WO1996035668A1 - A process for the preparation of lercanidipine hydrochloride - Google Patents
A process for the preparation of lercanidipine hydrochloride Download PDFInfo
- Publication number
- WO1996035668A1 WO1996035668A1 PCT/EP1996/002122 EP9602122W WO9635668A1 WO 1996035668 A1 WO1996035668 A1 WO 1996035668A1 EP 9602122 W EP9602122 W EP 9602122W WO 9635668 A1 WO9635668 A1 WO 9635668A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- process according
- dimethyl
- lercanidipine
- diphenylpropyl
- propanol
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- WMFYOYKPJLRMJI-UHFFFAOYSA-N Lercanidipine hydrochloride Chemical compound Cl.COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)(C)CN(C)CCC(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 WMFYOYKPJLRMJI-UHFFFAOYSA-N 0.000 title description 16
- 229960002162 lercanidipine hydrochloride Drugs 0.000 title description 12
- 239000000010 aprotic solvent Substances 0.000 claims abstract description 11
- ZDXUKAKRHYTAKV-UHFFFAOYSA-N lercanidipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)(C)CN(C)CCC(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZDXUKAKRHYTAKV-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229960004294 lercanidipine Drugs 0.000 claims abstract description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- MQWDISMNBYOLAB-UHFFFAOYSA-N 1-[3,3-diphenylpropyl(methyl)amino]-2-methylpropan-2-ol Chemical compound C=1C=CC=CC=1C(CCN(C)CC(C)(C)O)C1=CC=CC=C1 MQWDISMNBYOLAB-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000004820 halides Chemical class 0.000 claims abstract description 4
- 238000002425 crystallisation Methods 0.000 claims abstract 5
- 230000008025 crystallization Effects 0.000 claims abstract 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 5
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 5
- 230000002140 halogenating effect Effects 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 3
- 238000002844 melting Methods 0.000 claims description 3
- 230000008018 melting Effects 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 2
- 150000001924 cycloalkanes Chemical class 0.000 claims description 2
- 230000026030 halogenation Effects 0.000 claims description 2
- 238000005658 halogenation reaction Methods 0.000 claims description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Natural products OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 2
- 235000001968 nicotinic acid Nutrition 0.000 claims description 2
- 239000011664 nicotinic acid Substances 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003586 protic polar solvent Substances 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- JPXPPUOCSLMCHK-UHFFFAOYSA-N 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid Chemical compound COC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC=CC([N+]([O-])=O)=C1 JPXPPUOCSLMCHK-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- -1 1 , 1 ,N-trimethyl-N-(3 ,3-diphenylpropyl)-2-aminoethyl α-acetyl-3-nitrocinnamate Chemical compound 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- XKORCTIIRYKLLG-ARJAWSKDSA-N methyl (z)-3-aminobut-2-enoate Chemical compound COC(=O)\C=C(\C)N XKORCTIIRYKLLG-ARJAWSKDSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 description 1
- 229910001488 sodium perchlorate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000003643 water by type Substances 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the invention relates to a process for the preparation of lercanidipine hydrochloride.
- Lercanidipine is methyl l, l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl l,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate. It has the formula I:
- Lercanidipine was disclosed in United States Patent No 4705797. It is an antagonist of type-L calcium channels, and has been found to be very active as an antihypertensive and as an agent for the treatment of angina and coronary disease.
- the aminoalcohol (1) is esterified with diketene to form the corresponding acetoacetate (2), which is then coupled with 3-nitrobenzaldehyde to give 1 , 1 ,N-trimethyl-N-(3 ,3-diphenylpropyl)-2-aminoethyl ⁇ -acetyl-3-nitrocinnamate (3) .
- This is cyclised with methyl 3-aminocrotonate in refluxing isopropanol.
- the product obtained by this process is lercanidipine hydrochloride hemihydrate, melting at 119 to 123°C.
- This product is somewhat hygroscopic, which can lead to inconstancy of composition and difficulties in handling during the preparation of pharmaceutical formulations.
- the stability of the lercanidipine hydrochloride hemihydrate is not entirely satisfactory.
- the invention provides a process for the preparation of lercanidipine hydrochloride, the process comprising: a) halogenating 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-l ,4-dihydro- pyridine-3-carboxylic acid with a halogenating agent in an aprotic solvent; b) adding 2,N-dimethyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol dissolved in an aprotic solvent to the resultant acid halide; and c) isolating the resultant lercanidipine as its anhydrous hydrochloride.
- the process of the invention is illustrated by the following reaction scheme.
- the halogenation is a chlorination. It may be conducted in chlorinated or non-chlorinated aprotic solvents, e.g. chloroform, dichloromethane, dichloroethane, chlorobenzene, 1,1,1-trichloroethane, ethyl acetate, methyl acetate, tetrahydrofuran, dioxane, dimethylformamide, dimethyl carbonate or any mixture thereof, using known chlorinating agents, e.g.
- thionyl chloride phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, oxalyl chloride or other commercial chlorinating agents, operating at a temperature ranging from -15°C to +40°C, optionally in an inert gas atmosphere such as nitrogen or argon.
- the duration of the chlorination reaction may be from 15 minutes to 3 hours.
- aprotic solvent e.g. toluene, xylene or an alkane or cycloalkane having from 5 to 7 carbon atoms
- the process of the invention is an esterification of the corresponding dihydropyridine acid. Since the acid halide does not need to be isolated, it is in effect a one-step process. Compared to the prior art process, described above, fewer reaction by-products are formed. As a result, an improved yield is obtained and this is accompanied by simpler purification and isolation of the lercanidipine. This may be conducted by conventional methods based, for instance, on extraction with solvents from basified solutions, re-salification with hydrochloric acid and re-crystallisation. Thus the use of chromatographic columns to isolate the desired final product can be avoided. As column chromatography always requires the use of high amounts of organic eluants, its avoidance clearly contributes to the industrial applicability of the process in terms of improved product quality, lower manufacturing costs and easier ecological disposal of process waste.
- the lercanidipine hydrochloride prepared according to the present invention is in an anhydrous crystalline form and melts within two degrees Celsius in the 185 to 190°C range after re-crystallization of the crude hydrochloride first from aprotic solvents, such as ethyl acetate, methyl acetate or acetone, and then from protic solvents, such as one or more of methanol, ethanol, n-propanol, i-propanol, n-butanol, s-butanol and t-butanol, optionally in admixture with other solvents, including water.
- aprotic solvents such as ethyl acetate, methyl acetate or acetone
- the organic solution was washed sequentially with a saturated NaCl solution (700 ml), 10% Na 2 CO 3 (700 ml x 5), saturated NaCl solution (700 ml), IN HC1 (700 ml x 5) and saturated NaCl solution (700 ml).
- the organic layer was separated off, dried over anhydrous Na 2 SO 4 for 30 minutes, filtered, treated with 23 g of carbon and re-filtered.
- the resulting solution was then concentrated in vacuo to a volume of about one litre and seeded with lercanidipine hydrochloride crystals.
- the anhydrous form of lercanidipine hydrochloride is clearly less hygroscopic than the hemihydrate.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Urology & Nephrology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Vascular Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
Priority Applications (19)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL96323236A PL185260B1 (pl) | 1995-05-12 | 1996-05-09 | Sposób wytwarzania chlorowodorku lerkanidypiny |
| RO97-02101A RO119616B1 (ro) | 1995-05-12 | 1996-05-09 | Procedeu de preparare a clorhidratului de lercanidipină |
| UA97125981A UA46769C2 (uk) | 1995-05-12 | 1996-05-09 | Спосіб одержання метил-1,1,n-триметил-n-(3,3-дифенілпропіл)-2-аміноетил-1,4-дигідро-2,6-диметил-4-(3-нітрофеніл)-піридин-3,5- дикарбоксилату (лерканідипіну) гідрохлориду |
| SI9630493T SI0824517T1 (en) | 1995-05-12 | 1996-05-09 | A process for the preparation of lercanidipine hydrochloride |
| NZ309059A NZ309059A (en) | 1995-05-12 | 1996-05-09 | A process for the preparation of lercanidipine hydrochloride |
| EE9700303A EE03351B1 (et) | 1995-05-12 | 1996-05-09 | Meetod lerkanidipiinhüdrokloriidi valmistamiseks |
| SK1514-97A SK283321B6 (sk) | 1995-05-12 | 1996-05-09 | Spôsob prípravy lerkanidipínhydrochloridu |
| AU58985/96A AU694046B2 (en) | 1995-05-12 | 1996-05-09 | A process for the preparation of lercanidipine hydrochloride |
| AT96916111T ATE221050T1 (de) | 1995-05-12 | 1996-05-09 | Verfahren zur herstellung von lercanidipin hydrochlorid |
| EP96916111A EP0824517B1 (en) | 1995-05-12 | 1996-05-09 | A process for the preparation of lercanidipine hydrochloride |
| BR9608374A BR9608374A (pt) | 1995-05-12 | 1996-05-09 | Processo para a prepara-Æo de cloridrato de lercanidipina |
| HU9801913A HU226709B1 (en) | 1995-05-12 | 1996-05-09 | Process for the preparation of lercanidipine hydrochloride |
| EA199700374A EA000346B1 (ru) | 1995-05-12 | 1996-05-09 | Способ получения гидрохлорида лерканидипина |
| DK96916111T DK0824517T3 (da) | 1995-05-12 | 1996-05-09 | Fremgangsmåde til fremstilling af lercanidipinhydrochlorid |
| JP53379796A JP4038622B2 (ja) | 1995-05-12 | 1996-05-09 | レルカニジピン・ハイドロクロリドの調製方法 |
| CA002217849A CA2217849C (en) | 1995-05-12 | 1996-05-09 | A process for the preparation of lercanidipine hydrochloride |
| DE69622552T DE69622552T2 (de) | 1995-05-12 | 1996-05-09 | Verfahren zur herstellung von lercanidipin hydrochlorid |
| BG102034A BG62400B1 (bg) | 1995-05-12 | 1997-11-07 | Метод за получаване на лерканидипин хидрохлорид |
| NO975176A NO309423B1 (no) | 1995-05-12 | 1997-11-11 | Fremgangsmåte ved fremstilling av lercanidipinhydroklorid |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI950957A IT1274480B (it) | 1995-05-12 | 1995-05-12 | Procedimento migliorato per la preparazione della lercanidipina cloridrato |
| ITMI95A000957 | 1995-05-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996035668A1 true WO1996035668A1 (en) | 1996-11-14 |
Family
ID=11371581
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1996/002122 WO1996035668A1 (en) | 1995-05-12 | 1996-05-09 | A process for the preparation of lercanidipine hydrochloride |
Country Status (37)
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003014084A1 (en) * | 2001-08-06 | 2003-02-20 | Recordati Ireland Limited | Novel crystalline polymorphic forms of lercanidipine hydrochloride and process for their preparation |
| US6852737B2 (en) | 2001-08-06 | 2005-02-08 | Recordati Ireland Limited | Crude and crystalline forms of lercanidipine hydrochloride |
| WO2006134606A1 (en) * | 2005-06-15 | 2006-12-21 | Hetero Drugs Limited | A novel process for the preparation of lercanidipine |
| WO2007031865A2 (en) | 2005-09-16 | 2007-03-22 | Glenmark Pharmaceuticals Limited | Polymorphic form of lercanidipine hydrochloride and process for the preparation thereof |
| EP1856051A1 (en) | 2005-02-25 | 2007-11-21 | Recordati Ireland Limited | Amorphous lercanidipine hydrochloride |
| EP1860102A1 (en) * | 2006-05-24 | 2007-11-28 | CF Pharma Ltd. | Process for Producing Lercanidipine |
Families Citing this family (11)
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| CN109956943B (zh) * | 2019-04-18 | 2021-07-20 | 合肥合源药业有限公司 | 一种二氢吡啶类药物中脱羧缩合杂质及其制备、控制方法 |
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| AU2002327924B2 (en) * | 2001-08-06 | 2008-04-24 | Recordati Ireland Limited | Novel crystalline polymorphic forms of lercanidipine hydrochloride and process for their preparation |
| US6852737B2 (en) | 2001-08-06 | 2005-02-08 | Recordati Ireland Limited | Crude and crystalline forms of lercanidipine hydrochloride |
| EP1600441A2 (en) | 2001-08-06 | 2005-11-30 | Recordati Ireland Limited | Novel crystalline form of lercanidipin hydrochloride and processes for its preparation |
| EP1600441A3 (en) * | 2001-08-06 | 2005-12-07 | Recordati Ireland Limited | Novel crystalline form of lercanidipin hydrochloride and processes for its preparation |
| HRP20040156B1 (en) * | 2001-08-06 | 2012-03-31 | Recordati Ireland Limited | Novel crystalline polymorphic forms of lercanidipine hydrochloride and process for their preparation |
| AU2002327924C1 (en) * | 2001-08-06 | 2009-12-10 | Recordati Ireland Limited | Novel crystalline polymorphic forms of lercanidipine hydrochloride and process for their preparation |
| AP1766A (en) * | 2001-08-06 | 2007-08-10 | Recordati Ireland Ltd | Novel crystalline polymorphic forms of lercanidipine hydrochloride and process for their preparation. |
| EP2036890A1 (en) * | 2001-08-06 | 2009-03-18 | Recordati Ireland Limited | Crystalline form (i) of lercanidipine hydrochloride |
| WO2003014084A1 (en) * | 2001-08-06 | 2003-02-20 | Recordati Ireland Limited | Novel crystalline polymorphic forms of lercanidipine hydrochloride and process for their preparation |
| EP1856051A1 (en) | 2005-02-25 | 2007-11-21 | Recordati Ireland Limited | Amorphous lercanidipine hydrochloride |
| EP1856051B1 (en) | 2005-02-25 | 2019-11-13 | Recordati Ireland Limited | Amorphous lercanidipine hydrochloride |
| NO344559B1 (no) * | 2005-02-25 | 2020-02-03 | Recordati Ireland Ltd | Amorf lerkanidipinhydroklorid |
| US7687653B2 (en) | 2005-06-15 | 2010-03-30 | Hetero Drugs Limited | Process for the preparation of lercanidipine |
| US7772401B2 (en) | 2005-06-15 | 2010-08-10 | Hetero Drugs Limited | Process for the preparation of lercanidipine |
| WO2006134606A1 (en) * | 2005-06-15 | 2006-12-21 | Hetero Drugs Limited | A novel process for the preparation of lercanidipine |
| WO2007031865A3 (en) * | 2005-09-16 | 2007-08-30 | Glenmark Pharmaceuticals Ltd | Polymorphic form of lercanidipine hydrochloride and process for the preparation thereof |
| WO2007031865A2 (en) | 2005-09-16 | 2007-03-22 | Glenmark Pharmaceuticals Limited | Polymorphic form of lercanidipine hydrochloride and process for the preparation thereof |
| US8097729B2 (en) | 2005-09-16 | 2012-01-17 | Glenmark Generics Ltd. | Polymorphic form of lercanidipine hydrochloride and process for the preparation thereof |
| EP1860102A1 (en) * | 2006-05-24 | 2007-11-28 | CF Pharma Ltd. | Process for Producing Lercanidipine |
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