CN104292150A - Synthetic process of manidipine hydrochloride - Google Patents
Synthetic process of manidipine hydrochloride Download PDFInfo
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- CN104292150A CN104292150A CN201310302663.4A CN201310302663A CN104292150A CN 104292150 A CN104292150 A CN 104292150A CN 201310302663 A CN201310302663 A CN 201310302663A CN 104292150 A CN104292150 A CN 104292150A
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- synthesis technique
- diphenyl
- piperazine
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- MGHPNCMVUAKAIE-UHFFFAOYSA-N NC(c1ccccc1)c1ccccc1 Chemical compound NC(c1ccccc1)c1ccccc1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 2
- MVUFJEMBZPRPCG-UHFFFAOYSA-N CC(C1c2cccc([N+]([O-])=O)c2)=C(C)NC(C)=C1C(OCCN)=C=C Chemical compound CC(C1c2cccc([N+]([O-])=O)c2)=C(C)NC(C)=C1C(OCCN)=C=C MVUFJEMBZPRPCG-UHFFFAOYSA-N 0.000 description 1
- XCKBUDHUYMUEMA-UHFFFAOYSA-N CC(CC(OCCNCCNC(c1ccccc1)c1ccccc1)=O)=O Chemical compound CC(CC(OCCNCCNC(c1ccccc1)c1ccccc1)=O)=O XCKBUDHUYMUEMA-UHFFFAOYSA-N 0.000 description 1
- 0 CC1=C(*)C(c2cccc(*)c2)C(C(OCCNCCNC(c2ccccc2)c2ccccc2)=O)=C(C)N1 Chemical compound CC1=C(*)C(c2cccc(*)c2)C(C(OCCNCCNC(c2ccccc2)c2ccccc2)=O)=C(C)N1 0.000 description 1
- ZDVDCDLBOLSVGM-UHFFFAOYSA-N ClC(c1ccccc1)c1ccccc1 Chemical compound ClC(c1ccccc1)c1ccccc1 ZDVDCDLBOLSVGM-UHFFFAOYSA-N 0.000 description 1
- LHIJANUOQQMGNT-UHFFFAOYSA-N NCCNCCO Chemical compound NCCNCCO LHIJANUOQQMGNT-UHFFFAOYSA-N 0.000 description 1
- SIXYIEWSUKAOEN-UHFFFAOYSA-N Nc1cc(C=O)ccc1 Chemical compound Nc1cc(C=O)ccc1 SIXYIEWSUKAOEN-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Abstract
The invention discloses a synthetic process of manidipine hydrochloride. The method uses N-hydroxyethyl piperazine as an initial raw material, which is subjected to diketene acylation, and then condensation with m-nitrobenzaldehyde and 3-amino methyl crotonate to obtain the manidipine; and the manidipine is subjected to hydrogen chloride organic solvent salt forming to obtain the manidipine hydrochloride. The invention improves synthetic process of 1-benzhydryl-4-(2-hydroxy ethyl) piperazine; and a catalyst is introduced into the diketene acylation reaction, and the salt forming process uses a novel hydrogen chloride organic solvent method, so as to ensure product quality, improve yield and facilitate industrial production.
Description
Technical field
The present invention relates to chemical pharmacy field, is exactly a kind of synthesis technique of CV-4093.
Background technology
CV-4093, i.e. Isosorbide-5-Nitrae-dihydro-2,6-dimethyl-4-m-nitro base-3,5-pyridine dicarboxylic acid methyl esters 2-(4-diphenyl-methyl-1-piperazinyl) carbethoxy hydrochloride (I), its structure is as follows:
CV-4093 is third generation dihydropyridines L-type, T-shaped calcium ion two channels antagonist; be used for the treatment of Mild or moderate hypertension; gone on the market in Japan first in nineteen ninety by Japanese Takede Chemical Industries Ltd; the clinical first-line drug as vascular hypertension, has without negative inotropic action clinically, does not accelerate heart rate, extra natriuretic diuretic effect, renal function protecting, increase insulin sensitivity, reduces the advantages such as ankle oedema untoward reaction.CV-4093 is included by Japanese Pharmacopoeia, and its curative effect, safety and stability are good.
Summary of the invention
The invention provides a kind of synthesis technique of CV-4093, this technique can realize suitability for industrialized production, and operation is simple, and cost is low, and yield is high, and can reduce environmental pollution.
The technical solution used in the present invention can be divided into four steps:
The first step, first N-hydroxyethyl piperazine (V), action solvent N, dinethylformamide (DMF) and acid binding agent salt of wormwood are added in reactor, then in reactor, add diphenyl methyl chloride to react, reaction is finished, washing, drying, concentrates to obtain 1-diphenyl methyl 04-(2-hydroxyethyl) piperazine (IV).The mol ratio of described N-hydroxyethyl piperazine (V), salt of wormwood and diphenyl methyl chloride is 1: (1.8 ~ 3): (1 ~ 1.5), preferably 1: (2.0 ~ 2.5): (1 ~ 1.15), DMF usage quantity is every 1gN-hydroxyethyl piperazine (V) is (2 ~ 10ml).Described temperature of reaction is 20 ~ 30 DEG C, and the reaction times is 1.5 ~ 4 hours.
Second step, gained 1-diphenyl methyl-4-(2-hydroxyethyl) piperazine (IV), action solvent and catalyzer DMAP (DMAP) are added in reactor, add ketene dimer again to react, reaction is finished, use diluted alkaline water washing, drying, concentrates to obtain 2-(4-diphenyl-methyl-1-piperazinyl) ethyl acetoacetic ester (III).The mol ratio of described 1-diphenyl methyl-4-(2-hydroxyethyl) piperazine (IV), DMAP and ketene dimer is 1: (0.001 ~ 0.05): (0.5 ~ 3), preferably 1: (0.001 ~ 0.02): (1.0 ~ 1.5).Described action solvent is acetonitrile, tetrahydrofuran (THF), dioxane, normal hexane, dme, ethyl acetate, butylacetate, toluene, dimethylbenzene, hexanaphthene, solvent usage quantity is that every 1g (IV) uses (0.5 ~ 50ml), preferably (5 ~ 25ml).Described temperature of reaction is 20 ~ 30 DEG C, and the reaction times is 10 ~ 24 hours.
3rd step, gained 2-(4-diphenyl-methyl-1-piperazinyl) ethyl acetoacetic ester (III), m-nitrobenzaldehyde, 3-aminobutene acid methyl esters and action solvent Virahol are added in reactor and reacts, reaction is finished, concentrating under reduced pressure, with acetic acid ethyl dissolution, washing, dry, concentrate to obtain Manidipine (II).The mol ratio of described 2-(4-diphenyl-methyl-1-piperazinyl) ethyl acetoacetic ester (III), m-nitrobenzaldehyde and 3-aminobutene acid methyl esters is 1: (0.95 ~ 1.5): (0.95 ~ 1.5), preferably 1: (1 ~ 1.1): (1 ~ 1.1), action solvent Virahol usage quantity is every 1g (III) is (5 ~ 10ml).Described temperature of reaction is 75 ~ 85 DEG C, and the reaction times is 6 ~ 20 hours.
4th step, adds gained Manidipine (II) and hydrogenchloride organic solvent in reactor and reacts, and reaction is finished, and concentrating under reduced pressure obtains crude product CV-4093, recrystallization, suction filtration, dry CV-4093.Described hydrogenchloride organic solvent is methanolic hydrogen chloride, ethanolic hydrogen chloride, hydrogenchloride ethyl acetate, hydrogenchloride dioxane etc.Described Manidipine (II) and the mol ratio of hydrogenchloride are 1: (2.0 ~ 3.0), preferably 1: (2.0 ~ 2.2).Described recrystallization solvent is the mixed solvent of ethanol, methyl alcohol, ethyl acetate or both arbitrary proportions any.Described temperature of reaction is 20 ~ 30 DEG C, and the reaction times is 0.5 ~ 2 hour.
Synthetic route of the present invention is:
Owing to have employed technique scheme, the present invention has following beneficial effect:
One be due to the first step with the ripe commercially available industrial goods N-hydroxyethyl piperazine of current industrialization for starting raw material, thus ensure that industrialized a large amount of production.Two is because second step acylation reaction introduces catalyzer DMAP, thus makes the by product of reaction few, and yield and purity are also all higher.Three is that Manidipine free alkali salification process uses hydrogenchloride organic solvent, thus can simplify the operation, and effectively reduce production cost, the purity of target product also effectively improves.
Embodiment
With reference to the following examples, the present invention can be explained in more detail, but it should be noted that the present invention is not limited to following embodiment.
Embodiment 1:
37.83g (291mmol) N-hydroxyethyl piperazine (V) is added in 1000ml three-necked bottle, DMF330ml and salt of wormwood 80.18 (581mmol) stir and make it dissolve, add diphenyl methyl chloride 61.79g (305mmol) again, stirring reaction 2 hours at 20 ~ 30 DEG C, reaction is finished, add 500ml water, be extracted with ethyl acetate (4 times again, each 200ml), organic phase saturated nacl aqueous solution washing (2 times, each 100ml), dry, concentrating under reduced pressure obtains oily matter 1-diphenyl methyl-4-(2-hydroxyethyl) piperazine (IV) 47.44g (yield: 55%).
Gained diphenyl methyl-4-(2-hydroxyethyl) piperazine (IV) 47.42g (160mmol), normal hexane 300ml and DMAP0.07g (0.57mmol) are added in 1000ml three-necked bottle, stirs and make it dissolve.Then be cooled to-15 ~-10 DEG C, add ketene dimer 15.29g (182mmol).First stir 30 minutes at-15 ~-10 DEG C, stirring reaction 15.5 hours at 20 ~ 30 DEG C.Reaction is finished, and is cooled to 0 DEG C, adds 0.1% aqueous sodium hydroxide solution 500ml, washing, water phase separated and organic phase.Aqueous phase is with n-hexane extraction (3 times, each 300ml).Merge whole organic phase, first with 0.1% aqueous sodium hydroxide solution washing (2 times, each 500ml), wash (2 times again with water, each 500ml), drying, concentrating under reduced pressure obtains 2-(4-diphenyl-methyl-1-piperazinyl) ethyl acetoacetic ester (III) 53.94g (yield: 88.6%).
Gained 2-(4-diphenyl-methyl-1-piperazinyl) ethyl acetoacetic ester (III) 28.88g (75.9mmol), m-nitrobenzaldehyde 11.44g (75.7mmol) and 3-aminobutene acid methyl esters 8.73g (75.8mmol) are joined in 500ml three-necked bottle, then adds Virahol 300ml.Under whipped state, be warmed up to 75 ~ 85 DEG C and carry out reaction 16 hours.Reaction is finished, concentrating under reduced pressure, then adds 120ml acetic acid ethyl dissolution, and with 50 ~ 60 DEG C of warm water washing (4 times, each 100ml), dry, concentrating under reduced pressure obtains Manidipine (II) 24.43g (yield: 52.7%).
Gained Manidipine (II) 20.5g (30mmol) and hydrogenchloride dioxane solution (1.2mol/L, 52.8ml) are added in 500ml three-necked bottle, stirring reaction 30 minutes at 20 ~ 30 DEG C.Reaction is finished, and concentrating under reduced pressure obtains crude product CV-4093, then adds 300ml methyl alcohol, under whipped state, temperature rising reflux 1 hour, is cooled to 0 DEG C, stir 5 hours, suction filtration, decompression drying obtains CV-4093 (I) 14.83g (yield: 72.3%).
Embodiment 2:
27.3g (210mmol) N-hydroxyethyl piperazine (V) is added in 1000ml three-necked bottle, DMF55ml and salt of wormwood 29.0 (210mmol) stir and make it dissolve, add diphenyl methyl chloride 63.82g (315mmol) again, stirring reaction 4 hours at 20 ~ 30 DEG C, reaction is finished, add 350ml water, be extracted with ethyl acetate (4 times again, each 150ml), organic phase saturated nacl aqueous solution washing (2 times, each 70ml), dry, concentrating under reduced pressure obtains oily matter 1-diphenyl methyl-4-(2-hydroxyethyl) piperazine (IV) 28g (yield: 45%).
Gained diphenyl methyl-4-(2-hydroxyethyl) piperazine (IV) 25.3g (85.36mmol), tetrahydrofuran (THF) 165ml and DMAP0.75g (6.14mmol) are added in 1000ml three-necked bottle, stirs and make it dissolve.Then be cooled to-5 ~ 0 DEG C, add ketene dimer 21.5g (256mmol).First stir 30 minutes at-5 ~ 0 DEG C, stirring reaction 10 hours at 20 ~ 30 DEG C.Reaction is finished, and is cooled to 0 DEG C, adds 1% wet chemical 275ml, washing, water phase separated and organic phase.Aqueous phase is with n-hexane extraction (3 times, each 165ml).Merge whole organic phase, first with 1% wet chemical washing (2 times, each 275ml), wash (2 times again with water, each 275ml), drying, concentrating under reduced pressure obtains 2-(4-diphenyl-methyl-1-piperazinyl) ethyl acetoacetic ester (III) 25.14g (yield: 77.4%).
Gained 2-(4-diphenyl-methyl-1-piperazinyl) ethyl acetoacetic ester (III) 23.2g (61.0mmol), m-nitrobenzaldehyde 13.8g (91.3mmol) and 3-aminobutene acid methyl esters 10.5g (91.2mmol) are joined in 500ml three-necked bottle, then adds Virahol 120ml.Under whipped state, be warmed up to 75 ~ 85 DEG C and carry out reaction 6 hours.Reaction is finished, concentrating under reduced pressure, then adds 100ml acetic acid ethyl dissolution, and with 50 ~ 60 DEG C of warm water washing (4 times, each 80ml), dry, concentrating under reduced pressure obtains Manidipine (II) 15.27g (yield: 41%).
Gained Manidipine (II) 15g (24.56mmol) and hydrogen chloride methanol solution (1.2mol/L, 75ml) are added in 500ml three-necked bottle, stirring reaction 30 minutes at 20 ~ 30 DEG C.Reaction is finished, and concentrating under reduced pressure obtains crude product CV-4093, then adds 100ml methyl alcohol, under whipped state, temperature rising reflux 1 hour, is cooled to-5 DEG C, stir 5 hours, suction filtration, decompression drying obtains CV-4093 (I) 11.76g (yield: 70%).
Embodiment 3:
45.5g (350mmol) N-hydroxyethyl piperazine (V) is added in 1000ml three-necked bottle, DMF250ml and salt of wormwood 101.5 (735.5mmol) stir and make it dissolve, add diphenyl methyl chloride 74.5g (367.7mmol) again, stirring reaction 4 hours at 20 ~ 30 DEG C, reaction is finished, add 500ml water, be extracted with ethyl acetate (4 times again, each 200ml), organic phase saturated nacl aqueous solution washing (2 times, each 100ml), dry, concentrating under reduced pressure obtains oily matter 1-diphenyl methyl-4-(2-hydroxyethyl) piperazine (IV) 60.17g (yield: 58%).
Gained diphenyl methyl-4-(2-hydroxyethyl) piperazine (IV) 58.6g (197.7mmol), ethyl acetate 500ml and DMAP0.3g (2.45mmol) are added in 1000ml three-necked bottle, stirs and make it dissolve.Then be cooled to-10 ~-5 DEG C, add ketene dimer 17.44g (207.6mmol).First stir 30 minutes at-10 ~-5 DEG C, stirring reaction 20 hours at 20 ~ 30 DEG C.Reaction is finished, and is cooled to 0 DEG C, adds 0.1% aqueous sodium hydroxide solution 500ml, washing, water phase separated and organic phase.Aqueous phase is extracted with ethyl acetate (3 times, each 400ml).Merge whole organic phase, first with 0.1% aqueous sodium hydroxide solution washing (2 times, each 500ml), wash (2 times again with water, each 500ml), drying, concentrating under reduced pressure obtains 2-(4-diphenyl-methyl-1-piperazinyl) ethyl acetoacetic ester (III) 72.2g (yield: 96%).
Gained 2-(4-diphenyl-methyl-1-piperazinyl) ethyl acetoacetic ester (III) 69.5g (182.6mmol), m-nitrobenzaldehyde 29g (191.7mmol) and 3-aminobutene acid methyl esters 22.06g (191.8mmol) are joined in 1000ml three-necked bottle, then adds Virahol 600ml.Under whipped state, be warmed up to 75 ~ 85 DEG C and carry out reaction 10 hours.Reaction is finished, concentrating under reduced pressure, then adds 400ml acetic acid ethyl dissolution, and with 50 ~ 60 DEG C of warm water washing (4 times, each 400ml), dry, concentrating under reduced pressure obtains Manidipine (II) 63.56g (yield: 57%).
Gained Manidipine (II) 62.5g (102.3mmol) and hydrogen chloride methanol solution (2.4mol/L, 93.8ml) are added in 1000ml three-necked bottle, stirring reaction 30 minutes at 20 ~ 30 DEG C.Reaction is finished, and concentrating under reduced pressure obtains crude product CV-4093, then adds 500ml methyl alcohol, under whipped state, temperature rising reflux 1 hour, is cooled to 0 DEG C, stir 5 hours, suction filtration, decompression drying obtains CV-4093 (I) 49g (yield: 70%).
Claims (10)
1. a synthesis technique for CV-4093, comprises following reactions steps:
A: first N-hydroxyethyl piperazine (V), action solvent N, dinethylformamide (DMF) and acid binding agent salt of wormwood are added in reactor, then in reactor, add diphenyl methyl chloride to react, reaction is finished, washing, drying, concentrates to obtain 1-diphenyl methyl-4-(2-hydroxyethyl) piperazine (IV).
B: gained 1-diphenyl methyl-4-(2-hydroxyethyl) piperazine (IV), action solvent and catalyzer DMAP (DMAP) are added in reactor, add ketene dimer again to react, reaction is finished, use diluted alkaline water washing, drying, concentrates to obtain 2-(4-diphenyl-methyl-1-piperazinyl) ethyl acetoacetic ester (III).
C: gained 2-(4-diphenyl-methyl-1-piperazinyl) ethyl acetoacetic ester (III), m-nitrobenzaldehyde, 3-aminobutene acid methyl esters and action solvent Virahol are added in reactor and reacts, reaction is finished, concentrating under reduced pressure, with acetic acid ethyl dissolution, washing, drying, concentrates to obtain Manidipine (II).
D: gained Manidipine (II) and hydrogenchloride organic solvent are added in reactor and react, reaction is finished, and concentrating under reduced pressure obtains crude product CV-4093, recrystallization, suction filtration, dry CV-4093.
2. according to the synthesis technique of the CV-4093 in claim 1 described in steps A, the mol ratio that it is characterized in that described N-hydroxyethyl piperazine (V), salt of wormwood and diphenyl methyl chloride is 1: (1.8 ~ 3): (1 ~ 1.5), preferably 1: (2.0 ~ 2.5): (1 ~ 1.15), action solvent DMF usage quantity is every 1gN-hydroxyethyl piperazine (V) is (2 ~ 10ml).
3., according to the synthesis technique of the CV-4093 in claim 1 described in steps A, it is characterized in that described temperature of reaction is 20 ~ 30 DEG C, the reaction times is 1.5 ~ 4 hours.
4. according to the synthesis technique of the CV-4093 in claim 1 described in step B, the mol ratio that it is characterized in that described 1-diphenyl methyl-4-(2-hydroxyethyl) piperazine (IV), DMAP (DMAP) and ketene dimer is 1: (0.001 ~ 0.05): (0.5 ~ 3), preferably 1: (0.001 ~ 0.02): (1.0 ~ 1.5).
5. according to the synthesis technique of the CV-4093 in claim 1 described in step B, it is characterized in that described action solvent is acetonitrile, tetrahydrofuran (THF), dioxane, normal hexane, dme, ethyl acetate, butylacetate, toluene, dimethylbenzene, hexanaphthene, solvent usage quantity is that every 1g (IV) uses (0.5 ~ 50ml), preferably (5 ~ 25ml).
6., according to the synthesis technique of the CV-4093 in claim 1 described in step B, it is characterized in that described temperature of reaction is 20 ~ 30 DEG C, the reaction times is 10 ~ 24 hours.
7. according to the synthesis technique of the CV-4093 in claim 1 described in step C, the mol ratio that it is characterized in that described 2-(4-diphenyl-methyl-1-piperazinyl) ethyl acetoacetic ester (III), m-nitrobenzaldehyde and 3-aminobutene acid methyl esters is 1: (0.95 ~ 1.5): (0.95 ~ 1.5), preferably 1: (1 ~ 1.1): (1 ~ 1.1), action solvent Virahol usage quantity is every 1g (III) is (5 ~ 10ml).
8., according to the synthesis technique of the CV-4093 in claim 1 described in step C, it is characterized in that described temperature of reaction is 75 ~ 85 DEG C, the reaction times is 6 ~ 20 hours.
9., according to the synthesis technique of the CV-4093 in claim 1 described in step D, it is characterized in that described hydrogenchloride organic solvent is methanolic hydrogen chloride, ethanolic hydrogen chloride, hydrogenchloride ethyl acetate, hydrogenchloride dioxane etc.Described Manidipine (II) and the mol ratio of hydrogenchloride are 1: (2.0 ~ 3.0), preferably 1: (2.0 ~ 2.2).Described recrystallization solvent is the mixed solvent of ethanol, methyl alcohol, ethyl acetate or both arbitrary proportions any.
10., according to the synthesis technique of the CV-4093 in claim 1 described in step D, it is characterized in that described temperature of reaction is 20 ~ 30 DEG C, the reaction times is 0.5 ~ 2 hour.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107337632A (en) * | 2017-08-22 | 2017-11-10 | 江西永通科技股份有限公司 | A kind of preparation method of CV-4093 |
| CN108129383A (en) * | 2017-12-22 | 2018-06-08 | 临沂齐泽医药技术有限公司 | A kind of preparation process for treating hypertension optical voidness manidipine hydrochloride |
| CN113861131A (en) * | 2021-11-08 | 2021-12-31 | 深圳菲斯生物科技有限公司 | Preparation method of cetirizine impurity C |
| CN113861131B (en) * | 2021-11-08 | 2024-04-19 | 深圳菲斯生物科技有限公司 | Preparation method of cetirizine impurity C |
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| EP0138505A2 (en) * | 1983-10-17 | 1985-04-24 | Takeda Chemical Industries, Ltd. | Dihydropyridine derivatives, their production and use |
| CN101177404A (en) * | 2007-11-30 | 2008-05-14 | 山东金城医药化工有限公司 | Method for preparing high-purity p-chloro-m-nitroacetoacetanilide |
| CN101575313A (en) * | 2009-01-20 | 2009-11-11 | 许昌恒生制药有限公司 | Production technique for synthesizing Manidipine Hydrochloride through separation with non-column chromatography |
| WO2010056865A1 (en) * | 2008-11-14 | 2010-05-20 | Gilead Palo Alto, Inc. | Quinoline derivatives as ion channel modulators |
| WO2011023954A2 (en) * | 2009-08-27 | 2011-03-03 | Cipla Limited | Polymorphic forms of manidipine |
| CN102875451A (en) * | 2012-04-05 | 2013-01-16 | 常州制药厂有限公司 | Improved method for synthesis process of manidipine hydrochloride |
-
2013
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP0138505A2 (en) * | 1983-10-17 | 1985-04-24 | Takeda Chemical Industries, Ltd. | Dihydropyridine derivatives, their production and use |
| CN101177404A (en) * | 2007-11-30 | 2008-05-14 | 山东金城医药化工有限公司 | Method for preparing high-purity p-chloro-m-nitroacetoacetanilide |
| WO2010056865A1 (en) * | 2008-11-14 | 2010-05-20 | Gilead Palo Alto, Inc. | Quinoline derivatives as ion channel modulators |
| CN101575313A (en) * | 2009-01-20 | 2009-11-11 | 许昌恒生制药有限公司 | Production technique for synthesizing Manidipine Hydrochloride through separation with non-column chromatography |
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| CN102875451A (en) * | 2012-04-05 | 2013-01-16 | 常州制药厂有限公司 | Improved method for synthesis process of manidipine hydrochloride |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107337632A (en) * | 2017-08-22 | 2017-11-10 | 江西永通科技股份有限公司 | A kind of preparation method of CV-4093 |
| CN108129383A (en) * | 2017-12-22 | 2018-06-08 | 临沂齐泽医药技术有限公司 | A kind of preparation process for treating hypertension optical voidness manidipine hydrochloride |
| CN108129383B (en) * | 2017-12-22 | 2021-02-12 | 青岛市市立医院 | Preparation process of optically pure manidipine hydrochloride for treating hypertension |
| CN113861131A (en) * | 2021-11-08 | 2021-12-31 | 深圳菲斯生物科技有限公司 | Preparation method of cetirizine impurity C |
| CN113861131B (en) * | 2021-11-08 | 2024-04-19 | 深圳菲斯生物科技有限公司 | Preparation method of cetirizine impurity C |
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Application publication date: 20150121 |