- Preparation method of high-purity pramipexole
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The invention relates to the technical field of pharmacy, and provides a preparation method of high-purity pramipexole. According to the invention, raceme 2, 6-diamino 4, 5, 6, 7-tetrahydrobenzothiazole is used as an initial raw material, and pramipexole is obtained through a three-step chemical reaction, so the introduction of uncontrollable factors of drug quality is reduced, and the requirements of drug application are better met; the market price of the initial raw materials is low, so that the preparation cost of pramipexole can be greatly reduced; the solvent used in the method is green, environmentally friendly, cheap, easy to obtain and suitable for industrial production, the HPLC purity of the obtained pramipexole can reach 99.86%, and the isomer purity can reach 99.89%.
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Paragraph 0059; 0064-0068; 0073-0076
(2021/04/07)
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- Preparation method of pramipexole
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The invention discloses a preparation method of pramipexole. The method comprises the following steps: adding (S)-2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole into tetrahydrofuran, and carrying out a reduction reaction by using a sodium borohydride/boron trifluoride complex, wherein a molar ratio of (S)-2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole to sodium borohydride to boron trifluoride complex is 1:1:2-1:3:4; and separating to obtain a target product (S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole. The method provided by the invention has the advantages that the required raw materials are simple and easily available, the reaction conditions are mild, the use amount of the sodium borohydride/boron trifluoride complex is greatly reduced compared with theprior art, the reaction safety is greatly improved while the cost is saved, and the yield and the purity are higher, so that the method is suitable for industrial production.
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Paragraph 0025-0032
(2020/04/17)
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- Preparation method of pramipexole dihydrochloride
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The invention relates to a preparation method of pramipexole dihydrochloride in the technical field of medicine preparation. The method includes adding (S)-2,6-diamino-4, 6-diamino-4,5,6,7-tetrahydrobenzothiazole adopted as an initial raw material I together with n-propyl p-toluenesulfonate into a toluene solvent; carrying out N-alkylation by the n-propyl p-toluenesulfonate under the action of analkali and a phase transfer catalyst to generate (S)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzothiazole (II); and dropwise adding hydrochloric acid for salifying the compound II in toluene to obtain the pramipexole dihydrochloride. According to the method, the n-propyl p-toluenesulfonate is selected as an alkylation reagent, an alkylation reaction of amino is completed in one step to obtain pramipexole, the hydrochloric acid is directly dropwise added into the pramipexole to form the salt without separation, the reaction steps are shortened, and the economic benefits of the product are improved.
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Paragraph 0017-0025
(2020/05/09)
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- Pramipexole related compound and preparation method and usage thereof
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The invention discloses a pramipexole related compound and a preparation method and a usage thereof. The pramipexole related compound is a compound as shown in a formula (I) or salt thereof. The compound as shown in the formula (I) or the salt thereof can be used as a standard substance (a reference substance) of related substances in pramipexole, and used for controlling quality of a pramipexolecrude drug or preparation.
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Paragraph 0048-0050
(2019/01/23)
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- Preparation method of pramipexole dihydrochloride and intermediate thereof
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The invention discloses a preparation method of pramipexole dihydrochloride and an intermediate thereof. The invention provides a preparation of pramipexole II. The preparation method of the pramipexole II comprises the following steps: performing condensation reaction and reduction reaction on a pramipexole intermediate III, propylamine and hydrogen in an organic solvent and under the existence of a chiral catalyst, and performing one-pot method to obtain the pramipexole II. According to the preparation method provided by the invention, the route step is short, chiral resolution is not neededand the total molar yield is high; furthermore, the prepared product has high purity, can reach to the standard of raw material medicines and is suitable for industrialized production. (The formula is shown in the description).
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- Industrial preparation method for pramipexole and hydrochloride thereof
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The invention relates to a preparation method for S-(-)pramipexole. The method comprises the following steps: (1) dissolving S-(-)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole in a mixed solvent, carrying out stirring, adding a basic catalyst and n-propyl p-toluenesulfonate, carrying out heating after completion of addition, then carrying out a stirring reaction, and carrying out filtering and drying after completion of the reaction so as to obtain white S-(-)pramipexole p-toluenesulfonate solid; and (2) adding S-(-)pramipexole p-toluenesulfonate into an aqueous solution of salt, adding an inorganic base under stirring, carrying out stirring at room temperature after completion of addition, and carrying out filtering and drying so as to obtain a white S-(-)pramipexole solid, wherein no organic solvent is used in the step (2).
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Paragraph 0064-0087; 0099-0103
(2018/04/01)
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- Synthesis method of high-purity pramipexole
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The invention discloses a synthesis method of high-purity pramipexole, which includes the steps of: 1) an acylation reaction; 2) crystallization; 3) preparation of an intermediate; 4) a reduction reaction; 5) extraction and purification; 6) reflux decolorization; and 7) recrystallization. In the method, through the acylation reaction then the reduction reaction, reaction efficiency of a raw material, S-(-)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole, is increased, thereby increasing the yield of the pramipexole; and through operations of decolorization, extraction, recrystallization and the like, purity and quality of the pramipexole are increased effectively. The method has gentle and controllable reaction conditions, is simple in operations in crystallization, recrystallization and purification steps and has high practicability. The pramipexole is high in yield and purity, is low in impurity content and has great market prospect.
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Paragraph 0017; 0018
(2018/01/11)
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- Convenient N-Alkylation of amines using an effective magnetically separable supported ionic liquid containing an anionic polyoxometalate
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Abstract: An effective synthesis of anion-exchanged supported ionic liquid using magnetically separable nanoparticles and its catalytic effect on N-alkylation reactions is described. Anionic polyoxometalate derivative was used in the anion-exchange step in catalyst design. The catalytic system can be easily separated from the reaction mixture with external magnetic field and recycled in subsequent reactions. In order to evaluate catalyst repeatability, N-alkylation of some more amines such as Aniline, 4-aminobenzenesulfonamide, 4-methoxyaniline, 2-aminopyrimidin and 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine in the presence of recoverable catalyst was successfully examined in this article. In addition, pramipexole dihydrochloride as an active pharmaceutical ingredient was successfully synthesized using the catalytic system. The structure of catalyst was determined by infrared spectroscopy, X-ray powder diffraction, and scanning electron microscope techniques. The structure of organic products was determined by 1H NMR, 13C NMR, infrared and Mass spectroscopy. Graphical Abstract: [Figure not available: see fulltext.]
- Ghasemi, Mohammad Hadi,Kowsari, Elaheh
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p. 1957 - 1968
(2017/02/15)
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- Synthesis method of pramipexole hydrochloride intermediate
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The invention discloses a synthesis method of a pramipexole hydrochloride intermediate, wherein the method comprises the following steps: under the protection of inert gas, carrying out a contact reaction of (S)-2-amino-6-aminopropyl-4,5,6,7-tetrahydrobenzothiazole with NaBH4 and a solid super-strong acid in a reaction solvent to generate the pramipexole hydrochloride intermediate. In the synthesis method of the pramipexole hydrochloride intermediate, use of flammable and explosive reducing agents such as borane, lithium aluminum hydride, red aluminum and the like is avoided, and thus the process is safe; moreover, the used solid super-strong acid can be recycled and reused, so the cost is reduced; and the synthesis method has important application value.
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Paragraph 0042; 0043; 0044; 0045
(2017/01/12)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE
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The present invention relates to an improved process for the preparation of the dihydrochloride monohydrate salt of (S)-2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole (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 the solvent to obtain the compound of formula I; followed by converting the compound of formula I into its monohydrochloride salt; purifying the monohydrochloride salt of the compound of formula I; and finally converting the pure monohydrochloride salt of the compound of formula I into the dihydrochloride monohydrate salt.
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Page/Page column 15
(2015/11/03)
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- IMPROVED PROCESS FOR THE PREPARATION OF (S)-2-AMINO-4,5,6,7-TETRAHYDRO-6 - (PROPYLAMINO) BENZOTHIAZOLE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention relates to an improved process for the preparation of of (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole and its pharmaceutically acceptable salts. Specifically relates to the compound represented by the following structural formula- Ia.
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Page/Page column 10; 13; 14
(2011/04/13)
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- A novel scalable synthesis of pramipexole
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Pramipexole is a dopamine D2 subfamily receptor agonist that is used for the treatment of Parkinsons disease. We report here on the successful application of the Fukuyama alkylation protocol to the development of a novel and scalable process for synthesis of pramipexole and its pharmaceutically acceptable salts. The synthesis consists of converting the crucial intermediate (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole to (6S)-N-(2-amino-4,5,6,7- tetrahydrobenzothiazole-6-yl)-2-nitrobenzenesulfonamide, which is in turn monoalkylated to (6S)-N-(2-amino-4,5,6,7-tetrahydrobenzothiazole-6-yl)-2-nitro- N-propylbenzenesulfonamide. Deprotection of the latter yields pramipexole base, which is finally converted to a crude pramipexole dihydrochloride monohydrate with a yield of over 50% over four steps. The process allows for the telescoping of the final three steps, has high conversion rates of intermediates, offers ease of purification, and preserves high optical purity throughout all of the stages.
- Zivec, Matej,Anzic, Borut,Gobec, Stanislav
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experimental part
p. 1125 - 1129
(2011/04/12)
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- COMPOSITIONS AND METHODS OF USING (R)-PRAMIPEXOLE
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Pharmaceutical compositions of (R)-pramipexole and one or more secondary therapeutic agents such as, for example, dopamine agonists, dopaminergic agonists, COMT inhibitors, MOA inhibitors, excitatory amino acid antagonists, growth factors, neurotrophic factors, antioxidants, anti-inflammatory agents, immunomodulators, anti-glutamatergics, ion channel blockers, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, heat shock protein inducers/ protein disaggregators and downregulators, monoamine oxidase type B (MOAB) inhibitors, multi-target agents, kinase inhibitors, Bcl inducers, histone deacetylase (HDAC) mediators, glial modulators, mitochondrial energy promoting agents, myostatin inhibitors, caspase inhibitors and combinations thereof or those related to mitochondrial dysfunction or increased oxidative stress are disclosed.
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Page/Page column 100-101
(2010/04/03)
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- PROCESS FOR THE PREPARATION OF PRAMIPEXOLE AND NEW ANHYDROUS FORMS OF ITS DIHYDROCHLORIDE
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The present invention provides processes for the preparation of (?) pramipexole or an acid addition salt thereof of Formula I. The present invention further provides for the novel polymorphic Forms A and B of anhydrous pramipexole dihydrochloride.
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Page/Page column 4
(2009/04/24)
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- PROCESS FOR PREPARING (S)-PRAMIPEXOLE AND ITS INTERMEDIATES
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The present invention relates to an improved process for the preparation of (S)- 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole of formula (II) useful in the preparation of pramipexole or (S)-2,6-amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) and its pharmaceutically acceptable salts or solvates thereof. The present invention further provides a process for the preparation of Pramipexole and its pharmaceutically acceptable salts, hydrates, solvates thereof.
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Page/Page column 18
(2008/06/13)
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- Process for producing pramipexole
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The present invention relates to a process for preparing (S)-pramipexole and to certain intermediates useful therein.
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Page/Page column 11
(2008/06/13)
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- NOVEL PROCESS FOR SYNTHESIS OF PRAMIPEXOLE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention relates to a novel process for synthesis of pramipexole, shown in the synthesis scheme. Formulae (I), (II), (III), (IV), (V) and (VI).
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Page/Page column 16-17
(2008/12/08)
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- METHOD FOR THE RESOLUTION OF 2-AMINO-6-PROPYLAMINO-4,5,6,7-TETRAHYDROBENZOTHIAZOL AND INTERMEDIATE COMPOUNDS
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The invention relates to a novel method for the resolution of the racemic mixture of compound (R,S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole, or the enrichment of same with in one of its enantiomers, and to intermediate compounds which can be used to perform said method.
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Page/Page column 11
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF PRAMIPEXOLE BASE AND/OR ITS SALTS
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The process for the preparation of pramipexole base and/or its pharmaceutically accepted salts, especially hydrochloride salt, is based on the reaction of (S)-(-)2,6-diamino-4,5,6,7-tetrahydrobenzothiazole with an alkylating agent, wherein the reaction is carried out with the absence of a base, in a solvent from which the resulting N-monoalkylated product selectively precipitates out as a salt, which, after isolation from the reaction mixture: a) upon the treatment of inorganic base is converted into free pramipexole base, and then into another pharmaceutically accepted pramipexole salt, or b) is converted directly into another pharmaceutically accepted pramipexole salt or the hydrate thereof.
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Page/Page column 7-8
(2008/06/13)
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- NOVEL PROCESS
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A novel process for the preparation of S(-)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole (pramipexole).
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Page/Page column 9-11
(2008/06/13)
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- PROCESS FOR PREPARING CHIRALLY PURE 2-AMINO-6-(ALKYL)AMINO-4,5,6,7-TETRAHYDROBENZOTHIAZOLES BY LIQUID CHROMATOGRAPHIC RESOLUTION
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Processes for obtaining single enantiomers of 2-amino-6-(alkyl)amino-4,5,6,7-tetrahydrobenzothiazoles by liquid chromatography are disclosed.
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Page/Page column 18-19
(2008/06/13)
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- IMPROVED PROCESS FOR THE PREPARATION OF BIOLOGICALLY ACTIVE TETRAHYDROBENZTHIAZOLE DERIVATIVE
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Improved process for the preparation of the intermediate compound of formula II for formation pramipezole of formula (I) as well as the biological active tetrahydrobenzothiazole compound of formula (I) and/or its pharmaceutically acceptable salts or solvates.
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Page/Page column 10; 18-19
(2008/06/13)
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- Novel process for preparing pramipexole and its optical isomeric mixture by reduction with sodium triacetoxyborohydride
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A novel process is provided for producing pramipexole base or its optical isomeric mixture as defined hereinabove i.e. (R,S)-2-amino-6-propyl-4,5,6,7-tetrahydrobenzothiazole avoiding the use of borane tetrahydrofuran complex and using a more convenient reducing agent like sodium triacetoxyborohydride instead. The provided process comprises reacting the starting material (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole or its optical isomeric mixture as defined hereinabove i.e. (R,S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole with propionaldehyde in an organic solvent to obtain the respective enamine, which is subsequently reduced in situ, optionally without isolation, to obtain pramipexole or its optical isomeric mixture as defined hereinabove i.e. (R,S)-2-amino-6-propyl-4,5,6,7-tetrahydrobenzothiazole, and the acid addition salts thereof. The present invention also provides a process for purifying pramipexole dihydrochloride or the dihydrochloride salt of its optical isomeric mixture as defined hereinabove i.e. (R,S)-2-amino-6-propyl-4,5,6,7-tetrahydrobenzothiazole dihydrochloride by re-crystallization from a suitable solvent.
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Page/Page column 2; 4
(2008/06/13)
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- Process for the reduction of (S)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzo-thiazole
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A process is disclosed for the reduction of (S)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzothiazole, which comprises reacting (S)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzothiazole with a borane reagent in the presence of suitable organic solvent to yield (S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole base, which may be converted to an acid addition salt thereof. The process provided herein can be easily, conveniently and inexpensively scaled-up.
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Page/Page column 3
(2008/06/13)
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- INTERMEDIATES FOR THE PREPARATION OF PRAMIPEXOLE
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Intermediates useful for the preparation of pramipexole and the use thereof in such synthesis.
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Page/Page column 25
(2010/02/14)
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- PRAMIPEXOLE ACID ADDITION SALTS
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The benzene sulfonic acid salts of pramipexole have moderate water solubility and are useful pharmaceutical active agents.
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Page/Page column 15
(2008/06/13)
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- Dopamine autoreceptor agonists: Resolution and pharmacological activity of 2,6-diaminotetrahydrobenzothiazole and an aminothiazole analogue of apomorphine
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The enantiomers of the aminothiazole analogues of the known dopaminergic agonists apomorphine (1) and 2-aminohydroxytetralin (2) have been prepared. The absolute configurations of the enantiomers of 2,6-diaminotetrahydrobenzothiazole have been established by X-ray crystallographic analysis. Dopamine (DA) autoreceptor agonist activities of the compounds were evaluated. Testing revealed (-)-5, the S enantiomer, to be the most active compound tested (inhibition of GBL accelerated dopamine synthesis and inhibition of α-methyltyrosine-induced decline of DA). In addition (-)-5 does not exhibit stereotyped behavior, suggesting a pronounced selectivity for DA autoreceptors.
- Schneider, Claus S.,Mierau, Joachim
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p. 494 - 498
(2007/10/02)
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