram of a microchannel reactor.

Detailed Description

The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto; the experimental method of the present invention, in which the specific conditions are not specified, is usually a conventional method or a method according to the conditions recommended by the manufacturers of the raw materials or the commercial products. The reagent of which the source is not indicated is usually a conventional reagent commercially available.

The microchannel reactor used in the examples was a corning G1-Hybrid reactor (i.e., a reactor with a high temperature range)G1-Hybrid reactor), as shown in FIG. 1.

The material is conveyed by a feed pump to a G1 reactor, H₂And the material A enters a T1 module area (1 st-9 th module, high-temperature reaction area) from the 1 st module to be fully mixed and reacted, and the reaction liquid flows out from a T2 module area (10 th reactor, low-temperature cooling area).

Example 1

Preparing materials: adding 150g of raw material abamectin and 3.0g of catalyst (accounting for 2% of the raw material abamectin) into 1950mL of isopropanol serving as a solvent, uniformly stirring to obtain a clear solution, and stably pumping the clear solution into a reaction channel for reaction at a set flow rate by a mechanical pump.

The microchannel reactor is firstly replaced by nitrogen, then the reaction temperature of a T1 zone is set to be 120 ℃, the cooling temperature of a T2 zone is set to be 20 ℃, the flow rate of a material A is 40mL/min, the hydrogen gas inlet pressure is 9bar, the reaction is carried out under the conditions that the reaction liquid stays for 85 seconds, a High Performance Liquid Chromatograph (HPLC) analyzes the reaction liquid, the result (area normalization method) is that the product is 90.70%, the raw material is 4.06%, the conversion rate is 95.94%, the selectivity is 94.54%, the content of key by-products (RRT is 1.3-1.5) is 2.37%, and is less than 2.5%, and the product conforms to the EP standard (the condition of HPLC, see the 'reaction liquid').

And (3) post-treatment: concentrating the reaction solution, dissolving the concentrated crude product in 75% ethanol with 2 times volume, adding sodium diethyldithiocarbamate trihydrate (0.02w/w), stirring at room temperature for 1 hour, and filtering with a filter membrane (less than 1 um); sodium diethyldithiocarbamate trihydrate (0.02w/w) was added to the filtrate again, stirred at room temperature for 1 hour, and filtered (<1 um); supplementing 75% ethanol into the filtrate to 8 times of the volume, adding formamide of 1 time of the volume, dropwise adding purified water of 20 times of the volume at room temperature, dropping for 30 minutes to separate out solids, and stirring for 1 hour at room temperature; filtering, and vacuum drying the filter cake at 70 ℃ for about 18 hours to obtain the product with the yield of 90.1 percent and the purity of 96.12 percent.

	Raw material/%)	Product/%)	Impurity/% (RRT ═ 1.3-1.5)
				Reaction solution	4.06	90.70	2.37
Finished product	0.25	96.12	2.03

Example 2

Preparing a material A: the solvent is 1030mL dichloromethane, 206g of raw material abamectin and 3.09g of catalyst (accounting for 1.5 percent of the mass of the raw material abamectin) are added, the mixture is uniformly stirred to obtain a clear solution, and the clear solution is stably pumped into a reaction channel by a mechanical pump at a set flow rate for reaction.

The microchannel reactor is subjected to nitrogen replacement, then the reaction temperature in a T1 area is set to be 120 ℃, the cooling temperature in a T2 area is set to be 20 ℃, the flow rate of a material A is 30mL/min, the hydrogen inlet pressure is 11.5bar, the reaction is carried out under the conditions that the reaction liquid stays for 130 seconds, and a High Performance Liquid Chromatograph (HPLC) analyzes the reaction liquid, so that the result (area normalization method) is 66.43% of a product, 27.52% of a raw material, the conversion rate is 72.48%, the selectivity is 91.66%, and the content of a key byproduct (RRT is 1.3-1.5) is 1.41%. The work-up was as in example 1, with a yield of 60.3%, a purity of 94.26% and a critical by-product content (RRT ═ 1.3 to 1.5) of 1.07%.

Example 3

Preparing a material A: the solvent is 515mL tetrahydrofuran, 103g of raw material abamectin and 1.55g of catalyst (accounting for 1.5 percent of the mass of the raw material abamectin) are added, the mixture is uniformly stirred to obtain a clear solution, and the clear solution is stably pumped into a reaction channel by a mechanical pump at a set flow rate for reaction.

The microchannel reactor is subjected to nitrogen replacement, then the reaction temperature in a T1 area is set to be 110 ℃, the cooling temperature in a T2 area is set to be 20 ℃, the flow rate of a material A is 40mL/min, the hydrogen inlet pressure is 10bar, the reaction is carried out under the conditions that the reaction liquid stays for 95 seconds, and a High Performance Liquid Chromatograph (HPLC) analyzes the reaction liquid, so that the result (area normalization method) is 65.47% of a product, 29.41% of a raw material, the conversion rate is 70.59%, the selectivity is 92.74%, and the content of a key byproduct (RRT is 1.3-1.5) is 1.39%. The work-up was as in example 1, 59.6% yield, 93.52% purity and a critical by-product content (RRT ═ 1.3-1.5) of 1.05%.

Example 4

Preparing a material A: adding 150g of raw material abamectin and 4.5g of catalyst (accounting for 3.0 percent of the mass of the raw material abamectin) into 1950mL of isopropanol serving as a solvent, uniformly stirring to obtain a clear solution, and stably pumping the clear solution into a reaction channel for reaction at a set flow rate by a mechanical pump.

The microchannel reactor is subjected to nitrogen replacement, then the reaction temperature in a T1 area is set to be 110 ℃, the cooling temperature in a T2 area is set to be 20 ℃, the flow rate of a material A is 45mL/min, the hydrogen gas inlet pressure is 9bar, the reaction is carried out under the conditions that the reaction liquid stays for 90 seconds, and a High Performance Liquid Chromatograph (HPLC) analyzes the reaction liquid, so that the result (area normalization method) is that the product is 73.50%, the raw material is 21.60%, the conversion rate is 78.40%, the selectivity is 93.75%, and the content of a key byproduct (RRT is 1.3-1.5) is 1.21%. The work-up was as in example 1, with a yield of 68.6%, a purity of 94.47% and a critical by-product content (RRT ═ 1.3 to 1.5) of 1.02%.

Examples 5,

Preparing a material A: the solvent is 1550mL of isopropanol, 155g of raw material abamectin and 3.1g of catalyst (accounting for 2% of the mass of the raw material abamectin) are added, the mixture is uniformly stirred to obtain a clear solution, and the clear solution is stably pumped into a reaction channel by a mechanical pump at a set flow rate to carry out reaction.

The microchannel reactor is subjected to nitrogen replacement, then the reaction temperature in a T1 area is set to be 110 ℃, the cooling temperature in a T2 area is set to be 20 ℃, the flow rate of a material A is 40mL/min, the hydrogen gas inlet pressure is 9bar, the reaction is carried out under the conditions that the reaction liquid stays for 95 seconds, and a High Performance Liquid Chromatograph (HPLC) analyzes the reaction liquid, so that the result (area normalization method) is 89.88% of a product, 5.25% of a raw material, the conversion rate is 94.75%, the selectivity is 94.86%, and the content of a key byproduct (RRT is 1.3-1.5) is 2.17%. The work-up was as in example 1, 85.2% yield, 97.11% purity and a critical by-product content (RRT ═ 1.3-1.5) of 1.35%.

Example 6

Preparing a material A: the solvent is 2250mL of isopropanol, 150g of raw material abamectin and 1.5g of catalyst (accounting for 1.0% of the mass of the raw material abamectin) are added, the mixture is uniformly stirred to obtain a clear solution, and the clear solution is stably pumped into a reaction channel for reaction at a set flow rate by a mechanical pump.

The microchannel reactor is subjected to nitrogen replacement, then the reaction temperature in a T1 area is set to be 90 ℃, the cooling temperature in a T2 area is set to be 20 ℃, the flow rate of a material A is 25mL/min, the hydrogen inlet pressure is 7bar, the reaction is carried out under the conditions that the reaction liquid stays for 95 seconds, a High Performance Liquid Chromatograph (HPLC) analyzes the reaction liquid, and the result (area normalization method) is that the product is 66.42%, the raw material is 27.50%, the conversion rate is 72.50%, the selectivity is 91.61%, and the content of key by-products (RRT is 1.3-1.5) is 1.41%. The workup was as in example 1, with a yield of 62.1%, a purity of 93.94% and a critical by-product content (RRT ═ 1.3 to 1.5) of 1.11%.

Example 7

Preparing a material A: the solvent is 1500mL of isopropanol, 150g of raw material abamectin and 3.0g of catalyst (accounting for 2.0% of the mass of the raw material abamectin) are added, the mixture is uniformly stirred to obtain a clear solution, and the clear solution is stably pumped into a reaction channel for reaction at a set flow rate by a mechanical pump.

The microchannel reactor is subjected to nitrogen replacement, then the reaction temperature in a T1 area is set to be 130 ℃, the cooling temperature in a T2 area is set to be 20 ℃, the flow rate of a material A is 40mL/min, the hydrogen gas inlet pressure is 9bar, the reaction is carried out under the conditions that the reaction liquid stays for 130 seconds, and a High Performance Liquid Chromatograph (HPLC) analyzes the reaction liquid, so that the result (area normalization method) is 88.58% of a product, 6.69% of a raw material, the conversion rate is 93.31%, the selectivity is 94.94%, and the content of a key byproduct (RRT is 1.3-1.5) is 2.05%. The work-up was as in example 1, with a yield of 83.5%, a purity of 96.91% and a critical by-product content (RRT ═ 1.3 to 1.5) of 1.52%.

Example 8

Preparing a material A: the solvent is 1000mL of toluene, 100g of raw material abamectin and 2g of catalyst (accounting for 2% of the raw material abamectin) are added, the mixture is uniformly stirred to obtain a clear solution, and the clear solution is stably pumped into a reaction channel for reaction at a set flow rate by a mechanical pump.

The microchannel reactor is subjected to nitrogen replacement, then the reaction temperature in a T1 area is set to be 110 ℃, the cooling temperature in a T2 area is set to be 20 ℃, the flow rate of a material A is 40mL/min, the hydrogen gas inlet pressure is 9bar, the reaction is carried out, the residence time of the reaction liquid is 95 seconds, and a High Performance Liquid Chromatograph (HPLC) analyzes the reaction liquid, so that the result (area normalization method) is that the product is 1.20%, the raw material is 89.08%, the conversion rate is 10.92%, the selectivity is 10.99%, and the content of key by-products (RRT is 1.3-1.5) is not detected. The conversion rate is low and no post-treatment is carried out.

Example 9

Preparing a material A: the solvent is 500mL of dichloromethane, 100g of raw material abamectin and 1.5g of catalyst (accounting for 1.5 percent of the mass of the raw material abamectin) are added, the mixture is uniformly stirred to obtain a clear solution, and the clear solution is stably pumped into a reaction channel by a mechanical pump at a set flow rate for reaction.

The microchannel reactor is subjected to nitrogen replacement, then the reaction temperature in a T1 area is set to be 80 ℃, the cooling temperature in a T2 area is set to be 20 ℃, the flow rate of a material A is 30mL/min, the hydrogen inlet pressure is 11.5bar, the reaction is carried out under the conditions that the reaction liquid stays for 130 seconds, a High Performance Liquid Chromatograph (HPLC) analyzes the reaction liquid, the result (area normalization method) is that the product is 9.99%, the raw material is 86.88%, the conversion rate is 13.12%, the selectivity is 76.14%, and the content of key by-products (RRT is 1.3-1.5) is not detected. And no post-treatment.

Example 10

Preparing a material A: the solvent is 1500mL of isopropanol, 100g of raw material abamectin and 1.0g of catalyst (accounting for 1% of the mass of the raw material abamectin) are added, the mixture is uniformly stirred to obtain a clear solution, and the clear solution is stably pumped into a reaction channel for reaction at a set flow rate by a mechanical pump.

The microchannel reactor is subjected to nitrogen replacement, then the reaction temperature of a T1 area is set to be 90 ℃, the cooling temperature of a T2 area is set to be 20 ℃, the flow rate of a material A is 25mL/min, the hydrogen inlet pressure is 7bar, the reaction is carried out under the conditions that the reaction liquid stays for 70 seconds, a High Performance Liquid Chromatograph (HPLC) analyzes the reaction liquid, and the result (area normalization method) is that the product is 41.22%, the raw material is 54.64%, the conversion rate is 45.36%, the selectivity is 90.87%, and the content of key by-products (RRT is 1.3-1.5) is 0.68%. And no post-treatment.

Example 11

Preparing a material A: the solvent is 500mL of dichloromethane, 100g of raw material abamectin and 1.5g of catalyst (accounting for 1.5 percent of the mass of the raw material abamectin) are added, the mixture is uniformly stirred to obtain a clear solution, and the clear solution is stably pumped into a reaction channel by a mechanical pump at a set flow rate for reaction.

The microchannel reactor is subjected to nitrogen replacement, then the reaction temperature in a T1 area is set to be 120 ℃, the cooling temperature in a T2 area is set to be 20 ℃, the flow rate of a material A is 20mL/min, the hydrogen inlet pressure is 11.5bar, the reaction is carried out under the conditions that the reaction liquid stays for 130 seconds, and a High Performance Liquid Chromatograph (HPLC) analyzes the reaction liquid, so that the result (area normalization method) is that the product is 50.55%, the raw material is 40.12%, the conversion rate is 59.88%, the selectivity is 84.42%, and the content of key by-products (RRT is 1.3-1.5) is 0.99%. And no post-treatment.

Example 12

Preparing a material A: the solvent is 1500mL of isopropanol, 100g of raw material abamectin and 1.0g of catalyst (accounting for 1.0% of the mass of the raw material abamectin) are added, the mixture is uniformly stirred to obtain a clear solution, and the clear solution is stably pumped into a reaction channel for reaction at a set flow rate by a mechanical pump.

The microchannel reactor is subjected to nitrogen replacement, then the reaction temperature in a T1 area is set to be 90 ℃, the cooling temperature in a T2 area is set to be 20 ℃, the flow rate of a material A is 25mL/min, the hydrogen inlet pressure is 6bar, the reaction is carried out under the conditions that the reaction liquid stays for 95 seconds, a High Performance Liquid Chromatograph (HPLC) analyzes the reaction liquid, and the result (area normalization method) is that the product is 34.62%, the raw material is 59.72%, the conversion rate is 40.28%, the selectivity is 85.95%, and the content of key by-products (RRT is 1.3-1.5) is 0.61%. And no post-treatment.

Example 13

Preparing a material A: the solvent is 1000mL of isopropanol, 100g of raw material abamectin and 0.65g of catalyst (accounting for 0.65% of the mass of the raw material abamectin) are added, the mixture is uniformly stirred to obtain a clear solution, and the clear solution is stably pumped into a reaction channel for reaction at a set flow rate by a mechanical pump.

The microchannel reactor is subjected to nitrogen replacement, then the reaction temperature in a T1 area is set to be 130 ℃, the cooling temperature in a T2 area is set to be 20 ℃, the flow rate of a material A is 40mL/min, the hydrogen gas inlet pressure is 9bar, the reaction is carried out under the conditions that the reaction liquid stays for 130 seconds, and a High Performance Liquid Chromatograph (HPLC) analyzes the reaction liquid, so that the results (area normalization method) are that the product is 6.05%, the raw material is 77.93%, the conversion rate is 22.07%, the selectivity is 27.41%, and the content of key byproducts (RRT is 1.3-1.5) is 0.31%. And no post-treatment.