WO2015155704A1 - Procédé amélioré de préparation du monohydrate du dichlorhydrate de pramipexole - Google Patents
Procédé amélioré de préparation du monohydrate du dichlorhydrate de pramipexole Download PDFInfo
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- WO2015155704A1 WO2015155704A1 PCT/IB2015/052542 IB2015052542W WO2015155704A1 WO 2015155704 A1 WO2015155704 A1 WO 2015155704A1 IB 2015052542 W IB2015052542 W IB 2015052542W WO 2015155704 A1 WO2015155704 A1 WO 2015155704A1
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- WIPO (PCT)
- Prior art keywords
- formula
- compound
- salt
- methanol
- dihydrochloride monohydrate
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 66
- 230000008569 process Effects 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 229950010601 pramipexole dihydrochloride monohydrate Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 121
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 90
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 74
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 64
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 claims abstract description 46
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims abstract description 46
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000000203 mixture Substances 0.000 claims abstract description 28
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 26
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 26
- 239000002904 solvent Substances 0.000 claims abstract description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 abstract description 15
- 238000006243 chemical reaction Methods 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 35
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- 239000012535 impurity Substances 0.000 description 16
- 229960003089 pramipexole Drugs 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 7
- 239000010410 layer Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000006207 propylation Effects 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000005932 reductive alkylation reaction Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- DRRYZHHKWSHHFT-BYPYZUCNSA-N (6s)-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine Chemical compound C1[C@@H](N)CCC2=C1SC(N)=N2 DRRYZHHKWSHHFT-BYPYZUCNSA-N 0.000 description 1
- HYBCFWFWKXJYFT-UHFFFAOYSA-N 1,3-benzothiazole-2,6-diamine Chemical compound C1=C(N)C=C2SC(N)=NC2=C1 HYBCFWFWKXJYFT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FDILCXYULUBXSL-DKNRTOFZSA-N NC=1SC2=C(N1)CC[C@H](C2)NCC(C(CC)N[C@@H]2CC1=C(N=C(S1)N)CC2)C Chemical compound NC=1SC2=C(N1)CC[C@H](C2)NCC(C(CC)N[C@@H]2CC1=C(N=C(S1)N)CC2)C FDILCXYULUBXSL-DKNRTOFZSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940101972 mirapex Drugs 0.000 description 1
- -1 monohydrate salt Chemical class 0.000 description 1
- WZEMYWNHKFIVKE-UHFFFAOYSA-N n-(4-oxocyclohexyl)acetamide Chemical compound CC(=O)NC1CCC(=O)CC1 WZEMYWNHKFIVKE-UHFFFAOYSA-N 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/82—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
Definitions
- the present invention relates to a process for the preparation of the dihydrochloride monohydrate salt of (S)-2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole ("referred to herein as 'Pramipexole' or the compound of formula I").
- the present invention provides an improved process for the preparation of the compound of formula I from (S)-2,6- diamino-4,5,6,7-tetrahydrobenzthiazole (referred to herein as the compound of formula II) and further conversion of the compound of formula I into its dihydrochloride monohydrate salt.
- Pramipexole (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole, represented by the following formula I (the compound of formula I), is a dopamine D2/D3 agonist used for treatment of Schizophrenia, and particularly for the treatment of Parkinson's disease. Pramipexole is marketed in the form of dihydrochloride monohydrate salt under the brand name Mirapex.
- the compound of formula I is disclosed in US Patent no. 4,886,812 (US '812 Patent).
- US' 812 Patent also describes a process for the preparation of the compound of formula I and its dihydrochloride monohydrate salt involving the propylation reaction of the compound of formula II with n-propylbromide as a propylating agent in the presence of potassium carbonate by using methanol as a solvent to provide the reaction mixture.
- the resulting reaction mixture is then refluxed for 3 hours. After completion of the reaction, water is added to the reaction mixture.
- the reaction mixture is then extracted with ethyl acetate and concentrated to obtain the residue.
- Indian Patent Application no. 694/MUM/2006 describes a process for the preparation of the dihydrochloride monohydrate salt of the compound of formula I involving treating the alcoholic solution of the compound of formula I with hydrochloric acid and precipitating the dihydrochloride monohydrate salt of the compound of formula I by addition of water.
- the process disclosed in this patent application does not involve any purification step for the purification of the compound of formula I or its dihydrochloride monohydrate salt and thus, the final active pharmaceutical ingredient (API), the dihydrochloride monohydrate salt of the compound of formula I prepared by this process does not have the desired pharmaceutically acceptable purity.
- Indian patent application no. 605/MUM/2008 describes a process for the preparation of the dihydrochloride salt of the compound of formula I.
- the process for the preparation of the dihydrochloride salt of the compound of formula I involves the propylation reaction of the compound of formula II with n-propanal as a propylating agent by using a mixture of methanol and water as the solvent.
- glacial acetic acid and sodium borohydride are charged and the reaction mixture is stirred for 30-40 minutes at a temperature of 15 to 20°C.
- the reaction mixture is then cooled to -5 to 0°C and to the reaction mixture; second lot of n-propanal with methanol and sodium borohydride is added.
- the resulting reaction mixture is stirred for 30-40 minutes and quenched with brine solution.
- the reaction mixture is distilled under vacuum to obtain a residue.
- the precipitated dihydrochloride salt of the compound of formula I is dissolved in a mixture of ethanol and water; and filtered through hyflo. The filtrate is then distilled under vacuum and recrystallised by using ethanol to obtain the pure dihydrochloride salt of the compound of formula I.
- the process disclosed in said patent involves the use of 3 molar equivalents of sodium borohydride and n- propanal which renders the process costlier and hence, this process is not viable for scale up.
- the processes for the preparation of the compound of formula I as disclosed in the afore discussed patent documents involve the alkylation reaction of the compound of formula II with the 3-4 molar equivalents of propylating agent in the presence of an organic solvent to obtain (S)-2-amino-6-propinamido- 4,5,6,7-tetrahydrobenzothiazole.
- the obtained (S)-2-amino-6-propinamido- 4,5,6,7-tetrahydrobenzothiazole is reduced insitu by addition of 3-4 molar equivalents of sodium borohydride to obtain the compound of formula I,which is further converted into its dihydrochloride monohydrate salt.
- the process for the preparation of the compound of formula I involves the reductive alkylation of the compound of formula II.
- one major impurity viz (6S)-,2,6-benzothiazolediamine,4,5,6,7- tetrahydro-N ⁇ A ⁇ -dipropyl of formula III (hereinafter referred to as 'impurity B') is generated.
- the purification of the compound of formula I by using acetonitrile does not provide the product, the dihydrochloride monohydrate salt of the compound of formula I having pharmaceutical acceptable purity.
- the process described in said patent application requires 3 molar equivalents of n-propanal and sodium borohydride based on the compound of formula II. N-propanal and sodium borohydride are expensive reagents and therefore, use of the same in an excess amount renders the whole process costly.
- An object of the present invention is to provide an improved process for the preparation of the dihydrochloride monohydrate salt of the compound of formula I comprising reacting the compound of formula II with n-propanal and sodium borohydride using a mixture of methanol and dichloromethane (DCM) as a solvent.
- Another object of the present invention is to provide an improved process for the preparation of the dihydrochloride monohydrate salt of the compound of formula I using minimum molar equivalents of n-propanal and sodium borohydride.
- Another object of the present invention is to provide an improved process for the preparation of the dihydrochloride monohydrate salt of the compound of formula I comprising the preparation of the compound of formula I by the reaction of the compound of formula II with n-propanal and sodium borohydride using a mixture of methanol and dichloromethane (DCM) as the solvent and conversion of the resulting compound of formula I to its monohydrochloride salt followed by recrystallisation of the monohydrochloride salt of the compound of formula I and finally, its conversion to the dihydrochloride monohydrate salt of the compound of formula I.
- DCM dichloromethane
- the process for the preparation of the compound of formula I comprising the reaction of the compound of formula II with n-propanal and sodium borohydride using the mixture of methanol and DCM as a solvent to obtain the compound of formula I requires less molar equivalents of sodium borohydride and n-propanal.
- the further conversion of the compound of formula I to its monohydrochloride salt followed by recrystallisation of the resulting monohydrochloride salt of the compound of formula I and further conversion of the pure monohydrochloride salt to the dihydrochloride monohydrate salt of the compound of formula I results in removing the individual impurity A, B and C less than 0.15% which ultimately results the product, the dihydrochloride monohydrate salt of the compound of formula I with higher purity.
- the present invention relates to an improved process for the preparation of the dihydrochloride monohydrate salt of the compound of formula I.
- the improved process for the preparation of the dihydrochloride monohydrate salt of the compound of formula I involves reaction of the compound of formula II with n-propanal and sodium borohydride using the mixture of methanol and DCM as a solvent to obtain the compound of formula I and further conversion of the compound of formula I to its monohydrochloride salt followed by recrystallisation of the resulting monohydrochloride salt of the compound of formula I and further conversion of the pure monohydrochloride salt to the dihydrochloride monohydrate salt of the compound of formula I.
- the compound of formula I is obtained by reacting the compound of formula II with propanal and sodium borohydride using a mixture of methanol and dichloromethane (DCM) as the solvent.
- the compound of formula I as obtained in the step (A) is further converted into its monohydrochloride salt in the step (B).
- step (C) the monohydrochloride salt as obtained in step (B) purified with the mixture of methanol-water and further converted into dihydrochloride monohydrate salt in the step (D).
- n- propanal is used in an amount ranging from 1 to 2 molar equivalents based on the compound of formula II.
- step (A) of the process sodium borohydride is used in an amount ranging from 0.4 to 1 molar equivalent based on the compound of formula II.
- methanol is used in an amount ranging from 15 to 20 volumes based on the compound of formula II.
- DCM is used in an amount ranging from 15 to 20 volumes based on the compound of formula II.
- the ratio of methanol to DCM used is 1: 1.
- the organic solvent used in the step (B) of the process is selected from the group consisting of methanol, isopropyl alcohol, toluene, methyl tert-butyl ether (MTBE), n-hexane and ethyl acetate or a mixture thereof.
- the organic solvent or the mixture of organic solvents is used in an amount ranging from 1 to 10 volumes based on the compound of formula II.
- methanol is used in an amount ranging from 2 to 15 volumes based on the compound of formula II.
- step (C) of the process water is used in an amount ranging from 0.03 to 0.07% based on the compound of formula II.
- step (D) of the process isopropyl alcohol is used in an amount ranging from 2 to 15 volumes based on the compound of formula II.
- the starting material of the process i.e. the compound of formula II is a known compound and can be prepared by a person skilled in the art by following methods described in the art, for example, by the process described in WO2008104847.
- the process involves reaction of N-(4-oxocyclohexyl) acetamide with thiourea in the presence of bromine and acetic acid to obtain a reaction mixture.
- dilute sulphuric acid was added to obtain sulphate salt of the compound of formula II.
- sodium hydroxide was added to obtain the racemic compound of formula II.
- the racemic compound of formula II was further resolved using tartaric acid to obtain the S isomer of the compound of formula II.
- the process for the preparation of the dihydrochloride monohydrate salt of the compound of formula I involves reaction of the compound of formula II with n-propanal and sodium borohydride using a mixture of methanol and dichloromethane (DCM) as the solvent at a temperature of 25-30°C. After completion of the reaction, the reaction mixture was quenched with brine solution. The quenched reaction mixture was further concentrated up to 15-16 volumes under vacuum at a temperature of 50-55°C. The reaction mixture was cooled to a temperature of 15-20°C. To the reaction mixture, potassium carbonate, ethyl acetate and methanol were charged. The two layers formed were separated. The organic layer was then concentrated up to 7 to 8 volumes.
- DCM dichloromethane
- the conversion of the compound of formula I into its monohydochoride salt involves the addition of 1 mole equivalent of concentrated hydrochloric acid to the solution of the compound of formula I in isopropyl alcohol (IPA) at a temperature of 15-20°C to obtain monohydrochloride salt of the compound of formula I.
- IPA isopropyl alcohol
- the obtained monohydrochloride salt of the compound of formula I was then filtered and washed with isopropyl alcohol.
- the monohydrochloride salt of the compound of formula I was then purified using a mixture of methanol and water.
- the purification of the monohydrochloride salt of the compound of the formula I involves the charging of the monohydrochloride salt of the compound of formula I and the mixture of methanol-water to the reaction flask and the reaction mixture was heated to the reflux temperature. The reaction mixture was then cooled to a temperature of 25-30°C to precipitate solid. The precipitated solid was then filtered and washed with isopropyl alcohol (IPA) to obtain the pure monohydrochloride salt of the compound of formula I which was further converted into the dihydrochloride monohydrate salt of the compound of formula I.
- IPA isopropyl alcohol
- the process for the conversion of the pure monohydrochloride salt of the compound of formula I into the corresponding dihydrochloride monohydrate salt involves the charging of the pure monohydrochloride salt of the compound of formula I and isopropyl alcohol to the reaction flask at 25-30°C. To the reaction mass 1 mole equivalent of concentrate dihydrochloric acid was added at a temperature of 10-15°C to precipitate solid. The precipitated solid was then filtered and dried under vacuum to obtain the dihydrochloride monohydrate salt of the compound of formula I.
- the inventors of the present invention have observed that the dihydrochloride monohydrate salt of the compound of formula I prepared from the compound of formula II through an improved process involving the reductive amination of the compound of formula II with n-propanal and sodium borohydride using a mixture of methanol and dichloromethane (DCM) as a solvent to obtain the compound of formula I, conversion of the compound of formula I into its monohydrate salt followed by the recrystallization of the monohydrochloride salt of the compound of formula I with a mixture of methanol-water to obtain the pure monohydrochloride salt of the compound of formula I and conversion of the pure monohydrochloride salt of the compound of formula I into the dihydrochloride monohydrate salt of the compound of formula I having individual impurity A, B and C below 0.15% and having pharmaceutical acceptable purity.
- DCM dichloromethane
- reaction mixture was quenched with brine solution.
- the quenched reaction mixture was further concentrated up to 15-16 volumes at 50-55°C under vacuum.
- the reaction mixture was cooled to 15-20°C.
- potassium carbonate (150 g) ethyl acetate (900 ml) and methanol (100 ml) were charged. The two layers formed were separated. The organic layer was then concentrated up to 7 to 8 volumes.
- ethyl acetate (500 ml) and brine solution (240 g) were added. The two layers formed were separated. The organic layer was treated with activated charcoal and filtered through hyflo. The organic layer was then concentrated under vacuum to obtain residue.
- SPL (Area) - is area of peak due to impurities in sample preparation.
- STD (Area) - is mean area of peak of Pramipexole in reference solution (a) for injections.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne un procédé amélioré de préparation du sel monohydrate du dichlorhydrate de (S)-2-amino-4,5,6,7-tétrahydro-6-(propylamino)benzothiazole (le composé de formule I) consistant à faire réagir le composé de formule II avec du n-propanal et du borohydrure de sodium en faisant appel à un mélange de méthanol et de dichlorométhane (DCM) en tant que solvant afin d'obtenir le composé de formule I ; puis à convertir le composé de formule I en son sel monochlorhydrate ; à purifier ledit sel monochlorhydrate du composé de formule I ; et enfin à convertir ledit sel monochlorhydrate pur du composé de formule I en sel monohydrate de dichlorhydrate.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN1307/MUM/2014 | 2014-04-09 | ||
IN1307MU2014 | 2014-04-09 |
Publications (1)
Publication Number | Publication Date |
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WO2015155704A1 true WO2015155704A1 (fr) | 2015-10-15 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/IB2015/052542 WO2015155704A1 (fr) | 2014-04-09 | 2015-04-08 | Procédé amélioré de préparation du monohydrate du dichlorhydrate de pramipexole |
Country Status (1)
Country | Link |
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WO (1) | WO2015155704A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107540632A (zh) * | 2016-06-27 | 2018-01-05 | 江苏神龙药业股份有限公司 | 一种普拉克索单盐酸盐的新晶型及其制备方法 |
CN107540634A (zh) * | 2016-06-27 | 2018-01-05 | 江苏神龙药业股份有限公司 | 一种普拉克索单盐酸盐的新晶型及其制备方法 |
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CN103626718A (zh) * | 2013-12-13 | 2014-03-12 | 山东新华制药股份有限公司 | 盐酸普拉克索的工业化制备方法 |
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WO2011021214A2 (fr) * | 2009-08-07 | 2011-02-24 | Msn Laboratories Limited | Procédé amélioré pour la préparation de (s)-2-amino-4,5,6,7-tétrahydro-6-(propylamino)benzothiazole et de ses sels pharmaceutiquement acceptables |
CN104072442A (zh) * | 2013-03-28 | 2014-10-01 | 成都弘达药业有限公司 | 一种化合物及其制备方法 |
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CN107540632A (zh) * | 2016-06-27 | 2018-01-05 | 江苏神龙药业股份有限公司 | 一种普拉克索单盐酸盐的新晶型及其制备方法 |
CN107540634A (zh) * | 2016-06-27 | 2018-01-05 | 江苏神龙药业股份有限公司 | 一种普拉克索单盐酸盐的新晶型及其制备方法 |
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