CN1882543A - Process for preparation of chiral amlodipine salts - Google Patents
Process for preparation of chiral amlodipine salts Download PDFInfo
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- CN1882543A CN1882543A CNA2004800343754A CN200480034375A CN1882543A CN 1882543 A CN1882543 A CN 1882543A CN A2004800343754 A CNA2004800343754 A CN A2004800343754A CN 200480034375 A CN200480034375 A CN 200480034375A CN 1882543 A CN1882543 A CN 1882543A
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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- 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
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Abstract
A process for the preparation of pharmaceutically acceptable salts of chiral Amlodipine namely S(-) Amlodipine and R(+) Amlodipine without isolation of the chiral free base wherein the product has optical purity ranging between 96-99% is described in the present invention. The process comprises resolving RS amlodipine base using L(+) or D(-) tartaric acid followed by reaction of the separated tartrate salt with an organic acid to obtain the salt corresponding to the acid used in ee ranging from 96-99%.
Description
Invention field
The present invention relates to prepare improving one's methods of chiral amlodipine salts.More particularly, the present invention relates in the presence of dimethyl sulfoxide (DMSO), be prepared as follows S (-) amlodipine shown in the literary composition and the acceptable salt of medicine with R (+) amlodipine of formula (2) structure with formula (1) structure, and under the condition that need not separated free alkali, it is converted into the method for benzene sulfonate, wherein, R=Phenylsulfonic acid, succsinic acid, toxilic acid, oxalic acid, tosic acid.
Formula-1 formula-2
Background of invention
In above-mentioned all S (-) Amlodipines, S (-) amlodipine besylate (4-S)-2-{[(2-aminoethyl) oxygen] methyl }-4-(2-chloro-phenyl-) 6-methyl isophthalic acid, 4-dihydropyridine-3,5-dicarboxylic ester benzene sulfonate has commercial significance as effective long-acting calcium channel blocker.
It is reported that R (+) amlodipine is effective inhibitor (referring to PCT/EP-94/02697) of smooth muscle cell migration.(R, S) amlodipine and salt thereof are long lasting calcium channel blockers, and are used for the treatment of cardiovascular disorder.Racemic amlodipine is used for the treatment of hypertension and stenocardia with the form of benzene sulfonate at present.The preparation of racemic compound is disclosed in No. 0089167 European patent of EP.Amlodipine is a racemic compound, and has chiral centre 4 of dihydropyridine ring.Described S (-) isomer has the activity of calcium channel blocker, and R (+) isomer is effective inhibitor of smooth muscle cell migration.The prior art that is used to prepare R and S enantiomer is a) to split amlodipine nitrine ester (referring to J.Med.Chem.29 with 2-methoxyl group-2-phenylethyl alcohol of optically active, 1696,1986, European application 0331315A number), perhaps b) dextrocamphoric acid with optically active splits amlodipine base (referring to J.Med.Chem.35,3341,1992), c) in organic solvent DMSO, use L (+) or D (-) tartrate to split RS amlodipine base (referring to United States Patent (USP) 6,046,338 (2000) PCT95/25722 1995) respectively, d) split the inferior terminal nitrine ester precursor of amlodipine (referring to United States Patent (USP) 6 with cinchovatin, 291,490 (2001), ChemPharm Bull.28 (9), 2809-2812,1980).
The preparation of S (-) amlodipine besylate is disclosed in publication; (referring to J.Chem.B.; 693; 1997; 367-375); describe in detail in patent application NF347/02 number of pending trial at the same time subsequently and claimed, this patent application relates to the method for preparing the acceptable salt of medicine of S (-) amlodipine from S (-) amlodipine for NF347/02 number, for example benzene sulfonate, succinate, maleate, oxalate and tosylate.
The main drawback of prior art is:
1. use resolution reagent such as the costliness of dextrocamphoric acid, 2-methoxyl group-2-phenylethyl alcohol, cinchovatin.
2. use 0.5 mole L (+) or D (-) tartrate, increased and reclaimed tartaric workload.
3. use more a spot of resolution reagent, make that the isolating fractionation salt yield of institute is low.
4. use a large amount of solvent (1: 10).
5. the chiral base of separated free from described salt, and handle to obtain benzene sulfonate with Phenylsulfonic acid.
Goal of the invention
The purpose of this invention is to provide that application D or L tartrate prepare S (-) and R (+) amlodipine besylate from racemic amlodipine and the method that need not the amlodipine base of separated free.
Summary of the invention
Therefore, the invention provides the improving one's methods of the acceptable chirality salt of medicine of preparation amlodipine, promptly have S (-) Amlodipine of formula (1) structure and R (+) Amlodipine with formula (2) structure.
Formula-1 formula-2
Wherein R is selected from Phenylsulfonic acid, succsinic acid, toxilic acid, oxalic acid and tosic acid, and the separation that wherein need not free alkali prepares the salt that optical purity is described formula 1 and the formula 2 of 96-99%, and this method comprises:
(a) under 20-35 ℃ temperature, with L (+) or D (-) tartrate reaction in the solution of RS amlodipine base in the organic solvent and organic solvent 16-24 hour, to obtain to contain the solvate of amlodipine tartarate salt;
(b) separate and in 20-40 ℃ temperature, choose wantonly in the presence of organic solvent, the described amlodipine tartarate salt and the aqueous acid that will derive from step (a) react;
(c) water is joined in the reaction mixture of step (b),, separate the salt and the dry salt of this formula 1 or formula 2 with sour corresponding 96-99%ee used in acquisition and the step (2) to obtain the salt of described formula 1 or formula 2.
In embodiment of the present invention, used solvent is DMSO in the step (a).
In another embodiment of the present invention, the RS amlodipine base is 0.16-0.40g/ml to the concentration of solvent (DMSO).
In another embodiment of the present invention, used L (+) tartrate or D (-) tartrate are 0.25 molar equivalent of described amlodipine base.
In another embodiment of the present invention, the described solvate that derives from step (a) is the precipitation that comprises S (-) amlodipine half D (-) tartrate list DMSO solvate or R (+) amlodipine half L (+) tartrate list DMSO solvate.
In another embodiment of the present invention, the described solvent that is used for salt formation in the step (b) is selected from dimethyl sulfoxide (DMSO), Virahol and ethanol.
In another embodiment of the present invention, step (b) and (c) in the ratio of the water that uses of accumulative total and solvent be 5: 1-8: 1.
In another embodiment of the present invention, used acid is selected from Phenylsulfonic acid, toxilic acid, oxalic acid and tosic acid in the step (b).
In another embodiment of the present invention, amlodipine tartarate salt is 1 with the ratio of organic solvent in the step (b): 1-1: 5.
In another embodiment of the present invention, the molar equivalent of used Phenylsulfonic acid is 0.9-1.
In another embodiment of the present invention, the optical purity of R (+) amlodipine besylate or S (-) amlodipine besylate brings up to 99% from 95%.
Detailed description of the invention
The invention provides S (-) Amlodipine that comprises (1) structure that has formula and have the preparation method of the acceptable chiral amlodipine salts of medicine of R (+) Amlodipine of formula (2) structure.
Formula-1 formula-2
In above-mentioned formula 1 and formula 2, R is selected from Phenylsulfonic acid, succsinic acid, toxilic acid, oxalic acid and tosic acid.Need not separated free alkali, preparation has the salt that optical purity is described formula 1 and the formula 2 of 96-99%.
The method of the invention comprises:
(a) under 20-35 ℃ temperature, with L (+) in the solution of RS amlodipine base in the organic solvent and the organic solvent or the tartaric solution reaction 16-24 of D (-) hour.
(b) separation derives from the described tartrate of step (a), and in 20-40 ℃ temperature, chooses wantonly in the presence of organic solvent, with described salt and aqueous acid reaction.
(c) in the described reaction mixture that derives from step (b), add water to obtain described salt, separate this salt and dry, used sour corresponding salt in acquisition and the step (b) with 96-99%ee.
Used solvent is preferably dimethyl sulfoxide (DMSO) (DMSO) in the step (a), and described RS amlodipine base is 0.16-0.40g/ml to the concentration of solvent (DMSO).L (+) tartrate or D (-) tartrate used in the step (a) are 0.25 molar equivalent of this alkali.Preferably obtain described tartrate, and sedimentary solvate is S (-) amlodipine half D (-) tartrate list DMSO solvate or R (+) amlodipine half L (+) tartrate list DMSO solvate through precipitation.The solvent that is used for salt formation in step (b) is selected from dimethyl sulfoxide (DMSO), Virahol or ethanol.The Amlodipine that is used for salt formation in the step (b) is 1 with the ratio of organic solvent: 1-1: 5.In step (b) and step (c), the water that accumulative total is used is 5 with the ratio of solvent: 1-8: 1.Used acid is selected from Phenylsulfonic acid, toxilic acid, oxalic acid and tosic acid in the step (b).The molar equivalent of used Phenylsulfonic acid is 0.9-1.
The optical purity of R (+) amlodipine besylate or S (-) amlodipine besylate brings up to 99% from 95%.
Unique distinction of the present invention is, with good yield (87-92%), produce have high antimer purity, meet pharmaceutical composition, i.e. S (-) amlodipine of the quality requirements of tablet preparation or R (+) Amlodipine.R, the split process of S amlodipine and benzene sulfonate forming process are as follows:
Describe method of the present invention at this by reference following examples, this description is explanation of the present invention and should not be interpreted as limitation of the scope of the invention by any way just.
Use chirality HPLC post and measure optical purity (enantiomeric excess e.e.): chirality Chrompak15cm, ultron (ultron).Moving phase is used the Sodium phosphate dibasic damping fluid of pH 6.9: acetonitrile (80: 20), flow velocity are 1ml/min, Rt-R=6.1min. when 360nm, S=7.3min.
Embodiment 1: prepare R (+) amlodipine half L (+) tartrate list DMSO solvate from the RS amlodipine
In the 30ml DMSO that stirs, add 1.93g (0.0128moles, 0.5 equivalent (eq.)) the tartaric solution of L (+) among the 30ml DMSO in the solution of 10.50g (0.0256mole) RS amlodipine.In 5-10 minute, solid begins to separate from clear soln.This reaction was stirred 3 hours and was leached solid, with washing with acetone and dry, obtained 6.66g (46.2%) R (+) amlodipine half L (+) tartrate list DMSO solvate.160-162 ℃ of fusing point (mp.) is determined as 95.2%d.e.[referring to J.Chrom.B.693 through chirality HPLC, and 367, (1997), J.Luksa, Dj.Josic, B.Podobric, B.Furlan, M.Kremser.].
Embodiment 2: prepare R (+) amlodipine half L (+) tartrate list DMSO solvate from the RS amlodipine
In stirring 300ml DMSO, add 9.2g (0.06mole, 0.25 equivalent (eq.)) the tartaric solution of L (+) among the 300ml DMSO in the solution of 100g (0.245mole) RS amlodipine.In 5-10 minute, solid begins to separate from clear soln.This reaction was stirred 3 hours and was leached solid, with washing with acetone and dry, obtained 52.3g (36.2%) R (+) amlodipine half L (+) tartrate list DMSO solvate.160-162 ℃ of fusing point (mp.), HPLC is determined as 98.2%d.e. through chirality.
Embodiment 3: prepare R (+) amlodipine half L (+) tartrate list DMSO solvate from the RS amlodipine
In the 150ml DMSO that stirs, add 9.2g (0.06mole, 0.25 equivalent (eq.)) the tartaric solution of L (+) among the 100ml DMSO in the solution of 100g (0.245mole) RS amlodipine.In 5-10 minute, solid begins to separate from clear soln.This reaction was stirred 3 hours and was leached solid, with washing with acetone and dry, obtained 58.6g (40.5%) R (+) amlodipine half L (+) tartrate list DMSO solvate.160-162 ℃ of fusing point (mp.), HPLC is determined as 96.8%d.e. through chirality.
Embodiment 4: prepare S (-) amlodipine half D (-) tartrate list DMSO solvate from the RS amlodipine
In the 500ml DMSO that stirs, add 9.2g (0.06mole, 0.25 equivalent (eq.)) the tartaric solution of D (-) among the 500ml DMSO in the solution of 100g (0.245mole) RS amlodipine.In 5-10 minute, solid begins to separate from clear soln.This reaction is at room temperature stirred and is spent the night and leach solid, with washing with acetone and dry, obtains 47.5g (34.6%) S (-) amlodipine half D (-) tartrate list DMSO solvate.159-161 ℃ of fusing point (mp.), HPLC is determined as 99.5%d.e. through chirality.
Embodiment 5: prepare S (-) amlodipine half D (-) tartrate list DMSO solvate from the RS amlodipine
In the 250ml DMSO that stirs, add 9.2g (0.06mole, 0.25 equivalent (eq.)) the tartaric solution of D (-) among the 250ml DMSO in the solution of 100g (0.245mole) RS amlodipine.In 5-10 minute, solid begins to separate from clear soln.This reaction is at room temperature stirred and is spent the night and leach solid, with washing with acetone and dry, obtains 56.2g (40.8%) S (-) amlodipine half D (-) tartrate list DMSO solvate.159-161 ℃ of fusing point (mp.), HPLC is determined as 98.4%d.e. through chirality.
Embodiment 6: prepare R (+) amlodipine besylate from R (+) amlodipine half L (+) tartrate list DMSO solvate
Will be according to the 68.8g (0.122mole of embodiment 2 preparations, 95.2%de) R (+) amlodipine half L (+) tartrate list DMSO solvate is suspended in (70ml IPA:250ml distilled water) in the aqueous Virahol, and Phenylsulfonic acid (19.35g of 90% technical grade, 0.110mole) solution in the adding 150ml water.Reaction mixture was stirred 2 hours and filter gained mud, with distilled water, hexane wash, dry this solid obtains R (+) amlodipine besylate (63.4g, yield 84.6%) to constant weight under the vacuum in 40 ℃, and HPLC is determined as 99.3ee through chirality.
Trace analysis: C 51.33%, H 6.13%, N 4.62%, S 5.51 be C as calculated
20H
24O
5N
2ClC
6H
6O
3S.2.5 (H
2O) theoretical value is C 51.1%, H 5.7%, N 4.58%, S 5.24%.
Embodiment 7: prepare R (+) amlodipine besylate from R (+) amlodipine half L (+) tartrate list DMSO solvate
Will be according to the 68.8g (0.122mole of embodiment 2 preparations, 95.2%de) R (+) amlodipine half L (+) tartrate list DMSO solvate is suspended in (70ml IPA:250ml distilled water) in the aqueous Virahol, and Phenylsulfonic acid (21.28g of 90% technical grade, 0.122mole) solution in the adding 150ml water.Reaction mixture was stirred 2 hours and filter gained mud, with distilled water, hexane wash, dry this solid obtains R (+) amlodipine besylate (66.74g, yield 89.1%) to constant weight under the vacuum in 40 ℃, and HPLC is determined as 98.7ee through chirality.
Embodiment 8: prepare S (-) amlodipine besylate from S (-) amlodipine half D (-) tartrate list DMSO solvate
To be suspended in (70ml IPA:150ml distilled water) in the aqueous Virahol according to 50g (0.089mole) S (-) amlodipine half D (-) the tartrate list DMSO solvate of embodiment 4 preparations, and Phenylsulfonic acid (14.1g of 90% technical grade, 0.081mole) solution in the adding 100ml water.Reaction mixture was stirred 2 hours and filter gained mud, with distilled water, hexane wash, dry this solid obtains S (-) amlodipine besylate (47.5g, yield 87.2%) to constant weight under the vacuum in 40 ℃, and HPLC is determined as 99.5ee through chirality.
Trace analysis: C 50.91%, H 6.3%, N 4.67%, S 5.91 be C as calculated
20H
24O
5N
2ClC
6H
6O
3S.2.5 (H
2O) theoretical value is C 51.1%, H 5.7%, N 4.58%, S 5.24%.
Embodiment 9: prepare S (-) amlodipine besylate from S (-) amlodipine half D (-) tartrate list DMSO solvate
To be suspended in (70ml IPA:150ml distilled water) in the aqueous Virahol according to 50g (O.089mole) S (-) amlodipine half D (-) the tartrate list DMSO solvate of embodiment 4 preparations, and Phenylsulfonic acid (15.47g of 90% technical grade, 0.089mole) solution in the adding 100ml water.Reaction mixture was stirred 2 hours and filter gained mud, with distilled water, hexane wash, dry this solid obtains S (-) amlodipine besylate (50.1g, yield 92.1%) to constant weight under the vacuum in 40 ℃, and HPLC is determined as 99.3ee through chirality.
Embodiment 10: prepare S (-) amlodipine besylate from S (-) amlodipine half D (-) tartrate list DMSO solvate
To place 200ml distilled water furnishing mud according to 50g (0.089mole) S (-) amlodipine half D (-) the tartrate list DMSO solvate of embodiment 4 preparations, and Phenylsulfonic acid (15.47g of 90% technical grade, 0.089mole) solution in the adding 125ml water.Reaction mixture was stirred 2 hours and filter gained mud, with distilled water, hexane wash, dry this solid obtains S (-) amlodipine besylate (50.1g, yield 92.1%) to constant weight under the vacuum in 40 ℃, and HPLC is determined as 99.3ee through chirality.
Embodiment 11: prepare R (+) amlodipine besylate from R (+) amlodipine half L (+) tartrate list DMSO solvate
Will be according to the 68.8g (0.122mole of embodiment 1 preparation, 95.2%de) R (+) amlodipine half L (+) tartrate list DMSO solvate is suspended in (90ml IPA:250ml distilled water) in the aqueous Virahol, and Phenylsulfonic acid (19.35g of 90% technical grade, 0.110mole) solution in the adding 150ml water.Reaction mixture was stirred 2 hours and filter gained mud, with distilled water, hexane wash, dry this solid obtains R (+) amlodipine besylate (51.6g, yield 69.4%) to constant weight under the vacuum in 40 ℃, and HPLC is determined as 99.3ee through chirality.
Embodiment 12: prepare S (-) amlodipine maleate from S (-) amlodipine half D (-) tartrate list DMSO solvate
With S (-) amlodipine half D (-) tartrate list DMSO solvate (6.8g 0.012mole) is dissolved in the ethanol (10ml), and under agitation add toxilic acid in the 70ml water (1.42g, 0.012mole).Filter the solid of being separated out,, obtain 5.32g (82.88%) S (-) amlodipine maleate, 176-177 ℃ of fusing point (mp.), specific rotation: [α] with dry under cold water, hexane wash and the vacuum
tD=-25.10 (c=1, MeOH) 98.31ee.
Embodiment 13: prepare S (-) oxalic acid amlodipine from S (-) amlodipine half D (-) tartrate list DMSO solvate
With S (-) amlodipine half D (-) tartrate list DMSO solvate (6.8g 0.012moles) is dissolved in the ethanol (10ml), and under agitation add oxalic acid in the 70ml water (1.54g, 0.012moles).Filter the solid of being separated out,, obtain 5.80g (89.2%) S (-) oxalic acid amlodipine, 201-203 ℃ of fusing point (mp.), specific rotation: [α] with dry under cold water, hexane wash and the vacuum
tD=-27.95 (c=1, MeOH) 98.41ee.
Advantage of the present invention:
1. avoid using tearing open such as the costliness of camphoric acid, 2-methoxyl group-2 phenylethyl alcohol, cinchonidine Divide reagent.
2. avoid reclaiming tartaric worker because using 0.5 mole of L (+) or D (-) tartaric acid to increase The work amount.
3. use the resolution reagent of small amount, the fractionation salt yield height that separates.
4. avoid using a large amount of solvent (1: 10).
5. avoid the chiral base of separated free from salt and process to obtain benzene sulfonic acid with benzene sulfonic acid Salt.
Claims (11)
1. the method for the acceptable chirality salt of medicine of preparation amlodipine promptly has S (-) Amlodipine of formula (1) structure and R (+) Amlodipine with formula (2) structure,
Formula-1 formula-2
Wherein R is selected from Phenylsulfonic acid, succsinic acid, toxilic acid, oxalic acid and tosic acid, and the salt that wherein prepares described formula 1 and formula 2 need not separated free alkali, and the salt of described formula 1 and formula 2 has 96% to 99% optical purity, and described method comprises:
(a) under 20-35 ℃ temperature, with L (+) in the solution of RS amlodipine base in the organic solvent and the organic solvent or the tartaric solution reaction 16-24 of D (-) hour, to obtain to comprise the solvate of amlodipine tartarate salt;
(b) separate and in 20-40 ℃ temperature, choose wantonly in the presence of organic solvent, described amlodipine tartarate salt and the aqueous acid that obtains in the step (a) reacted;
(c) water is joined in the described reaction mixture of step (b) to obtain the salt of described formula 1 and formula 2, separate described formula 1 and and 2 salt and dry, obtain with step (2) in the salt of the corresponding 96-99%ee of described acid that uses.
2. the method for claim 1, wherein the described solvent that uses in the step (a) is DMSO.
3. the method for claim 1, wherein said RS amlodipine base is 0.16g/ml to 0.40g/ml to the concentration of solvent (DMSO).
4. the method for claim 1, wherein employed described L (+) tartrate or D (-) tartrate are 0.25 molar equivalent of described amlodipine base.
5. the method for claim 1, wherein the described solvate that obtains in step (a) is the precipitation that comprises S (-) amlodipine half D (-) tartrate list DMSO solvate or R (+) amlodipine half L (+) tartrate list DMSO solvate.
6. the method for claim 1, the described solvent that wherein is used for salt formation in step (b) is selected from dimethyl sulfoxide (DMSO), Virahol and ethanol.
7. the method for claim 1, wherein in step (b) and the accumulative total ratio of water (c) and solvent be 5: 1 to 8: 1.
8. the method for claim 1, wherein the described acid of using in step (b) is selected from Phenylsulfonic acid, toxilic acid, oxalic acid and tosic acid.
9. the method for claim 1, wherein the ratio of amlodipine tartarate salt and organic solvent is 1: 1 to 1: 5 in step (b).
10. method as claimed in claim 8, wherein the molar equivalent of employed Phenylsulfonic acid is 0.9 to 1.
11. the method for claim 1, the optical purity of wherein said R (+) amlodipine besylate or S (-) amlodipine besylate brings up to 99% from 95%.
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| EP (1) | EP1687273A1 (en) |
| KR (1) | KR20060086432A (en) |
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| CN102516159A (en) * | 2011-12-15 | 2012-06-27 | 扬子江药业集团江苏海慈生物药业有限公司 | Method for producing S-(-)-amlodipine besylate |
| CN104592099A (en) * | 2014-12-30 | 2015-05-06 | 山东鲁抗医药股份有限公司 | Refining method for improving optical purity of levoamlodipine besylate |
| CN111689894A (en) * | 2019-03-13 | 2020-09-22 | 鲁南制药集团股份有限公司 | Levamlodipine besylate crystal form |
| CN112110850A (en) * | 2019-06-20 | 2020-12-22 | 鲁南制药集团股份有限公司 | Novel crystal form of levamlodipine besylate |
| CN116332832A (en) * | 2023-03-29 | 2023-06-27 | 安徽美致诚药业有限公司 | Maleic acid levo-amlodipine amorphous crystal form and preparation method thereof |
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| WO2006043148A1 (en) * | 2004-10-20 | 2006-04-27 | Emcure Pharmaceuticals Limited | Process for producing enantiomer of amlodipine in high optical purity |
| KR101235116B1 (en) * | 2005-10-17 | 2013-02-20 | 에스케이케미칼주식회사 | Process for preparation of chiral amlodipine gentisate |
| KR100843400B1 (en) * | 2006-11-14 | 2008-07-04 | 씨제이제일제당 (주) | Crystalline S---amlodipine maleic acid salt anhydrous and preparation method thereof |
| KR100979772B1 (en) * | 2008-06-12 | 2010-09-02 | 에이치 엘 지노믹스(주) | Process for preparing optically pure S---amlodipine benzensulfonate |
| KR101313842B1 (en) * | 2010-09-15 | 2013-10-01 | 대화제약 주식회사 | A manufacturing method of esamlodipine besilate and its hydrate |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9405833D0 (en) * | 1994-03-24 | 1994-05-11 | Pfizer Ltd | Separation of the enantiomers of amlodipine |
| BR0116557A (en) * | 2000-12-29 | 2003-10-28 | Pfizer Ltd | Process, process for making a substantially amlodipine aspartate free amlodipine maleate salt, process for purification, amlodipine maleate, pharmaceutical composition for treating or preventing angina or hypertension, method for treating hypertension, angina or heart attack, benzene sulfonate amlodipine, amlodipine hydrochloride and use of amlodipine substantially free of amlodipine aspartate maleate |
| US6608206B1 (en) * | 2002-10-30 | 2003-08-19 | Council Of Scientific & Industrial Research | Process for making S(-) Amlodipine salts |
-
2004
- 2004-10-19 EP EP04791865A patent/EP1687273A1/en not_active Withdrawn
- 2004-10-19 WO PCT/IN2004/000324 patent/WO2005049571A1/en not_active Application Discontinuation
- 2004-10-19 CN CNA2004800343754A patent/CN1882543A/en active Pending
- 2004-10-19 BR BRPI0416648-5A patent/BRPI0416648A2/en not_active IP Right Cessation
- 2004-10-19 KR KR1020067009616A patent/KR20060086432A/en not_active Application Discontinuation
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101468986B (en) * | 2007-12-26 | 2010-12-29 | 香港南北兄弟国际投资有限公司 | Method for splitting dihydropyrimidine racemic compound |
| CN102516159A (en) * | 2011-12-15 | 2012-06-27 | 扬子江药业集团江苏海慈生物药业有限公司 | Method for producing S-(-)-amlodipine besylate |
| CN104592099A (en) * | 2014-12-30 | 2015-05-06 | 山东鲁抗医药股份有限公司 | Refining method for improving optical purity of levoamlodipine besylate |
| CN111689894A (en) * | 2019-03-13 | 2020-09-22 | 鲁南制药集团股份有限公司 | Levamlodipine besylate crystal form |
| CN111689894B (en) * | 2019-03-13 | 2023-05-02 | 鲁南制药集团股份有限公司 | Levamlodipine besylate crystal form |
| CN112110850A (en) * | 2019-06-20 | 2020-12-22 | 鲁南制药集团股份有限公司 | Novel crystal form of levamlodipine besylate |
| CN112110850B (en) * | 2019-06-20 | 2023-05-02 | 鲁南制药集团股份有限公司 | Novel crystal form of levamlodipine besylate |
| CN116332832A (en) * | 2023-03-29 | 2023-06-27 | 安徽美致诚药业有限公司 | Maleic acid levo-amlodipine amorphous crystal form and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20060086432A (en) | 2006-07-31 |
| WO2005049571A1 (en) | 2005-06-02 |
| EP1687273A1 (en) | 2006-08-09 |
| BRPI0416648A2 (en) | 2009-01-13 |
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