WO2006003672A1 - Process for the preparation of pure amlodipine - Google Patents
Process for the preparation of pure amlodipine Download PDFInfo
- Publication number
- WO2006003672A1 WO2006003672A1 PCT/IN2004/000195 IN2004000195W WO2006003672A1 WO 2006003672 A1 WO2006003672 A1 WO 2006003672A1 IN 2004000195 W IN2004000195 W IN 2004000195W WO 2006003672 A1 WO2006003672 A1 WO 2006003672A1
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- WO
- WIPO (PCT)
- Prior art keywords
- amlodipine
- phthalimido
- solvent
- methyl
- preparation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Definitions
- the present invention relates to an improved process for the preparation of Amlodipine and its pharmaceutically acceptable salts via the effective purification of phthalimido Amlodipine.
- Amlodipine an active pharmaceutical ingredient, useful for treating cardiovascular diseases such as stenocardia, hypertension and congestive cardioplegic.
- cardiovascular diseases such as stenocardia, hypertension and congestive cardioplegic.
- Particularly useful forms of Amlodipine salts in human medicine are maleate and benzenesulfonate (besylate).
- European patent No 89,167 discloses the preparation of phthalimido Amlodipine and its conversion to Amlodipine, its different pharmaceutically acceptable salts.
- Amlodipine maleate salt was disclosed as being preferred salt than other pharmaceutically acceptable acid addition salts.
- European Patent No 244,944 discloses that the benzenesulphonate (besylate) salt of Amlodipine is the most preferred salt being its good formulation properties and also disclosed the process for the preparation of Amlodipine besylate by the reaction of Amlodipine base with benzene sulphonic acid in methanol.
- European Patent No. 089,167 discloses the preparation of phthalimido
- Amlodipine by the reaction of ethyl-4-[2-(phthalimido) ethoxy] acetoacetate with 2- chlorobenzaldehyde and methyl -3-amino crotonate in iso-propanol at reflux temperature for about 21 hrs followed by evaporation of iso-propanol, treating the residue with acetic acid overnight at room temperature affords the phthalimido Amlodipine which upon reaction with methyl amine in ethanol followed by removal of solvent affords Amlodipine which is directly converted to maleate salt in methanol. The purity of the obtained maleate salt and the Amlodipine was not disclosed.
- PCT Publication No WO 02/53535 discloses the preparation of phthalimido Amlodipine by reaction of 4-[2-(phthalimido) ethoxy] acetoacetate with 2-chloro benzaldehyde in iso-propanol at temperature 35 0 C - 40 0 C in presence of piperidine as catalyst followed by acidification with acetic acid, cooling to O 0 C - 5 0 C, separation of the organic layer, evaporation of solvent and isolation of the intermediate ethyl-2-(2- chlorobenzylidene)-4-[2-(phthalimido)ethoxy] acetoacetate which upon reaction with methyl 3-aminocrotonate in iso-propanol followed by removal of solvent and treating with acetic acid overnight affords the phthalimido Amlodipine: Phthalimido Amlodipine prepared as above is reacted with aqueous methylamine followed by extraction with an organic solvent. Separation of organic layer followed by e
- the main object of the present invention is to provide a process for the purification of phthalimido Amlodipine and its use for the preparation of Amlodipine and its pharmaceutically acceptable salts.
- Another object of the invention is to provide a process for the preparation of
- the precipitated and isolated Amlodipine base is identified by its characteristic X-ray diffraction pattern; IR spectrum, melting range and confirmed as polymorphic Form-I.
- the Phthalimido Amlodipine used as starting material is prepared as follows.
- 4-[2-(phthalimido) ethoxy] acetoacetate is reacted with 2-chloro benzaldehyde and molar excess equivalents of methyl 3-aminocrotonate, preferably 1.5 mole equivalents to 3.0 mole equivalents wrt to 4-[2-(phthalimido) ethoxy] acetoacetate in iso-propanol at temperature at 70 0 C to about 83 0 C for about 12 hrs to 24 hrs. After the completion of reaction, iso-propanol is distilled off under vacuum. The obtained residue is treated with acetic acid at room temperature for about 16 to 24 hrs crystallizes the crude phthalimido Amlodipine.
- Phthalimido Amlodipine thus obtained is purified by dissolving it in 1 to 6 volumes and more preferably 1 to 3 volumes of the solvent(s), preferably chlorinated hydrocarbons like methylene chloride, ethylene chloride, chloroform and tetrachloroethane, followed by removal of insoluble matter if any.
- the solvent(s) preferably chlorinated hydrocarbons like methylene chloride, ethylene chloride, chloroform and tetrachloroethane, followed by removal of insoluble matter if any.
- second solvent(s) preferably a hydrocarbon like n-hexane, n-heptane, methyl cyclohexane, cyclohexane and n-pentane to the clear solution in lot wise over a period of 1 to 6hrs.
- reaction mass for about 30 min to 3 hrs at temperature about 30 0 C to about 50 0 C 5 cooling and mixing the reaction mass to low temperature preferably to about 10 0 C to about 30 0 C for about lhr to about 5 hrs. Isolation and drying of the crystallized pure phthalimido Amlodipine.
- the invention can be further illustrated by a few non-limiting examples.
- Stage - 1 Preparation of Phthalimido amlodipine: 2-chlorobenzaldehyde (27 g) and methyl 3-amino crotonate (64.8 g) are added to the suspension of 4-[2-(Phthalimido) ethoxy] acetoacetate (60 g) in iso-propanol (300 ml). Temperature of the reaction mass is raised and maintained for 21 hrs at reflux temperature. Distilled off the solvent under vacuum at temperature below 75 0 C. Washed the residue with n-Hexane and again removed the low volatiles under vacuum to get residue. Acetic acid (300 ml) is added to the residue, mixed for 22 hrs at room temperature.
- Phthaliimido amlodipine is filtered and washed the wet cake with acetic acid and n- Hexane.
- the wet cake is again mixed with methanol (150 ml) at room temperature for about 30 min, filtered and dried at 55 0 C - 60 0 C till constant weight.
- Dry wt of the phthalimido Amlodipine crude is 26 g (Yield: 31.7%).
- Phthalimido amlodipine (25 g) prepared as above in stage- 1 is dissolved in MDC (50 ml) at 30 0 C - 35 0 C. Filtered the insoluble matter.
- n-Hexane (50 ml) is ' added to the filtrate slowly over lhr at 30 0 C - 35 0 C and mixed for another 2hrs. Again n-Hexane (50 ml) is added over 1 hr at 30 0 C - 35 0 C and maintained for another 2hrs at 20 0 C - 25 0 C.
- the precipitated product is filtered, washed the wet cake with n-Hexane and dried at 60 0 C - 65 0 C.
- Phthalimido amlodipine 50 g prepared as above is suspended in ethanolic methylamine (600 ml) and maintained for 17 hrs at 28 0 C - 32 0 C.
- the reaction mass is slowly poured into hot water (1200 ml) held at 50 0 C - 55 0 C over 45 min and mixed for about 1 hr at 50 0 C - 55 0 C.
- Reaction mass is slowly cooled and maintained for about 1 hr at 20 0 C - 25 0 C.
- the precipitated solid is filtered, washed the wet cake with water. Dried the product at 55 0 C - 60 0 C till constant weight.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The present invention relates to an improved process for the preparation of pure Amlodipine via the effective purification of phthalimido Amlodipine (3-ethyl-5-methyl -2-[(2-phthalimido ethoxy) methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-dicarboxylate).
Description
Process for the preparation of pure Amlodipine
The present invention relates to an improved process for the preparation of Amlodipine and its pharmaceutically acceptable salts via the effective purification of phthalimido Amlodipine.
3-Ethyl 5-methyl 2-[(2-phthalimidoethoxy) methyl] -4-(2-chloroρhenyl)- 1,4- dihydro-6-methyl-3,5-pyridine dicarboxylate (herein after called as phthalimido Amlodipine) has the following structure
3
Phthalimido Amlodipine
is an intermediate for the preparation of Amlodipine, an active pharmaceutical ingredient, useful for treating cardiovascular diseases such as stenocardia, hypertension and congestive cardioplegic. Particularly useful forms of Amlodipine salts in human medicine are maleate and benzenesulfonate (besylate).
European patent No 89,167 (equivalent US patent No 4,572,909) discloses the preparation of phthalimido Amlodipine and its conversion to Amlodipine, its different pharmaceutically acceptable salts. In particular, Amlodipine maleate salt was disclosed as being preferred salt than other pharmaceutically acceptable acid addition salts. European Patent No 244,944 (Equivalent US patent No 4,879,303) discloses that the
benzenesulphonate (besylate) salt of Amlodipine is the most preferred salt being its good formulation properties and also disclosed the process for the preparation of Amlodipine besylate by the reaction of Amlodipine base with benzene sulphonic acid in methanol.
European Patent No. 089,167 discloses the preparation of phthalimido
Amlodipine by the reaction of ethyl-4-[2-(phthalimido) ethoxy] acetoacetate with 2- chlorobenzaldehyde and methyl -3-amino crotonate in iso-propanol at reflux temperature for about 21 hrs followed by evaporation of iso-propanol, treating the residue with acetic acid overnight at room temperature affords the phthalimido Amlodipine which upon reaction with methyl amine in ethanol followed by removal of solvent affords Amlodipine which is directly converted to maleate salt in methanol. The purity of the obtained maleate salt and the Amlodipine was not disclosed.
PCT Publication No WO 02/53535 discloses the preparation of phthalimido Amlodipine by reaction of 4-[2-(phthalimido) ethoxy] acetoacetate with 2-chloro benzaldehyde in iso-propanol at temperature 350C - 400C in presence of piperidine as catalyst followed by acidification with acetic acid, cooling to O0C - 50C, separation of the organic layer, evaporation of solvent and isolation of the intermediate ethyl-2-(2- chlorobenzylidene)-4-[2-(phthalimido)ethoxy] acetoacetate which upon reaction with methyl 3-aminocrotonate in iso-propanol followed by removal of solvent and treating with acetic acid overnight affords the phthalimido Amlodipine: Phthalimido Amlodipine prepared as above is reacted with aqueous methylamine followed by extraction with an organic solvent. Separation of organic layer followed by evaporation until the precipitation occurs. The precipitated solid dissolved in ethanol and converted to pharmaceutically acceptable salts by reaction with suitable acids (Maleic acid).
The prior art methods for preparation of phthalimido Amlodipine suffers from the drawbacks of either with low purity or the use of extensive work-up, proceeds in two stages which requires the more processing time, usage of number of solvents. Further its conversion to Amlodipine employs the extraction with organic solvent, evaporation till
precipitation and then dissolving into a suitable alcohol then conversion to Amlodipine salts. In this method the obtained Amlodipine base or its salts may not be with good enough purity. To get the pure Amlodipine base or its salts, it requires the further purification, which results lengthy process, loss in the yield thereby increasing the production cost.
In view of the above problems still there is a requirement to get a pure phthalimido Amlodipine and its use for the preparation of Amlodipine, and its pharmaceutically acceptable salts with high purity.
The main object of the present invention is to provide a process for the purification of phthalimido Amlodipine and its use for the preparation of Amlodipine and its pharmaceutically acceptable salts.
Another object of the invention is to provide a process for the preparation of
Amlodipine and its pharmaceutically acceptable salts with high purity.
Thus according to the present invention 4-[2-(phthalimido) ethoxy] acetoacetate is reacted with 2-chlorobenzaldehyde, methyl 3-aminocrotonate in iso-propanol at reflux temperature followed by removal of solvent and treating with acetic acid at room temperature for overnight affords the phthalimido Amlodipine, and it is purified by dissolving in halogenated hydrocarbons, removal of insolubles, gradual addition of aliphatic hydrocarbons precipitates the phthalimido Amlodipine with sufficient purity which upon reaction with methylamine in ethanol followed by quenching into hot water affords the pure, crystalline Amlodipine which can be optionally converted into its pharmaceutically acceptable salts with high purity i.e. all individual impurities below 0.1%.
Synthetic scheme: STAGE - I:
sopropyl alcohol OH3 - Γ l ό ■ cHcoocn, >
Phthalimido ethoxyethyl 2-chlorobenzaldehyde Methyl-3 -amino 2-(2-phthalimido ethoxy) methyl]-(2-chloroρhenyl) acetoacetate Crotonate -3-ethoxy carbonyl-5-methoxy carbonyl-6-methyl
1,4-dihydro pyridine. (Phthalimido Amlodipine)
STAGE - II:
Phthalimido Amlodipine Phthalimido Amlodipine (pure)
STAGE - III:
The essential features of the present invention consists of:
- Dissolving phthalimido Amlodipine in organic solvent(s), Removing insoluble matter if any - Slowly adding second solvent(s) to the clear solution
Mixing the reaction mass for some time Further slow addition of second solvent(s)
- Mixing the reaction mass at selective temperature for some more time to complete the crystallization of the phthalimido Amlodipine - Isolating and drying the pure Phthalimido Amlodipine
- Reacting phthalimido Amlodipine with methyl amine in ethanol
- Precipitating and Isolating Amlodipine base by quenching the reaction mass in hot water at selective temperature
Isolating and drying the Amlodipine base - Optionally converting the Amlodipine base thus obtained into its pharmaceutically acceptable salts
The precipitated and isolated Amlodipine base is identified by its characteristic X-ray diffraction pattern; IR spectrum, melting range and confirmed as polymorphic Form-I.
The Phthalimido Amlodipine used as starting material is prepared as follows.
4-[2-(phthalimido) ethoxy] acetoacetate is reacted with 2-chloro benzaldehyde and molar excess equivalents of methyl 3-aminocrotonate, preferably 1.5 mole equivalents to 3.0 mole equivalents wrt to 4-[2-(phthalimido) ethoxy] acetoacetate in iso-propanol at temperature at 700C to about 830C for about 12 hrs to 24 hrs. After the completion of reaction, iso-propanol is distilled off under vacuum. The obtained residue is treated with acetic acid at room temperature for about 16 to 24 hrs crystallizes the crude phthalimido Amlodipine.
Phthalimido Amlodipine thus obtained is purified by dissolving it in 1 to 6 volumes and more preferably 1 to 3 volumes of the solvent(s), preferably chlorinated hydrocarbons like methylene chloride, ethylene chloride, chloroform and tetrachloroethane, followed by removal of insoluble matter if any. To the clear filtrate slow addition of 1 to 20 volumes of second solvent(s) preferably a hydrocarbon like n-hexane, n-heptane, methyl cyclohexane, cyclohexane and n-pentane to the clear solution in lot wise over a period of 1 to 6hrs. Mixing the reaction mass for about 30 min to 3 hrs at temperature about 300C to about 500C5 cooling and mixing the reaction mass to low temperature preferably to about 100C to about 300C for about lhr to about 5 hrs. Isolation and drying of the crystallized pure phthalimido Amlodipine.
The Phthalimido Amlodipine upon reaction with methylamine in ethanol at reflux temperature followed by slow transferring of the reaction mass into water at selective temperature preferably at about 450C to about 650C precipitates the Amlodipine base which can be converted into its pharmaceutically acceptable salts by conventional methods in pure form.
The invention can be further illustrated by a few non-limiting examples.
EXAMPLE
Stage - 1: Preparation of Phthalimido amlodipine: 2-chlorobenzaldehyde (27 g) and methyl 3-amino crotonate (64.8 g) are added to the suspension of 4-[2-(Phthalimido) ethoxy] acetoacetate (60 g) in iso-propanol (300 ml). Temperature of the reaction mass is raised and maintained for 21 hrs at reflux temperature. Distilled off the solvent under vacuum at temperature below 750C. Washed the residue with n-Hexane and again removed the low volatiles under vacuum to get residue. Acetic acid (300 ml) is added to the residue, mixed for 22 hrs at room temperature. Crystallized Phthaliimido amlodipine is filtered and washed the wet cake with acetic acid and n- Hexane. The wet cake is again mixed with methanol (150 ml) at room temperature for about 30 min, filtered and dried at 550C - 600C till constant weight.
Dry wt of the phthalimido Amlodipine crude is 26 g (Yield: 31.7%).
Stage - 2: Purification of Phthalimido amlodipine:
Phthalimido amlodipine (25 g) prepared as above in stage- 1 is dissolved in MDC (50 ml) at 300C - 350C. Filtered the insoluble matter. n-Hexane (50 ml) is' added to the filtrate slowly over lhr at 300C - 350C and mixed for another 2hrs. Again n-Hexane (50 ml) is added over 1 hr at 300C - 350C and maintained for another 2hrs at 200C - 250C. The precipitated product is filtered, washed the wet cake with n-Hexane and dried at 600C - 650C.
Dry wt of the pure Phthalimido amlodipine is 21.7 g (Yield: 87%).
Stage -3: Preparation of Amlodipine from Phthalimido amlodipine:
Pure Phthalimido amlodipine (50 g) prepared as above is suspended in ethanolic methylamine (600 ml) and maintained for 17 hrs at 280C - 320C. The reaction mass is slowly poured into hot water (1200 ml) held at 500C - 550C over 45 min and mixed for about 1 hr at 500C - 550C. Reaction mass is slowly cooled and maintained for about 1 hr at 200C - 250C. The precipitated solid is filtered, washed the wet cake with water. Dried the product at 550C - 600C till constant weight.
Dry weight of the Amlodipine base is 33.0 g (Yield: 87.2%)
XRD and IR of this product is matched with the standard data available for the Amlodipine
Form- 1.
Claims
1. An improved process for the preparation of Amlodipine comprising steps:
- Dissolving phthalimido Amlodipine in an organic solvent(s),
- Removing the insolubles if any by filtration
- Slowly adding the second solvent(s) to the clear filtrate
- Mixing the reaction mass for 30min to 3hrs - Further adding the second solvent(s) slowly
- Mixing the reaction mass at selective temperature for some more time to complete the crystallization of the phthalimido Amlodipine
- Isolating and drying of the pure phthalimido Amlodipine Reacting phthalimido Amlodipine with methyl amine in ethanol - Precipitating and isolating Amlodipine base by quenching the reaction mass in hot water at temperature
- Isolating and drying the Amlodipine base
2. A process as claimed in claim 1, wherein the organic solvent is selected from methylene chloride, ethylene chloride, chloroform and tetrachloroethane
3. A process as claimed in claim 1, wherein the organic solvent(s) volume is about 1 volume to 6 volumes with respect to phthalimido Amlodipine
4. A process as claimed in claim 1, wherein the second solvent is n-Hexane, n-Heptane, cyclohexane and methyl cyclohexane
5. A process as claimed in claim 1, wherein the addition of second solvent is slowly over a period of 1 to 6 hrs
6. A process as claimed in claims 1 and 6 wherein the volume of second solvent is 1 volume to 12 volumes with respect to phthalimido Amlodipine
7. A process as claimed in claim 1, wherein the hot water temperature is 45 0/ C-. i toΛ 6 z5eO, C
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2004/000195 WO2006003672A1 (en) | 2004-07-02 | 2004-07-02 | Process for the preparation of pure amlodipine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2004/000195 WO2006003672A1 (en) | 2004-07-02 | 2004-07-02 | Process for the preparation of pure amlodipine |
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| Publication Number | Publication Date |
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| WO2006003672A1 true WO2006003672A1 (en) | 2006-01-12 |
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| PCT/IN2004/000195 WO2006003672A1 (en) | 2004-07-02 | 2004-07-02 | Process for the preparation of pure amlodipine |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007096724A1 (en) * | 2006-02-21 | 2007-08-30 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of amlodipine besylate |
| US7671208B2 (en) | 2007-03-30 | 2010-03-02 | Esteve Quimica, S.A. | Acetone solvate of phthaloyl amlodipine |
| CN101367759B (en) * | 2008-10-06 | 2011-03-16 | 北京赛科药业有限责任公司 | Synthesis of high-purity amlodipine besylate |
| US7979778B2 (en) | 2004-09-25 | 2011-07-12 | Aware, Inc. | CRC counter normalization |
| WO2011117876A1 (en) | 2010-03-26 | 2011-09-29 | Fdc Limited | An improved process for the preparation of amlodipine free base and acid addition salts thereof |
| CN111948306A (en) * | 2020-07-27 | 2020-11-17 | 北京百奥药业有限责任公司 | Method for determining genotoxic impurities in amlodipine besylate |
| CN113024446A (en) * | 2021-03-15 | 2021-06-25 | 福建海西新药创制有限公司 | Method for preparing amlodipine besylate intermediate by using micro-reaction device |
| CN115536577A (en) * | 2022-11-09 | 2022-12-30 | 浙江昂利康制药股份有限公司 | Preparation method of amlodipine alkali |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0089167A2 (en) * | 1982-03-11 | 1983-09-21 | Pfizer Limited | Dihydropyridine anti-ischaemic and antihypertensive agents, processes for their production, and pharmaceutical compositions containing them |
| US20020143046A1 (en) * | 2000-12-29 | 2002-10-03 | Peters Theodorus H. A. | Process for making amlodipine, derivatives therof, and precursors therefor |
-
2004
- 2004-07-02 WO PCT/IN2004/000195 patent/WO2006003672A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0089167A2 (en) * | 1982-03-11 | 1983-09-21 | Pfizer Limited | Dihydropyridine anti-ischaemic and antihypertensive agents, processes for their production, and pharmaceutical compositions containing them |
| US20020143046A1 (en) * | 2000-12-29 | 2002-10-03 | Peters Theodorus H. A. | Process for making amlodipine, derivatives therof, and precursors therefor |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7979778B2 (en) | 2004-09-25 | 2011-07-12 | Aware, Inc. | CRC counter normalization |
| WO2007096724A1 (en) * | 2006-02-21 | 2007-08-30 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of amlodipine besylate |
| US7671208B2 (en) | 2007-03-30 | 2010-03-02 | Esteve Quimica, S.A. | Acetone solvate of phthaloyl amlodipine |
| CN101367759B (en) * | 2008-10-06 | 2011-03-16 | 北京赛科药业有限责任公司 | Synthesis of high-purity amlodipine besylate |
| WO2011117876A1 (en) | 2010-03-26 | 2011-09-29 | Fdc Limited | An improved process for the preparation of amlodipine free base and acid addition salts thereof |
| CN111948306A (en) * | 2020-07-27 | 2020-11-17 | 北京百奥药业有限责任公司 | Method for determining genotoxic impurities in amlodipine besylate |
| CN113024446A (en) * | 2021-03-15 | 2021-06-25 | 福建海西新药创制有限公司 | Method for preparing amlodipine besylate intermediate by using micro-reaction device |
| CN113024446B (en) * | 2021-03-15 | 2022-08-05 | 福建海西新药创制有限公司 | Method for preparing amlodipine besylate intermediate by using micro-reaction device |
| CN115536577A (en) * | 2022-11-09 | 2022-12-30 | 浙江昂利康制药股份有限公司 | Preparation method of amlodipine alkali |
| CN115536577B (en) * | 2022-11-09 | 2024-04-30 | 浙江昂利康制药股份有限公司 | Preparation method of amlodipine alkali |
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