CN110627694B - Method for recovering 3-ethoxy-4-methoxy-alpha- [ (methylsulfonyl) methyl ] -benzylamine - Google Patents
Method for recovering 3-ethoxy-4-methoxy-alpha- [ (methylsulfonyl) methyl ] -benzylamine Download PDFInfo
- Publication number
- CN110627694B CN110627694B CN201910991024.0A CN201910991024A CN110627694B CN 110627694 B CN110627694 B CN 110627694B CN 201910991024 A CN201910991024 A CN 201910991024A CN 110627694 B CN110627694 B CN 110627694B
- Authority
- CN
- China
- Prior art keywords
- compound
- methylsulfonyl
- ethoxy
- reaction
- methoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/16—Preparation of optical isomers
- C07C231/18—Preparation of optical isomers by stereospecific synthesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention relates to a method for recovering 3-ethoxy-4-methoxy-alpha- [ (methylsulfonyl) methyl ] -benzylamine, belonging to the technical field of chemical synthesis. The technical scheme of the invention is as follows: firstly, dissociating a byproduct compound I of the product to recover a compound III, carrying out deamination reaction on an intermediate II to generate an intermediate IV, and then carrying out addition reaction on the intermediate IV to generate a compound V. The invention has the beneficial effects that: (1) the synthetic method successfully recycles the split byproducts, prevents solid wastes from being generated and reduces environmental pollution; (2) the synthetic method successfully recycles the split byproducts, reduces the production cost from original 1504 yuan/kg to yuan 1002.67/kg, and can continuously reduce the cost after continuous production.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for recovering 3-ethoxy-4-methoxy-alpha- [ (methylsulfonyl) methyl ] -benzylamine.
Background
(S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine-N-acetyl-L-leucine salt is an important intermediate for the synthesis of apremilast. Synthesis of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine-N-acetyl-L-leucine salt was obtained mainly by resolution of 3-ethoxy-4-methoxy- α - [ (methylsulfonyl) methyl ] -benzylamine. The compound with the other configuration left after the resolution loses the use value and cannot be recycled, so that the waste of resources is caused, and the production cost is increased.
Disclosure of Invention
Aiming at the problem that the compound with another configuration of 3-ethoxy-4-methoxy-alpha- [ (methylsulfonyl) methyl ] -benzylamine cannot be utilized in the prior art, the invention provides a method for recovering 3-ethoxy-4-methoxy-alpha- [ (methylsulfonyl) methyl ] -benzylamine, so as to solve the problem.
The synthetic route of the invention is as follows:
the technical scheme of the invention is as follows: dissociating the compound I to recover a compound III, deaminating the intermediate II to generate an intermediate IV, and performing addition reaction on the intermediate IV to generate a compound V. Wherein compound I is (R) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine-N-acetyl-L-leucine salt, compound II is (R) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine, compound III is N-acetyl-L-leucine, compound IV is (E) -2-ethoxy-1-methoxy-4- (2- (methylsulfonyl) vinyl) benzene, and compound V is 3-ethoxy-4-methoxy- α - [ (methylsulfonyl) methyl ] -benzylamine.
The source of the starting compound I used in the present invention is: adding N-acetyl-L-leucine into 3-ethoxy-4-methoxy-alpha- [ (methylsulfonyl) methyl ] -benzylamine for chemical resolution to obtain (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine-N-acetyl-L-leucine salt, wherein the byproduct is the compound I used in the invention: (R) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine-N-acetyl-L-leucine salt. The compound I used in the invention is a byproduct generated in experiment or/and production.
The specific synthetic steps of the invention are as follows:
(1) synthesis of Compound II and Compound III
Weighing the compound I according to the weight of the compound I, adding 5-7 g/g of purified water and 0.09-0.1 g/g of sodium hydroxide, controlling the reaction temperature to be 40-80 ℃, preserving the heat for 1-3 hours, cooling to 10-30 ℃, and filtering to obtain a filter cake and a filtrate A. The filter cake is a wet product of the compound II for standby;
and (3) adding hydrochloric acid into the filtrate A to adjust the pH value to be 1-4, stirring for 1h at 20-30 ℃, and performing suction filtration to obtain a wet product of the compound III. Rinsing wet product of the compound III with water, and combining the rinsing liquid into the filtrate A; and drying the wet product of the compound III to obtain the compound III, namely the N-acetyl-L-leucine.
(2) Synthesis of Compound IV
And (2) adding sodium bicarbonate solid into the filtrate A obtained in the step (1) under stirring to adjust the pH of the reaction solution to be 5-9, adding the wet product of the compound II prepared in the step (1), controlling the reaction temperature to be 60-100 ℃, keeping the temperature, stirring, reacting for 10-50 h, cooling to 20-30 ℃ after the reaction is finished, crystallizing for 1-2 h, performing suction filtration, rinsing the filter cake with water, and drying to obtain a compound IV.
(3) Synthesis of Compound V
Weighing the compound IV by weight, adding 0.1-0.15 g/g triethylamine and 7-7.5 g/g ammonia water, uniformly stirring, introducing ammonia gas, heating to 40-60 ℃, controlling the pressure to be 0.3-0.8 MPa, carrying out heat preservation stirring reaction for 30-50 h, after the reaction is completed, balancing the pressure of a reaction system to normal pressure, cooling the reaction liquid to 10-30 ℃, stirring for crystallization for 1-2 h, carrying out suction filtration, and drying to obtain the compound V.
Preferably, in the step (1), the amount of the sodium hydroxide is 0.095 g/g.
Preferably, in the step (1), the pH value of the reaction solution is 2-3.
Preferably, in the step (2), the pH value of the reaction solution is 7-8.
Preferably, in the step (2), the reaction temperature is 90-100 ℃.
Preferably, in the step (2), the reaction is carried out for 30-40 h under the condition of heat preservation and stirring.
Preferably, in the step (3), the amount of triethylamine is 0.125 g/g.
Preferably, in the step (3), the amount of the ammonia water is 7.3 g/g.
Preferably, in the step (3), the reaction is carried out for 40 hours under the condition of heat preservation and stirring.
The invention has the beneficial effects that:
(1) the synthetic method successfully recycles the split byproducts, prevents solid wastes from being generated and reduces environmental pollution.
(2) The synthetic method successfully recycles the split byproducts, reduces the production cost from original 1504 yuan/kg to yuan 1002.67/kg, and can continuously reduce the cost after continuous production.
Drawings
In order to more clearly illustrate the embodiments or technical solutions in the prior art of the present invention, the drawings used in the description of the embodiments or prior art will be briefly described below, and it is obvious for those skilled in the art that other drawings can be obtained based on these drawings without creative efforts.
FIG. 1 is a HPLC chromatogram of the recovered compound III of example 1;
FIG. 2 is a chiral detection spectrum of the recovered compound III of example 1;
FIG. 3 is a HPLC chromatogram of the recovered compound V of example 1;
FIG. 4 is a HPLC chromatogram of the recovered compound III of example 2;
FIG. 5 is a chiral detection spectrum of the recovered compound III of example 2;
FIG. 6 is a HPLC chromatogram of recovered compound V of example 2.
Detailed Description
In order to make those skilled in the art better understand the technical solution of the present invention, the technical solution in the embodiment of the present invention will be clearly and completely described below with reference to the drawings in the embodiment of the present invention, and it is obvious that the described embodiment is only a part of the embodiment of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
(1) Synthesis of Compound II and Compound III
Weighing 100g of the compound I based on the weight of the compound I, adding 600g of purified water and 9.5g of sodium hydroxide, heating to 40-80 ℃, keeping the temperature for 2 hours, cooling to 10-30 ℃, and filtering to obtain a filter cake and a filtrate. The filter cake is a wet product of the compound II for standby;
and (3) adding hydrochloric acid into the filtrate to adjust the pH value to be 2-3, stirring for 1h at the temperature of 20-30 ℃, and performing suction filtration to obtain a wet product of the compound III. And (3) rinsing the wet product of the compound III with water, combining the rinsing liquid with the filtrate, and drying the wet product of the compound III to obtain 32.5g of the compound III, wherein the yield is as follows: 83.8 percent.
(2) Synthesis of Compound IV
Adding sodium bicarbonate solid into the filtrate obtained in the step (1) under stirring, adjusting the pH value of a reaction solution to be 7-8, adding a wet product of the compound II prepared in the step (1), heating to 90-100 ℃, keeping the temperature, stirring, reacting for 40 hours, cooling to 20-30 ℃ after the reaction is finished, crystallizing for 1.5 hours, performing suction filtration, leaching a filter cake with water, and drying to obtain 54.3g of a compound IV, wherein the yield is as follows: 94.6 percent.
(3) Synthesis of Compound V
Weighing 50.0g of compound IV by weight, adding 6.3g of triethylamine and 364g of ammonia water, uniformly stirring, introducing ammonia gas, heating to 40-60 ℃, controlling the pressure to be 0.3-0.8 MPa, carrying out heat preservation reaction for 40h, after the reaction is completed, balancing the pressure of a reaction system to normal pressure, cooling the reaction liquid to 10-30 ℃, stirring for crystallization for 1.5h, carrying out suction filtration, and drying to obtain 49.1g of compound V, yield: 92.1 percent.
The HPLC assay results for compound III recovered in example 1 are shown in table 1 below:
peak number | Retention time (min) | Peak height | Area of | Purity% |
1 | 3.752 | 34029 | 148016 | 1.2610 |
2 | 4.611 | 2030287 | 11590120 | 98.7390 |
Total of | —— | 2064316 | 11738136 | 100 |
The results of chiral detection of compound III recovered in example 1 are shown in table 2 below:
peak number | Retention time (min) | Peak height | Area of | Purity% |
1 | 6.693 | 10766 | 146879 | 0.5714 |
2 | 8.042 | 1700742 | 25559177 | 99.4286 |
Total of | —— | 1711508 | 25706056 | 100 |
The purity requirement of industrial N-acetyl-L-leucine (compound III) sold on the market at present is more than or equal to 98.0%, and the ee value is more than or equal to 99.0%, and the detection results in the tables 1 and 2 show that the purity and the ee value of the N-acetyl-L-leucine recovered by the method meet the requirements, and the method can be applied to secondary production.
The HPLC assay results of compound V recovered in example 1 are shown in table 3 below:
peak number | Retention time (min) | Peak area | Peak height | Purity% |
1 | 4.147 | 3823.02637 | 914.15051 | 92.7690 |
2 | 5.634 | 21.66365 | 4.90536 | 0.5257 |
3 | 6.564 | 33.03494 | 7.60004 | 0.8016 |
4 | 7.197 | 152.22496 | 20.50563 | 3.6938 |
5 | 7.383 | 91.06840 | 17.64030 | 2.2099 |
Total of | —— | 4121.01832 | 964.80184 | 100 |
As can be seen from the test results in Table 3, the purity of the compound V recovered by the invention is not less than 90%, the compound V can be recycled, and qualified subsequent products can be produced.
Example 2
(1) Synthesis of Compound II and Compound III
Weighing 500kg of the compound I by weight, adding 3000kg of purified water and 47.5kg of sodium hydroxide, heating to 40-80 ℃, keeping the temperature for 2 hours, cooling to 10-30 ℃, and filtering to obtain a filter cake and a filtrate. The filter cake is a wet product of the compound II for standby;
and (3) adding hydrochloric acid into the filtrate to adjust the pH value to be 2-3, stirring for 1h at the temperature of 20-30 ℃, and performing suction filtration to obtain a wet compound. And (3) rinsing wet compounds with water, combining the rinsing liquid with the filtrate, and drying the wet compounds to obtain 150kg of compounds III, wherein the yield is as follows: 77.4 percent.
(2) Synthesis of Compound IV
Adding sodium bicarbonate solid into the filtrate obtained in the step (1) under stirring, adjusting the pH value of a reaction solution to be 7-8, adding a wet product of the compound II prepared in the step (1), heating to 90-100 ℃, keeping the temperature, stirring, reacting for 40 hours, cooling to 20-30 ℃ after the reaction is finished, crystallizing for 1.5 hours, performing suction filtration, leaching a filter cake with water, and drying to obtain 281kg of a compound IV, wherein the yield is as follows: 97.9 percent.
(3) Synthesis of Compound V
Weighing 75kg of compound IV by weight, adding 9.3kg of triethylamine and 546kg of ammonia water, uniformly stirring, introducing ammonia gas, heating to 40-60 ℃, controlling the pressure to be 0.3-0.8 MPa, keeping the temperature for reaction for 40h, after the reaction is completed, balancing the pressure of a reaction system to normal pressure, cooling the reaction liquid to 10-30 ℃, stirring for crystallization for 1.5h, performing suction filtration, and drying to obtain 72kg of compound V, yield: 90.0 percent.
The HPLC assay results for compound III recovered in example 2 are shown in table 4 below:
peak number | Retention time (min) | Peak height | Area of | Purity% |
1 | 4.577 | 4008378 | 24655608 | 100.0000 |
Total of | —— | 4008378 | 24655608 | 100.0000 |
The results of chiral detection of compound III recovered in example 2 are shown in table 5 below:
peak number | Retention time (min) | Peak height | Area of | Purity% |
1 | 6.644 | 28217 | 360419 | 0.63 |
2 | 7.833 | 3216795 | 57097132 | 99.37 |
Total of | —— | 3245012 | 57457551 | 100.00 |
The HPLC assay results of compound V recovered in example 2 are shown in table 6 below:
peak number | Retention time (min) | Peak area | Peak height | Purity% |
1 | 3.674 | 215848181 | 30435179 | 92.1029 |
2 | 5.038 | 483424 | 104978 | 0.2063 |
3 | 5.955 | 1452021 | 289410 | 0.6196 |
4 | 6.499 | 12433370 | 2346056 | 5.3053 |
5 | 6.712 | 4138411 | 916183 | 1.7659 |
Total of | —— | 234355407 | 34091806 | 100.0000 |
As can be seen from the test results in tables 4, 5 and 6, after the production scale is enlarged to 500 kg/batch, the purity of the recovered N-acetyl-L-leucine and the compound V are both in accordance with the requirements, and the yield is in accordance with the experimental results of the bench test, and the preparation process of the invention is stable.
Although the present invention has been described in detail by referring to the drawings in connection with the preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made on the embodiments of the present invention by those skilled in the art without departing from the spirit and scope of the present invention, and these modifications or substitutions are within the scope of the present invention/any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (9)
1. A method for recovering 3-ethoxy-4-methoxy-alpha- [ (methylsulfonyl) methyl ] -benzylamine is characterized in that a byproduct compound I of a product is dissociated to recover a compound III, an intermediate II is subjected to deamination reaction to generate an intermediate IV, and the intermediate IV is subjected to addition reaction to generate a compound V; wherein compound I is (R) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine-N-acetyl-L-leucine salt, compound II is (R) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine, compound III is N-acetyl-L-leucine, compound IV is (E) -2-ethoxy-1-methoxy-4- (2- (methylsulfonyl) vinyl) benzene, compound V is 3-ethoxy-4-methoxy- α - [ (methylsulfonyl) methyl ] -benzylamine; the specific synthesis steps are as follows:
(1) synthesis of Compound II and Compound III
Weighing the compound I according to the weight of the compound I, adding 5-7 g/g of purified water and 0.09-0.1 g/g of sodium hydroxide, controlling the reaction temperature to be 40-80 ℃, preserving the heat for 1-3 hours, cooling to 10-30 ℃, and filtering to obtain a filter cake and a filtrate A; the filter cake is a wet product of the compound II for standby;
adding hydrochloric acid into the filtrate A to adjust the pH to be 1-4, stirring for 1h at 20-30 ℃, and performing suction filtration to obtain a wet product of a compound III; rinsing wet product of the compound III with water, merging the washing liquid into the filtrate A, and drying the wet product of the compound III to obtain the compound III, namely N-acetyl-L-leucine;
(2) synthesis of Compound IV
Adding sodium bicarbonate solid into the filtrate A obtained in the step (1) to adjust the pH of the reaction solution to be 5-9 under stirring, adding the wet product of the compound II prepared in the step (1), controlling the reaction temperature to be 60-100 ℃, keeping the temperature, stirring and reacting for 10-50 h, cooling to 20-30 ℃ after the reaction is finished, crystallizing for 1-2 h, performing suction filtration, rinsing the filter cake with water, and drying to obtain a compound IV;
(3) synthesis of Compound V
Weighing the compound IV by weight, adding 0.1-0.15 g/g triethylamine and 7-7.5 g/g ammonia water, uniformly stirring, introducing ammonia gas, heating to 40-60 ℃, controlling the pressure to be 0.3-0.8 MPa, carrying out heat preservation stirring reaction for 30-50 h, after the reaction is completed, balancing the pressure of a reaction system to normal pressure, cooling the reaction liquid to 10-30 ℃, stirring for crystallization for 1-2 h, carrying out suction filtration, and drying to obtain the compound V.
2. The process for recovering 3-ethoxy-4-methoxy- α - [ (methylsulfonyl) methyl ] -benzylamine according to claim 1, wherein in step (1), sodium hydroxide is used in an amount of 0.095 g/g.
3. The method for recovering 3-ethoxy-4-methoxy- α - [ (methylsulfonyl) methyl ] -benzylamine according to claim 1, wherein in step (1), hydrochloric acid is added to filtrate a to adjust pH = 2-3.
4. The method according to claim 1, wherein in the step (2), sodium bicarbonate solid is added to the filtrate A obtained in the step (1) to adjust the pH of the reaction solution to be = 7-8.
5. The method for recovering 3-ethoxy-4-methoxy- α - [ (methylsulfonyl) methyl ] -benzylamine according to claim 1, wherein the reaction temperature in step (2) is 90-100 ℃.
6. The method for recovering 3-ethoxy-4-methoxy-alpha- [ (methylsulfonyl) methyl ] -benzylamine according to claim 1, wherein in step (2), the reaction is performed with stirring at a constant temperature for 30-40 h.
7. The process for recovering 3-ethoxy-4-methoxy- α - [ (methylsulfonyl) methyl ] -benzylamine according to claim 1, wherein triethylamine is used in an amount of 0.125g/g in step (3).
8. The process for recovering 3-ethoxy-4-methoxy- α - [ (methylsulfonyl) methyl ] -benzylamine according to claim 1, wherein in step (3), the amount of ammonia used is 7.3 g/g.
9. The method for recovering 3-ethoxy-4-methoxy- α - [ (methylsulfonyl) methyl ] -benzylamine according to claim 1, wherein in step (3), the reaction is performed with stirring at constant temperature for 40 h.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910991024.0A CN110627694B (en) | 2019-10-18 | 2019-10-18 | Method for recovering 3-ethoxy-4-methoxy-alpha- [ (methylsulfonyl) methyl ] -benzylamine |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910991024.0A CN110627694B (en) | 2019-10-18 | 2019-10-18 | Method for recovering 3-ethoxy-4-methoxy-alpha- [ (methylsulfonyl) methyl ] -benzylamine |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110627694A CN110627694A (en) | 2019-12-31 |
CN110627694B true CN110627694B (en) | 2021-06-15 |
Family
ID=68976688
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910991024.0A Active CN110627694B (en) | 2019-10-18 | 2019-10-18 | Method for recovering 3-ethoxy-4-methoxy-alpha- [ (methylsulfonyl) methyl ] -benzylamine |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110627694B (en) |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2818336C (en) * | 2010-11-16 | 2018-04-24 | Texas Heart Institute | Agonists that enhance binding of integrin-expressing cells to integrin receptors |
MX2017016054A (en) * | 2015-06-09 | 2018-04-11 | Dr Reddys Laboratories Ltd | Process for preparation of apremilast and its intermediates. |
AU2018228541B2 (en) * | 2017-02-28 | 2020-07-16 | Kangpu Biopharmaceuticals, Ltd. | Novel isoindoline derivative, and pharmaceutical composition and application thereof |
-
2019
- 2019-10-18 CN CN201910991024.0A patent/CN110627694B/en active Active
Also Published As
Publication number | Publication date |
---|---|
CN110627694A (en) | 2019-12-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105646372B (en) | preparation method of 2-amino-4, 6-dichloro-5-formamido pyrimidine | |
CN109336831B (en) | Method for recovering triazine ring from triazine ring wastewater | |
CN113402494A (en) | Method for improving yield of chlorinated ethylene carbonate | |
CN104140420A (en) | Synthesis process of thiothiamine | |
CN110627694B (en) | Method for recovering 3-ethoxy-4-methoxy-alpha- [ (methylsulfonyl) methyl ] -benzylamine | |
CN104119243B (en) | A kind of energy-saving clean production method of iminodiethanoic acid | |
CN112979561B (en) | Post-treatment method for synthesizing 4, 6-dihydroxypyrimidine | |
CN112321729A (en) | Preparation method of hydroxypropyl methyl cellulose | |
CN108395381B (en) | Synthesis method of 1, 4-diamino anthraquinone leuco body | |
US4840749A (en) | Process for production of 1-aminoanthraquinone | |
CN111039794A (en) | Preparation method of high-purity dibenzylamine | |
CN106397347A (en) | Method for producing irganox 565 | |
CN107963986B (en) | Method for co-producing high-purity schofield salt and G salt | |
CN113527255A (en) | Method for synthesizing chlorantraniliprole intermediate | |
CN112898225A (en) | Synthesis method of 1, 2-benzisothiazolin-3-ketone | |
CN101130639A (en) | Novel technique for synthesizing solvent yellow 163 | |
CN110655513A (en) | Synthetic method of flumioxazin | |
CN111303045A (en) | Production process of 2-ethoxy-4, 6-difluoropyrimidine | |
CN110655531A (en) | Synthetic method of triisooctyl phosphate | |
CN109912430B (en) | Method for synthesizing chloro-p-phenylenediamine | |
CN109734645B (en) | Synthetic process of isatin | |
CN103483283A (en) | Synthesis method for antioxidant 1790 | |
CN113248355B (en) | Preparation method of p-chlorobenzaldehyde | |
CN106631956A (en) | Preparation method of N-substituent-3-hydroxytetrahydropyrrole | |
CN110437073B (en) | Comprehensive development and separation method of chloronitrobenzene meta-oil |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |