CN101029017A - Production indapamide - Google Patents
Production indapamide Download PDFInfo
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- CN101029017A CN101029017A CN 200710067907 CN200710067907A CN101029017A CN 101029017 A CN101029017 A CN 101029017A CN 200710067907 CN200710067907 CN 200710067907 CN 200710067907 A CN200710067907 A CN 200710067907A CN 101029017 A CN101029017 A CN 101029017A
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- CN
- China
- Prior art keywords
- indapamide
- amino
- preparation
- sulfahydantoin
- chloro
- 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.)
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- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 title claims description 43
- 229960004569 indapamide Drugs 0.000 title claims description 43
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 106
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 84
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 53
- YELHZVMLYJGTFN-UHFFFAOYSA-N 2-methyl-2,3-dihydroindol-1-amine Chemical compound C1=CC=C2N(N)C(C)CC2=C1 YELHZVMLYJGTFN-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000006482 condensation reaction Methods 0.000 claims abstract description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 47
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 30
- 238000002360 preparation method Methods 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 19
- 239000012046 mixed solvent Substances 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- 238000000967 suction filtration Methods 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 239000000376 reactant Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000001514 detection method Methods 0.000 claims description 3
- 238000004042 decolorization Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 abstract 1
- 238000012805 post-processing Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 5
- RITRKULRSHGFQQ-UHFFFAOYSA-N 2-methyl-2,3-dihydroindol-1-amine;hydrochloride Chemical compound Cl.C1=CC=C2N(N)C(C)CC2=C1 RITRKULRSHGFQQ-UHFFFAOYSA-N 0.000 description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- VSPPONOIKZXUBJ-UHFFFAOYSA-N n,n-diethylethanamine;oxolane Chemical compound C1CCOC1.CCN(CC)CC VSPPONOIKZXUBJ-UHFFFAOYSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
A process for preparing indapamine includes such steps as dissolving 4-Cl-3- sulfamino formyl chloride and 1-amino-2-methyl-indoline in tetrahydrofuran, dripping triethylamine, condensation reaction, and post-processing. It has high output rate.
Description
(1) technical field
The present invention relates to a kind of preparation method of compound indapamide, belong to chemical industry and chemical field of medicaments.
(2) background technology
The indapamide chemical name is 4-chloro-3-sulfahydantoin-N-(2,3-dihydro-2-Methyl-1H-indole) benzamide, and its structural formula is as follows:
Indapamide is a kind of novel depressor with diuretic properties and calcium antagonism, also can act synergistically with other depressor.It is good that it has an antihypertensive effect, long action time, and side effect is little, but advantages such as life-time service.
Compound patent US3565911 discloses the synthetic method of indapamide, 1-amino-2-methyl indoline and triethylamine are dissolved in the tetrahydrofuran (THF), stir the tetrahydrofuran solution that slowly is added dropwise to 4-chloro-3-sulfahydantoin Benzoyl chloride down, be concentrated into dried then, the isopropanol crystallization obtains indapamide, yield 70%.US5110946 disclose directly form with 1-amino-2-methyl indoline hydrochloride or mesylate under the triethylamine effect with the preparation method of 4-chloro-3-sulfahydantoin Benzoyl chloride condensation: earlier 1-amino-2-methyl indoline hydrochloride or mesylate are dissolved in the tetrahydrofuran (THF), add triethylamine, slowly be added dropwise to the tetrahydrofuran solution of 4-chloro-3-sulfahydantoin Benzoyl chloride then, be concentrated into dried after reaction finishes, the Virahol recrystallization obtains indapamide, yield 80%, in this way, add triethylamine earlier, slowly be added dropwise to the such order of tetrahydrofuran solution of 4-chloro-3-sulfahydantoin Benzoyl chloride then, can not crystallization, adopt the method crystallization yield of isopropanol mixed solvent recrystallization also to be about 70%, repeatedly experimental result still is difficult to reappear the result of this patent report.More than two patent report method yields not high, the tetrahydrofuran (THF) liquid measure of 4-chloro-3-sulfahydantoin Benzoyl chloride is bigger in the production process, the dropping time is longer, thereby and the condensation reaction that self easily takes place under the triethylamine effect of 4-chloro-3-sulfahydantoin Benzoyl chloride cause 1-amino-2-methyl indoline to be difficult to react completely.
(3) summary of the invention
The objective of the invention is to disclose that a kind of side reaction is few, yield is high and the preparation method of manageable indapamide, thereby the yield that prior art exists is not high to solve, the tetrahydrofuran (THF) liquid measure condensation reaction big, that the dropping time is long, self easily takes place 4-chloro-3-sulfahydantoin Benzoyl chloride of 4-chloro-3-sulfahydantoin Benzoyl chloride causes problems such as 1-amino-2-methyl indoline is difficult to react completely in the production process under the triethylamine effect.
For realizing purpose of the present invention, design of the present invention is as follows:
Because when being added dropwise to 4-chloro-3-sulfahydantoin Benzoyl chloride in 1-amino-2-methyl indoline and the triethylamine tetrahydrofuran (THF) mixed solution, triethylamine concentration is higher in the solution.Under the triethylamine effect of higher concentration, the degree of 4-chloro-3-sulfahydantoin Benzoyl chloride generation self condensation reaction is bigger, causes 1-amino-methyl indoline to be difficult to react completely, and yield is not high.This civilization has adopted new preparation method, earlier 4-chloro-3-sulfahydantoin Benzoyl chloride is dissolved in the tetrahydrofuran (THF) with 1-amino-2-methyl indoline, be added dropwise to alkali then and carry out condensation, thereby greatly reduced the condensation reaction of 4-chloro-3-sulfahydantoin Benzoyl chloride self, thereby 1-amino-methyl indoline more thoroughly reacts completely, and dripping quantity is little, and is more easy to control.
Based on above design, the present invention proposes following technical scheme:
4-chloro-3-sulfahydantoin Benzoyl chloride and 1-amino-2-methyl indoline are dissolved in the tetrahydrofuran (THF), are added dropwise to triethylamine then, carry out condensation reaction, react completely, the reaction solution aftertreatment is promptly obtained indapamide.
Above-mentioned reactant feeds intake amount of substance than 1-amino-2-methyl indoline: 4-chloro-3-sulfahydantoin Benzoyl chloride: triethylamine is 1: 0.95～5: 1～3, and the volumetric usage of described tetrahydrofuran (THF) is 5～30 times of 1-amino-2-methyl indoline quality (ml/g).
Described setting-up point is 10～40 ℃, and the reaction times is 1～20 hour.
Preparation method of the present invention is: 4-chloro-3-sulfahydantoin Benzoyl chloride and 1-amino-2-methyl indoline are dissolved in the tetrahydrofuran (THF), be added dropwise to triethylamine then, after dropwising, control reaction temperature is 10～40 ℃ and carries out condensation reaction, stirred 1～20 hour, the reaction solution aftertreatment is promptly obtained indapamide.
Described aftertreatment is with reaction solution decolouring, filters, and filtrate is concentrated into dried, gets described indapamide with the isopropanol mixed solvent crystallization of arbitrary proportion.
Described setting-up point is preferably 15～20 ℃, and the reaction times is preferably 1～3 hour.
The composition volume ratio Virahol of described isopropanol mixed solvent: water is 3～5: 5, and the consumption of isopropanol mixed solvent is 3～12 times of described indapamide theoretical value (ml/g).
Particularly, the preparation method of indapamide of the present invention is as follows just: 4-chloro-3-sulfahydantoin Benzoyl chloride is dissolved in the tetrahydrofuran (THF) with 1-amino-2-methyl indoline, stir under the room temperature, be added dropwise to triethylamine then, after dropwising, continue to stir 1～20 hour at 10～40 ℃, use the activated carbon decolorizing of 1～20wt% of indapamide theoretical value then, suction filtration, filtrate is concentrated into dried, with the volume ratio of Virahol and water is for isopropanol mixed solvent crystallization promptly to obtain indapamide at 3～5: 5, the consumption of described isopropanol mixed solvent is 3～12 times of indapamide theoretical value (ml/g), described reactant feeds intake amount of substance than 1-amino-2-methyl indoline: 4-chloro-3-sulfahydantoin Benzoyl chloride: triethylamine is 1: 0.95～5: 1～3, and the volumetric usage of described tetrahydrofuran (THF) is 5～30 times of 1-amino-2-methyl indoline quality (ml/g).
Recommend described preparation method as follows just: 4-chloro-3-sulfahydantoin Benzoyl chloride is dissolved in the tetrahydrofuran (THF) with 1-amino-2-methyl indoline, stir about is 5～10 minutes under the room temperature, be added dropwise to triethylamine under the room temperature then, dropwising the back continues to stir 1～3 hour at 15～20 ℃, point plate detection reaction is complete, use the activated carbon decolorizing of the 8wt% of indapamide theoretical value then, suction filtration, filtrate is concentrated into dried, with the volume ratio of Virahol and water is that 3～5: 5 isopropanol mixed solvent crystallization promptly obtains indapamide, the consumption of described isopropanol mixed solvent is 6 times of indapamide theoretical value (ml/g), described reactant feeds intake amount of substance than 1-amino-2-methyl indoline: 4-chloro-3-sulfahydantoin Benzoyl chloride: triethylamine is 1: 0.95～1.5: 1.5～2.5, and the volumetric usage of described tetrahydrofuran (THF) is 18～26 times of 1-amino-2-methyl indoline quality (ml/g).
The addition sequence of described isopropanol mixed solvent is: add Virahol in decolorization, add entry after the decolouring again.
Compared with prior art, the invention has the advantages that: earlier 4-chloro-3-sulfahydantoin Benzoyl chloride and 1-amino-2-methyl indoline are dissolved in the tetrahydrofuran (THF), be added dropwise to triethylamine then, carry out condensation reaction, the variation that adds the reactive material order like this, make the preparation method of indapamide greatly reduce the condensation reaction of 4-chloro-3-sulfahydantoin Benzoyl chloride self, thereby 1-amino-methyl indoline more thoroughly reacts completely, thereby yield significantly improves, about 86%～92%, and dripping quantity is little, and is more easy to control, is a method that is adapted to suitability for industrialized production.
(4) embodiment
Below with specific embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited thereto:
Embodiment 1
Add 21.2g (0.115mol) 1-amino-2-methyl indoline hydrochloride and 550mL tetrahydrofuran (THF) in 1 liter of there-necked flask, be added dropwise to 12.0g (0.118mol) triethylamine under the magnetic agitation, room temperature.Dropwise, continue to stir 0.5 hour, then suction filtration.
Filtrate is changed in 1 liter of there-necked flask, and stirring adds 4-chloro-3-sulfahydantoin Benzoyl chloride 30.0g (0.118mol) next time, stirs then 5～10 minutes.Be added dropwise to 12.2g (0.120mol) triethylamine under the room temperature.Every interval sampling in 1 hour TLC detects, and until reacting completely, adds gac 3g, continues to stir suction filtration 45 minutes.
Filtrate is concentrated into dried, adds the 120ml Virahol, it is clear to add thermosol, add gac 4g, about 1.5h that refluxes, heat filtering, be chilled to about 35 ℃ slightly, be added dropwise to 120ml elutriation crystalline substance, dropwise, cooling, ice-water bath continues to stir suction filtration 1 hour down, 50 ℃ of vacuum-dryings, obtain off-white color indapamide solid 38.3g, yield 91.2%, HPLC purity 99.5%.
Embodiment 2
Add 21.2g (0.115mol) 1-amino-2-methyl indoline hydrochloride and 400mL tetrahydrofuran (THF) in 1 liter of there-necked flask, magnetic agitation is added dropwise to 12.0g (0.118mol) triethylamine under 10～15 ℃.Dropwise, continue to stir 0.5 hour, then suction filtration.
Filtrate is changed in 1 liter of there-necked flask, 4-chloro-3-sulfahydantoin Benzoyl chloride 30.0g (0.118mol) is dissolved in the 100mL tetrahydrofuran (THF), stir impouring next time, stirred then 5～10 minutes.Be added dropwise to the tetrahydrofuran (THF) mixed solution of 12.2g (0.120mol) triethylamine and 50mL under the room temperature.Dropwise and continue to stir, every interval sampling in 1 hour TLC detection until reacting completely, adds gac 3g, and 15～25 ℃ are continued down to stir to spend the night.
Filtrate is concentrated into dried, adds the 120ml Virahol, it is clear to add thermosol, add gac 4g, about 1.5h that refluxes, heat filtering, be chilled to about 35 ℃ slightly, be added dropwise to 120ml elutriation crystalline substance, dropwise, cooling, ice-water bath continues to stir suction filtration 1 hour down, 50 ℃ of vacuum-dryings, obtain off-white color indapamide solid 37.4g, yield 89.1%, HPLC purity 99.4%.
Claims (10)
1. the preparation method of an indapamide, it is characterized in that described method for 4-chloro-3-sulfahydantoin Benzoyl chloride and 1-amino-2-methyl indoline are dissolved in the tetrahydrofuran (THF), is added dropwise to triethylamine then, carry out condensation reaction, react completely, the reaction solution aftertreatment is promptly obtained indapamide.
2. the preparation method of indapamide as claimed in claim 1, it is characterized in that described reactant feeds intake amount of substance than 1-amino-2-methyl indoline: 4-chloro-3-sulfahydantoin Benzoyl chloride: triethylamine is 1: 0.95～5: 1～3, and the volumetric usage of described tetrahydrofuran (THF) is 5～30 times of 1-amino-2-methyl indoline quality (ml/g).
3. the preparation method of indapamide as claimed in claim 1 is characterized in that described setting-up point is 10～40 ℃, and the reaction times is 1～20 hour.
4. the preparation method of indapamide as claimed in claim 1, it is characterized in that described method is for to be dissolved in 4-chloro-3-sulfahydantoin Benzoyl chloride and 1-amino-2-methyl indoline in the tetrahydrofuran (THF), be added dropwise to triethylamine then, after dropwising, control reaction temperature is 10～40 ℃ and carries out condensation reaction, stirred 1～20 hour, the reaction solution aftertreatment is promptly obtained indapamide.
5. as the preparation method of the described indapamide of one of claim 1～4, it is characterized in that described aftertreatment for the reaction solution decolouring, filters, it is dried that filtrate is concentrated into, and gets described indapamide with the isopropanol mixed solvent crystallization of arbitrary proportion.
6. the preparation method of indapamide as claimed in claim 1 is characterized in that described setting-up point is 15～20 ℃, and the reaction times is 1～3 hour.
7. the preparation method of indapamide as claimed in claim 5, the composition volume ratio Virahol that it is characterized in that described isopropanol mixed solvent: water is 3～5: 5, and the consumption of isopropanol mixed solvent is 3～12 times of described indapamide theoretical value (ml/g).
8. the preparation method of indapamide as claimed in claim 1, it is characterized in that described preparation method as follows just: 4-chloro-3-sulfahydantoin Benzoyl chloride is dissolved in the tetrahydrofuran (THF) with 1-amino-2-methyl indoline, stir under the room temperature, be added dropwise to triethylamine then, after dropwising, continue to stir 1～20 hour at 10～40 ℃, use the activated carbon decolorizing of 1～20wt% of indapamide theoretical value then, suction filtration, filtrate is concentrated into dried, with the volume ratio of Virahol and water is that 3～5: 5 isopropanol mixed solvent crystallization promptly obtains indapamide, the consumption of described isopropanol mixed solvent is 3～12 times of indapamide theoretical value (ml/g), described reactant feeds intake amount of substance than 1-amino-2-methyl indoline: 4-chloro-3-sulfahydantoin Benzoyl chloride: triethylamine is 1: 0.95～5: 1～3, and the volumetric usage of described tetrahydrofuran (THF) is 5～30 times of 1-amino-2-methyl indoline quality (ml/g).
9. the preparation method of indapamide as claimed in claim 1, it is characterized in that described preparation method as follows just: 4-chloro-3-sulfahydantoin Benzoyl chloride is dissolved in the tetrahydrofuran (THF) with 1-amino-2-methyl indoline, stir about is 5～10 minutes under the room temperature, be added dropwise to triethylamine under the room temperature then, dropwising the back continues to stir 1～3 hour at 15～20 ℃, point plate detection reaction is complete, use the 8wt% activated carbon decolorizing of indapamide theoretical value then, suction filtration, filtrate is concentrated into dried, with the volume ratio of Virahol and water is that 3～5: 5 isopropanol mixed solvent crystallization promptly obtains indapamide, the consumption of described isopropanol mixed solvent is 6 times of indapamide theoretical value (ml/g), described reactant feeds intake amount of substance than 1-amino-2-methyl indoline: 4-chloro-3-sulfahydantoin Benzoyl chloride: triethylamine is 1: 0.95～1.5: 1.5～2.5, and the volumetric usage of described tetrahydrofuran (THF) is 18～26 times of 1-amino-2-methyl indoline quality (ml/g).
10. the preparation method of indapamide as claimed in claim 8 or 9 is characterized in that described isopropanol mixed solvent is to add Virahol in decolorization, adds entry again after the decolouring.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200710067907 CN101029017A (en) | 2007-03-31 | 2007-03-31 | Production indapamide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200710067907 CN101029017A (en) | 2007-03-31 | 2007-03-31 | Production indapamide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101029017A true CN101029017A (en) | 2007-09-05 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200710067907 Pending CN101029017A (en) | 2007-03-31 | 2007-03-31 | Production indapamide |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101717359B (en) * | 2009-07-15 | 2012-09-05 | 北京成宇药业有限公司 | Method for synthesizing indapamide |
| CN101756927B (en) * | 2008-12-23 | 2013-04-10 | 北京科信必成医药科技发展有限公司 | Indapamide sustained release tablet and preparation method thereof |
| CN103467355A (en) * | 2013-09-12 | 2013-12-25 | 迪沙药业集团有限公司 | Preparation method of indapamide |
| CN105418479A (en) * | 2015-11-18 | 2016-03-23 | 天津市亨必达化学合成物有限公司 | Indapamide synthetic method |
| CN108558729A (en) * | 2018-05-21 | 2018-09-21 | 日照市普达医药科技有限公司 | A kind of hypotensive compound and its pharmaceutical composition and application |
| CN112142643A (en) * | 2020-10-10 | 2020-12-29 | 天津和治药业集团有限公司 | Synthetic method of indapamide |
-
2007
- 2007-03-31 CN CN 200710067907 patent/CN101029017A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101756927B (en) * | 2008-12-23 | 2013-04-10 | 北京科信必成医药科技发展有限公司 | Indapamide sustained release tablet and preparation method thereof |
| CN101717359B (en) * | 2009-07-15 | 2012-09-05 | 北京成宇药业有限公司 | Method for synthesizing indapamide |
| CN103467355A (en) * | 2013-09-12 | 2013-12-25 | 迪沙药业集团有限公司 | Preparation method of indapamide |
| CN105418479A (en) * | 2015-11-18 | 2016-03-23 | 天津市亨必达化学合成物有限公司 | Indapamide synthetic method |
| CN108558729A (en) * | 2018-05-21 | 2018-09-21 | 日照市普达医药科技有限公司 | A kind of hypotensive compound and its pharmaceutical composition and application |
| CN112142643A (en) * | 2020-10-10 | 2020-12-29 | 天津和治药业集团有限公司 | Synthetic method of indapamide |
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