CN113185442A - Pramipexole hydrate crystal and preparation method thereof - Google Patents
Pramipexole hydrate crystal and preparation method thereof Download PDFInfo
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- CN113185442A CN113185442A CN202110511609.5A CN202110511609A CN113185442A CN 113185442 A CN113185442 A CN 113185442A CN 202110511609 A CN202110511609 A CN 202110511609A CN 113185442 A CN113185442 A CN 113185442A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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 to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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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
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to the technical field of compound preparation, and particularly relates to a pramipexole hydrate crystal and a preparation method thereof. The preparation method of the pramipexole dihydrate crystal comprises the following steps: (a) dropwise adding a mixed solution of N- [ (2- (diisopropylamino) ethyl) -chloroacetamide and a second organic solvent into a mixed solution of pyrrolidone, alkali and a first organic solvent for reaction, separating to obtain an organic phase, and drying to obtain a crude product of the pramipexole; (b) and (3) dropwise adding a fourth organic solvent into the mixture of the crude product of pramipexole, the third organic solvent and water, cooling, stirring, collecting solids, and drying until the water content of the crystals is 10-12%. And further drying the pramipexole dihydrate crystal until the water content is 5% -7%, so as to obtain the pramipexole monohydrate crystal. The method disclosed by the invention is safe and controllable, environment-friendly, high in product yield, high in purity and low in production cost, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of compound preparation, and particularly relates to a pramipexole hydrate crystal and a preparation method thereof.
Background
Pramipexole, a pyrrolidone brain function improver, is chemically named as N- [2- (N, N-diisopropyl) ethyl ] -2-oxo-1-pyrrolidine acetamide, and has the following structural formula:
pramitant was developed by the american Warner-Lambert company and was first marketed in italy in 1993 and subsequently in argentina, australia, france and japan. At present, China does not import relevant preparations of the product.
The pramipexole is a high-efficiency, low-toxicity and good-tolerance cognitive activator, has strong capacities of enhancing memory, improving brain function and promoting brain alertness, and is suitable for age-related hypomnesis such as Alzheimer's disease. Due to the characteristics of low toxicity and good tolerance, the medicine can be used for long-term administration of the Alzheimer disease. In recent years, the incidence of senile dementia has been increasing with the aging of the world population, and thus, the method has important significance for research and development of drugs for alzheimer's disease.
In the prior art, the preparation of pramipexole is as follows:
the synthetic route reported in the document (J Ibanez Catalan, Sinteside O- [1- (m-trifluoromethane) -indazol-3-il ] -N- (dialiquinoalqui) -2-tetrahydroxamidas, Anales de Quimica,1974,70(9-10):733-737.) uses 1, 2-dibromoethane as starting material to react with phthalimide to obtain an N- (2-bromoethyl) phthalimide intermediate, which is then subjected to nucleophilic substitution reaction with diisopropylamine and hydrolysis reaction to obtain N, N-diisopropylethylenediamine. In the route, diisopropylethylamine has large steric hindrance, so that the method is not favorable for nucleophilic substitution reaction, needs to be carried out under a tube sealing condition, has harsh reaction conditions, and is not favorable for large-scale preparation.
In EP2011587, the synthesis route is to use chloroacetyl chloride and N, N-diisopropylethylenediamine as starting materials to obtain N- [ (2-diisopropylamino) ethyl ] -chloroacetamide intermediate in a toluene-water two-phase reaction system, and to prepare 2-pyrrolidone sodium salt under the action of sodium methoxide, and then to perform a one-step reaction to obtain pramipexole. The yield of the route is high. However, the two-phase reaction in the route can affect the reaction speed, so that the reaction time is prolonged, the required reaction temperature is higher, the yield is not too high, more byproducts are generated, the subsequent reaction has more impurities due to unrefined reaction, the crystallization after salification is difficult, the purity of the product is affected, and the industrial production is not facilitated.
In US4145347, the synthesis route uses pyrrolidone ethyl acetate and N, N-diisopropylethylenediamine as starting materials to synthesize pramiperacetam, and a phase transfer catalyst TEBA is required in the route, so that the temperature is high in the reaction process, reaction byproducts are more, the reaction is reversible, and purification is not facilitated. Moreover, pyrrolidone ethyl acetate is expensive, high in production cost and not beneficial to industrial production.
In CN103012236, the synthesis route is to use diisopropylethylenediamine and chloroacetyl chloride as starting materials, perform condensation reaction, dissolve and filter, then perform re-dissolution and extraction to obtain N- (2- (diisopropyl) ethyl) -2-chloroacetamide intermediate, and then react with 2-pyrrolidone under the action of sodium hydride to prepare pramitacin. The route has the characteristics of short route and high yield, but sodium hydride is used as alkali, a large amount of hydrogen is generated in the reaction process, and the process is easy to explode when meeting dust or inflammable matters in the air, so that potential safety hazards exist in the process.
In CN104341333, in the synthetic route, N-diisopropylethylamine alcohol is used as a starting material, chlorination reaction is carried out under the action of thionyl chloride, then aminolysis is carried out to obtain an N, N-diisopropylethylenediamine intermediate, and then acylation, substitution, salification and refining are carried out to obtain the pramipexole. The route is in the synthesis of an intermediate N, N-diisopropylethylenediamine. The disadvantages of the above-mentioned document (J Ibanez Catalan, Sintesis de O- [1- (m-trifluoromethylfenil) -indazol-3-il ] -N- (dialiquinaloquil) -2-dihydroxiamide das, Anales de Quimica,1974,70(9-10): 733-.
In CN110903230, the synthetic route directly adopts N- (2- (diisopropyl) ethyl) -2-chloroacetamide hydrochloride as an initial raw material, firstly dissociating the initial raw material, and then reacting the dissociated initial raw material with 2-pyrrolidone to obtain the pramiperacetam. The route has shorter steps but higher production cost.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a preparation method of a pramipexole dihydrate crystal, which has the advantages of simple operation, mild reaction conditions, simple post-treatment, low cost, high yield, safety and no pollution.
Another object of the present invention is to provide a pramipexole dihydrate crystal obtained by the preparation method of the pramipexole dihydrate crystal, which has high yield and high purity.
The invention also aims to provide a preparation method of the pramipexole monohydrate crystal, which has the advantages of simple operation, mild reaction conditions, simple post-treatment, low cost, high yield, safety and no pollution.
Another object of the present invention is to provide a pramipexole monohydrate crystal obtained by the preparation method of the pramipexole monohydrate crystal, which has high yield and high purity.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
a preparation method of a pramipexole dihydrate crystal comprises the following steps:
(a) dropwise adding a mixed solution of N- [ (2- (diisopropylamino) ethyl) -chloroacetamide and a second organic solvent into a mixed solution of pyrrolidone, alkali and a first organic solvent for reaction, separating to obtain an organic phase, and drying to obtain a crude product of the pramipexole;
(b) and (3) dropwise adding a fourth organic solvent into the mixture of the crude product of pramipexole, the third organic solvent and water, cooling, stirring, collecting solids, and drying until the water content of the crystals is 10-12%.
Preferably, the first organic solvent comprises at least one of dichloromethane, acetonitrile, toluene, chloroform, N-dimethylformamide, and tetrahydrofuran;
preferably, the second organic solvent comprises dichloromethane and/or ethyl acetate;
preferably, the base comprises at least one of sodium hydride, potassium tert-butoxide, sodium methoxide, sodium hydroxide and sodium ethoxide;
preferably, the third organic solvent comprises at least one of tetrahydrofuran, methanol, ethanol, isopropanol, acetone, dioxane, toluene, dichloromethane, ethyl acetate, methyl tert-butyl ether, and acetonitrile;
preferably, the fourth organic solvent includes at least one of petroleum ether, diethyl ether, methyl tert-butyl ether, n-pentane, n-hexane, and n-heptane.
Preferably, in the dropping process of the step (a), the temperature of the mixed system is 10-20 ℃, and the dropping time is 0.5-2 h;
preferably, after the dropwise adding is completed, heating and carrying out a reflux reaction, wherein the time of the reflux reaction is 6-12 h.
Preferably, in the dropping process of the step (b), the temperature of the mixed system is 8-10 ℃, and the dropping time is 1-5 h.
Preferably, the ratio of the mass of the crude pramipexole to the volume of the third organic solvent is 1 g: (2-30) mL;
preferably, the volume ratio of the third organic solvent to water is (10-15): 1.
preferably, the temperature is reduced to 10-20 ℃;
preferably, the stirring time is 1-5 h;
preferably, in the step (b), the drying temperature is 25-50 ℃;
preferably, the means of collecting the solids comprises filtration;
preferably, the filtered solid is rinsed and then dried;
preferably, the rinsing is performed with the third organic solvent.
Preferably, the preparation method of the N- [ (2- (diisopropylamino) ethyl) -chloroacetamide comprises the following steps:
reacting the mixture of N, N-diisopropyl ethylenediamine, chloroacetyl chloride, the first organic solvent and alkali, collecting an organic phase, and drying;
preferably, the collecting the organic phase comprises: mixing the reacted system with water, separating to obtain an organic phase and a water phase, extracting the water phase with the second organic solvent, and combining the organic phases;
preferably, the reaction temperature of the mixture of the N, N-diisopropyl ethylenediamine, the chloroacetyl chloride, the first organic solvent and the base is 20-40 ℃, and the reaction time is 2-10 h;
preferably, in the reacting the mixture of N, N-diisopropylethylenediamine, chloroacetyl chloride, the first organic solvent and the base, the base comprises at least one of triethylamine, sodium bicarbonate, sodium carbonate, sodium hydroxide and diisopropylamine.
A crystalline pramipexole dihydrate obtained by the above-mentioned method for preparing a crystalline pramipexole dihydrate;
preferably, the crystalline pramipexole dihydrate has an X-powder diffraction pattern by Cu-ka radiation showing diffraction peaks at least diffraction angles 2 θ ± 0.2 ° of 4.5 °, 4.8 °, 9.6 °, 13.3 °, 13.8 °, 14.3 °, 15.1 °, 15.3 °, 16.6 °, 16.8 °, 17.0 °, 17.7 °, 18.9 °, 19.1 °, 19.9 °, 20.4 °, 22.4 °, 23.2 °, 23.6 °, 24.0 °, 24.8 °, 25.2 °, 26.1 °, 26.7 °, 27.4 °, 28.1 °, 28.7 °, 28.9 °, 29.6 °, 30.0 °, 31.2 °, 32.6 °, 33.8 °, 34.5 °, 35.0 °, 36.1 °, 37.1 °, 38.8 °.
A method for preparing a crystalline pramipexole monohydrate comprising the steps of:
preparing pramipexole dihydrate crystals by the method described above;
drying the pramipexole dihydrate crystal until the water content is 5-7%;
preferably, the drying temperature is 30-50 ℃.
The pramipexole monohydrate crystal obtained by the above-described method for preparing a pramipexole monohydrate crystal;
preferably, the crystalline pramipexole monohydrate has an X-powder diffraction pattern with Cu-ka radiation showing diffraction peaks at least diffraction angles 2 θ ± 0.2 ° of 4.5 °, 4.9 °, 8.9 °, 9.6 °, 9.7 °, 13.3 °, 13.9 °, 14.5 °, 14.8 °, 15.1 °, 15.4 °, 16.8 °, 17.2 °, 17.7 °, 19.0 °, 19.3 °, 20.4 °, 22.2 °, 23.7 °, 24.1 °, 24.9 °, 25.2 °, 25.3 °, 26.2 °, 26.8 °, 27.4 °, 27.9 °, 29.0 °, 29.9 °, 31.3 °, 32.9 °, 33.9 °, 34.6 °, 37.0 °, 39.0 °.
Compared with the prior art, the invention has the beneficial effects that:
(1) the preparation method of the pramipexole dihydrate crystal and the monohydrate crystal has the advantages of simple operation, mild reaction conditions, simple post-treatment, low cost, high yield, safety and no pollution.
(2) The pramipexole monohydrate crystal and the pramipexole dihydrate crystal have the total yield of over 70 percent and the purity HPLC (high performance liquid chromatography) of more than or equal to 99.5 percent, and are convenient for realizing industrial production.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
Figure 1 is the crystalline XRD pattern of pramipexole monohydrate of example 2;
figure 2 is the crystalline XRD pattern of pramipexole dihydrate of example 1;
figure 3 is a TGA/DSC plot of the crystalline pramipexole monohydrate of example 2;
figure 4 is a TGA/DSC plot of the crystalline pramipexole dihydrate of example 1;
figure 5 is a XRD comparison of the pramipexole monohydrate crystals with the dihydrate crystals.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
According to one aspect of the invention, the invention relates to a method for preparing crystalline pramipexole dihydrate comprising the steps of:
(a) dropwise adding a mixed solution of N- [ (2- (diisopropylamino) ethyl) -chloroacetamide and a second organic solvent into a mixed solution of pyrrolidone, alkali and a first organic solvent for reaction, separating to obtain an organic phase, and drying to obtain a crude product of the pramipexole;
(b) and (3) dropwise adding a fourth organic solvent into the mixture of the crude product of pramipexole, the third organic solvent and water, cooling, stirring, collecting solids, and drying until the water content of the crystals is 10-12%.
The invention provides an industrial preparation method of the pramipexole, which is simple to operate, mild in reaction conditions, simple in post-treatment, low in cost, high in yield, safe and pollution-free.
The preparation method of pramipexole provided by the invention comprises the steps of taking N, N-diisopropyl ethylenediamine and chloracetyl chloride as initial raw materials, and performing condensation reaction, substitution reaction, cooling, suction filtration and forced air drying. The synthetic route for pramitant is as follows:
in one embodiment, the drying is carried out until the water content of the crystals is 10% to 12%, and 10%, 11% and 12% may be selected.
Preferably, the first organic solvent comprises at least one of dichloromethane, acetonitrile, toluene, chloroform, N-dimethylformamide, and tetrahydrofuran.
Preferably, the second organic solvent comprises dichloromethane and/or ethyl acetate.
Preferably, the base comprises at least one of sodium hydride, potassium tert-butoxide, sodium methoxide, sodium hydroxide and sodium ethoxide.
Preferably, the third organic solvent comprises at least one of tetrahydrofuran, methanol, ethanol, isopropanol, acetone, dioxane, toluene, dichloromethane, ethyl acetate, methyl tert-butyl ether, and acetonitrile.
Preferably, the fourth organic solvent includes at least one of petroleum ether, diethyl ether, methyl tert-butyl ether, n-pentane, n-hexane, and n-heptane.
Preferably, in the dropping process of the step (a), the temperature of the mixed system is 10-20 ℃, and the dropping time is 0.5-2 h.
In one embodiment, in step (a), the temperature of the reaction solution is 10 to 20 ℃, and may be selected from 10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃, 15 ℃, 16 ℃, 17 ℃, 18 ℃,19 ℃ or 20 ℃.
In one embodiment, in the step (a), the dropping time is 0.5 to 2 hours, and 0.5 hour, 1 hour, 1.5 hour, 2 hours, 3 hours, 4 hours or 5 hours can be selected.
Preferably, after the dropwise addition is completed, the temperature is raised and a reflux reaction is carried out, wherein the time of the reflux reaction is 6-12 hours.
In one embodiment, the time of the reflux reaction is 6-12 h, and 6h, 7h, 8h, 9h, 10h, 11h or 12h can be selected.
Preferably, in the dropping process of the step (b), the temperature of the reaction solution is 8-10 ℃, and the dropping time is 1-5 h.
In one embodiment, in the step (b), the temperature of the mixed system is 8 to 10 ℃, and 8 ℃, 9 ℃ or 10 ℃ can be selected.
In one embodiment, in the step (b), the dropping time is 1 to 5 hours, and 1 hour, 2 hours, 3 hours, 4 hours or 5 hours can be selected.
Preferably, the ratio of the mass of the crude pramipexole to the volume of the third organic solvent is 1 g: (2-30) mL.
The invention adopts a proper amount of the third organic solvent, when the amount of the third organic solvent is too much, the pramipexole hydrate can be incompletely separated out, and when the amount of the third organic solvent is too little, the third organic solvent can be insufficiently dissolved.
In one embodiment, the ratio of the mass of the crude pramipexole to the volume of the third organic solvent is 1 g: (2-30) mL, optionally 1:2, 1:5, 1:10, 1:15, 1:20, 1:25 or 1: 30.
Preferably, the volume ratio of the third organic solvent to water is (10-15): 1.
in addition, in order to improve the dissolving effect, the dissolving temperature of the crude product of pramipexole in the third organic solvent and water can be selected from room temperature or heated to 30-50 ℃ until the solution is clear and transparent.
Preferably, the temperature is reduced to 10-20 ℃.
In one embodiment, the temperature is reduced to 10-20 ℃, and optionally 10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃, 15 ℃, 16 ℃, 17 ℃, 18 ℃,19 ℃ or 20 ℃.
Preferably, the stirring time is 1-5 h.
In one embodiment, the stirring time is 1-5 hours, and 1 hour, 2 hours, 3 hours, 4 hours or 5 hours can be selected.
Preferably, in the step (b), the drying temperature is 25 to 50 ℃.
In one embodiment, in the step (b), the drying temperature is 25 to 50 ℃, and 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃ or 50 ℃ can be selected.
Preferably, the means of collecting the solids comprises filtration;
preferably, the filtered solids are rinsed and then dried.
Preferably, the rinsing is performed with the third organic solvent.
Preferably, the preparation method of the N- [ (2- (diisopropylamino) ethyl) -chloroacetamide comprises the following steps:
and reacting the mixture of the N, N-diisopropyl ethylenediamine, the chloroacetyl chloride, the first organic solvent and the alkali, collecting an organic phase, and drying.
Preferably, the collecting the organic phase comprises: and mixing the reacted system with water, separating to obtain an organic phase and a water phase, extracting the water phase with the second organic solvent, and combining the organic phases.
Preferably, the reaction temperature of the mixture of the N, N-diisopropyl ethylenediamine, the chloroacetyl chloride, the first organic solvent and the base is 20-40 ℃, and the reaction time is 2-10 h.
In one embodiment, the temperature for reacting the mixture of N, N-diisopropylethylenediamine, chloroacetyl chloride, the first organic solvent, and the base is 20 to 40 ℃, and may be 20 ℃, 25 ℃, 30 ℃, 35 ℃, or 40 ℃.
Preferably, in the reacting the mixture of N, N-diisopropylethylenediamine, chloroacetyl chloride, the first organic solvent and the base, the base comprises at least one of triethylamine, sodium bicarbonate, sodium carbonate, sodium hydroxide and diisopropylamine.
According to another aspect of the present invention, the present invention also relates to crystalline pramipexole dihydrate obtainable by the process for the preparation of crystalline pramipexole dihydrate as described above.
Preferably, the crystalline pramipexole dihydrate has an X-powder diffraction pattern by Cu-ka radiation showing diffraction peaks at least diffraction angles 2 θ ± 0.2 ° of 4.5 °, 4.8 °, 9.6 °, 13.3 °, 13.8 °, 14.3 °, 15.1 °, 15.3 °, 16.6 °, 16.8 °, 17.0 °, 17.7 °, 18.9 °, 19.1 °, 19.9 °, 20.4 °, 22.4 °, 23.2 °, 23.6 °, 24.0 °, 24.8 °, 25.2 °, 26.1 °, 26.7 °, 27.4 °, 28.1 °, 28.7 °, 28.9 °, 29.6 °, 30.0 °, 31.2 °, 32.6 °, 33.8 °, 34.5 °, 35.0 °, 36.1 °, 37.1 °, 38.8 °.
According to another aspect of the invention, the invention also relates to a method for preparing pramipexole monohydrate crystals, comprising the following steps:
preparing pramipexole dihydrate crystals by the method described above;
drying the pramipexole dihydrate crystal until the water content is 5-7%.
In one embodiment, the pramipexole dihydrate crystals are dried to a moisture content of 5% to 7%, optionally 5%, 6% or 7%.
Preferably, the drying temperature is 30-50 ℃.
In one embodiment, the drying temperature is 30-50 ℃, and 30 ℃, 35 ℃, 40 ℃, 45 ℃ or 50 ℃ can be selected.
According to another aspect of the present invention, the present invention also relates to crystalline pramipexole monohydrate obtained by the process for the preparation of crystalline pramipexole monohydrate as described above;
preferably, the crystalline pramipexole monohydrate has an X-powder diffraction pattern with Cu-ka radiation showing diffraction peaks at least diffraction angles 2 θ ± 0.2 ° of 4.5 °, 4.9 °, 8.9 °, 9.6 °, 9.7 °, 13.3 °, 13.9 °, 14.5 °, 14.8 °, 15.1 °, 15.4 °, 16.8 °, 17.2 °, 17.7 °, 19.0 °, 19.3 °, 20.4 °, 22.2 °, 23.7 °, 24.1 °, 24.9 °, 25.2 °, 25.3 °, 26.2 °, 26.8 °, 27.4 °, 27.9 °, 29.0 °, 29.9 °, 31.3 °, 32.9 °, 33.9 °, 34.6 °, 37.0 °, 39.0 °.
In the synthetic route, the route is short, the steps are simple, the yield is high, the cost is low, the high-purity pramipexole monohydrate crystal and the high-purity pramipexole dihydrate crystal are obtained by controlling the drying conditions, the total yield can reach more than 70%, the purity HPLC (high performance liquid chromatography) is more than or equal to 99.5%, and the industrial production is convenient to realize.
In a preferred embodiment, a process for the preparation of crystalline pramipexole hydrate comprises the steps of:
(a) preparation of N- [ (2- (diisopropylamino) ethyl) -chloroacetamide
In a first organic solvent, stirring N, N-diisopropylethylenediamine and chloroacetyl chloride for 2-10 hours in the presence of alkali, controlling the reaction temperature at 20-40 ℃, after the reaction is finished, adding water into the reaction solution, separating an organic phase, extracting a water phase with an organic solvent II, combining the organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain N- [ (2- (diisopropylamino) ethyl) -chloroacetamide; wherein the first organic solvent is at least one of dichloromethane, acetonitrile, toluene, chloroform, N-dimethylformamide and tetrahydrofuran; the alkali is at least one of triethylamine, sodium bicarbonate, sodium carbonate, sodium hydroxide and diisopropylamine; the second organic solvent is dichloromethane and/or ethyl acetate;
(b) preparation of crude pramipentam
Controlling a certain temperature, adding pyrrolidone and alkali into a first organic solvent, dissolving N- [ (2- (diisopropylamino) ethyl) -chloroacetamide into a fourth organic solvent, dropwise adding into a reaction solution, controlling the dropwise adding time to be 0.5-2 h, controlling the dropwise adding temperature to be 10-20 ℃, heating to reflux reaction for 6-12 h after the dropwise adding is finished, pouring the reaction solution into ice water after the reaction is finished, separating an organic phase, extracting a water phase with a second organic solvent, combining the organic phases, drying anhydrous sodium sulfate, and evaporating to dryness to obtain a crude product of pramipexole; wherein the first organic solvent is at least one of dichloromethane, acetonitrile, toluene, chloroform, N-dimethylformamide and tetrahydrofuran; the alkali is any one of sodium hydride, potassium tert-butoxide, sodium methoxide, sodium hydroxide and sodium ethoxide; the second organic solvent is dichloromethane and/or ethyl acetate;
(c) preparation of crystalline pramipexole dihydrate
Dissolving the crude product of the pramipexole in a third organic solvent and distilled water at the room temperature, controlling the temperature to be 10 ℃, adding a fourth organic solvent into a reaction solution, controlling the dripping time to be 1-5 h, separating out crystals, cooling to 10-20 ℃, stirring for 1-5 h, performing suction filtration, leaching a filter cake with the third organic solvent, performing vacuum drying on the filter cake, controlling the temperature to be 25-50 ℃, and controlling the water content to be 10% -12% to obtain a pramipexole dihydrate crystal; wherein the third organic solvent is at least one of tetrahydrofuran, methanol, ethanol, isopropanol, acetone, dioxane, toluene, dichloromethane, ethyl acetate, methyl tert-butyl ether and acetonitrile; the fourth organic solvent is at least one of petroleum ether, diethyl ether, methyl tert-butyl ether, n-pentane, n-hexane and n-heptane; in the pramipexole solution, the ratio of the mass of pramipexole to the volume of the first organic solvent is 1: (2-30).
(d) Preparation of pramipexole monohydrate crystals
And (3) placing the pramipexole dihydrate in an oven for vacuum drying, controlling the temperature to be 30-50 ℃, and performing blast drying to ensure that the water content is 5% -7%, thus obtaining the pramipexole monohydrate crystal.
The invention will be further explained with reference to specific examples.
Example 1
A preparation method of a pramipexole dihydrate crystal comprises the following steps:
(1) preparation of N- [ (2- (diisopropylamino) ethyl) -chloroacetamide
Controlling the temperature to be below 5 ℃, sequentially adding 288.5g of N, N-diisopropylethylenediamine, 243.0g of triethylamine and 3kg of dichloromethane into a 5L reaction bottle, controlling the temperature to be below 20 ℃, dropwise adding 125.0g of chloroacetyl chloride, stirring at room temperature for 5 hours after the dropwise addition is finished, adding 1kg of water, stirring for layering, extracting a water layer with dichloromethane, combining organic layers, drying with anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain 419g of oily matter with the yield of 95%.
(2) Preparation of crude pramipentam
2L of tetrahydrofuran and 85.1g of pyrrolidone are added into a 5L reaction bottle, 40.0g of sodium hydroxide is added in batches, the mixture is stirred for 1h at room temperature, 220.7g of the intermediate N- [ (2- (diisopropylamino) ethyl) -chloroacetamide is added, the mixture is heated and refluxed for 10h, after the reaction is finished, the mixture is poured into 2L of ice water for layering, a water layer is extracted by ethyl acetate, an organic layer is combined, dried by anhydrous sodium sulfate and evaporated to dryness under reduced pressure, and 242.0g of oily matter is obtained, and the yield is 90%.
(3) Preparation of crystalline pramipexole dihydrate
Dissolving 269.2g of the pramipexole oily substance in 500mL of ethanol, adding 40g of pure water, slowly adding 2.5L of petroleum ether dropwise at room temperature for 2h, slowly separating out crystals, cooling to below 20 ℃, stirring for 1h, performing suction filtration, washing a filter cake with petroleum ether, and performing vacuum drying to obtain the pramipexole dihydrate which is 274.8g of white flaky crystals with the yield of 90%.
Example 2
A method for preparing a crystalline pramipexole monohydrate comprising the steps of:
the pramipexole dihydrate obtained in example 1 was placed in an oven and dried in vacuum for 12h to obtain pramipexole monohydrate as white flaky crystals with a yield of 100%.
Example 3
A preparation method of a pramipexole dihydrate crystal comprises the following steps:
(1) preparation of N- [ (2- (diisopropylamino) ethyl) -chloroacetamide
Controlling the temperature to be below 10 ℃, sequentially adding 1154.0g of N, N-diisopropylethylenediamine, 972.0g of triethylamine and 12kg of acetonitrile into a 20L reaction kettle, controlling the temperature to be below 20 ℃, dropwise adding 500.0g of chloroacetyl chloride, stirring at room temperature for 8h after the dropwise addition is finished, adding 3kg of water, stirring for layering, extracting a water layer with dichloromethane, combining organic layers, drying with anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain 1700.0g of oily matter with the yield of 96%.
(2) Preparation of crude pramipentam
Adding 8L of tetrahydrofuran and 340.4g of pyrrolidone into a 20L reaction bottle, adding 160.0g of sodium hydroxide in batches, stirring at room temperature for 1h, adding 883.0g of the intermediate N- [ (2- (diisopropylamino) ethyl) -chloroacetamide, heating and refluxing for 10h, pouring the mixture into 6L of ice water after the reaction is finished, separating layers, extracting a water layer by using dichloromethane, combining organic layers, drying by anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain 968.0g of oily matter with the yield of 90%.
(3) Preparation of crystalline pramipexole dihydrate
Dissolving 968.0g of the pramipexole oily substance in 2L of ethanol, adding 160g of pure water, slowly adding 10L of petroleum ether dropwise at room temperature for 5h, slowly separating out crystals, cooling to below 20 ℃, stirring for 3h, performing suction filtration, washing a filter cake with petroleum ether, and performing vacuum drying to obtain the pramipexole dihydrate which is 989.0g of white flaky crystals with the yield of 91%.
Example 4
A method for preparing a crystalline pramipexole monohydrate comprising the steps of:
the pramipexole dihydrate obtained in example 3 was placed in an oven and dried under vacuum for 10h to obtain pramipexole monohydrate as white flaky crystals with a yield of 100%.
Example 5
A preparation method of a pramipexole dihydrate crystal comprises the following steps:
(1) preparation of N- [ (2- (diisopropylamino) ethyl) -chloroacetamide
Controlling the temperature to be below 10 ℃, sequentially adding 288.5g of N, N-diisopropylethylenediamine, 255.0g of sodium carbonate and 3kg of acetonitrile into a 5L reaction bottle, controlling the temperature to be below 20 ℃, dropwise adding 125.0g of chloroacetyl chloride, stirring at room temperature for 5h after the dropwise addition, adding 1kg of water, stirring for layering, extracting a water layer with ethyl acetate, combining organic layers, drying with anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain 419g of an oily substance with the yield of 95%.
(2) Preparation of crude pramipentam
Adding 2L acetonitrile and 85.1g pyrrolidone into a 5L reaction bottle, adding 40.0g sodium hydroxide in batches, stirring at room temperature for 1h, adding 220.7g of the intermediate N- [ (2- (diisopropylamino) ethyl) -chloroacetamide, heating and refluxing for 10h, pouring the mixture into 2L ice water after the reaction is finished, carrying out layering, extracting a water layer by using ethyl acetate, combining organic layers, drying by anhydrous sodium sulfate, and carrying out reduced pressure evaporation to dryness to obtain 242.0g oily matter with the yield of 90%.
(3) Preparation of crystalline pramipexole dihydrate
Dissolving the obtained pramipexole oily substance in 500mL of ethanol, adding 40g of pure water, slowly dripping 2.5L of petroleum ether at room temperature for 2h, slowly separating out crystals, cooling to below 20 ℃, stirring for 2h, performing suction filtration, washing a filter cake with petroleum ether, and performing vacuum drying to obtain the pramipexole dihydrate which is 250.0g of white flaky crystals with the yield of 90%.
Example 6
A method for preparing a crystalline pramipexole monohydrate comprising the steps of:
the pramipexole dihydrate obtained in example 5 was placed in an oven and dried under vacuum for 10h to obtain pramipexole monohydrate as white flaky crystals with a yield of 100%.
Example 7
A preparation method of a pramipexole dihydrate crystal comprises the following steps:
(1) preparation of N- [ (2- (diisopropylamino) ethyl) -chloroacetamide
Controlling the temperature to be below 10 ℃, sequentially adding 288.5g of N, N-diisopropylethylenediamine, 96.1g of sodium hydroxide and 3kg of tetrahydrofuran into a 5L reaction bottle, controlling the temperature to be below 20 ℃, dropwise adding 125.0g of chloroacetyl chloride, stirring at room temperature for 5h after the dropwise addition is finished, adding 1kg of water, stirring for layering, extracting a water layer with ethyl acetate, combining organic layers, drying with anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain 410.0g of oily matter with the yield of 93%.
(2) Preparation of crude pramipentam
Adding 2L acetonitrile and 85.1g pyrrolidone into a 5L reaction bottle, adding 68.0g sodium ethoxide in batches, stirring at room temperature for 1h, adding 220.7g of the intermediate N- [ (2- (diisopropylamino) ethyl) -chloroacetamide, heating and refluxing for 10h, pouring the mixture into 2L ice water after the reaction is finished, carrying out layering, extracting a water layer by using dichloromethane, combining organic layers, drying by anhydrous sodium sulfate, and carrying out reduced pressure evaporation to dryness to obtain 240.0g of oily matter with the yield of 89%.
(3) Preparation of crystalline pramipexole dihydrate
Dissolving 240.0g of the pramipexole oily substance in 500mL of ethanol, adding 40g of pure water, slowly dropwise adding 2.5L of petroleum ether at room temperature for 2h, slowly separating out crystals, cooling to below 20 ℃, stirring for 1h, performing suction filtration, washing a filter cake with petroleum ether, and performing vacuum drying to obtain the pramipexole dihydrate which is 245.0g of white flaky crystals with the yield of 90%.
Example 8
A method for preparing a crystalline pramipexole monohydrate comprising the steps of:
the pramipexole dihydrate obtained in example 7 was placed in an oven and dried under vacuum for 12h to obtain pramipexole monohydrate as white flaky crystals with a yield of 100%.
Example 9
A preparation method of a pramipexole dihydrate crystal comprises the following steps:
(1) preparation of N- [ (2- (diisopropylamino) ethyl) -chloroacetamide
Controlling the temperature to be below 10 ℃, sequentially adding 288.5g of N, N-diisopropylethylenediamine, 243.0g of triethylamine and 3kg of tetrahydrofuran into a 5L reaction bottle, controlling the temperature to be below 20 ℃, dropwise adding 125.0g of chloroacetyl chloride, stirring at room temperature for 5h after the dropwise addition is finished, adding 1kg of water, stirring for layering, extracting a water layer with dichloromethane, combining organic layers, drying with anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain 425.0g of oily matter with the yield of 96%.
(2) Preparation of crude pramipentam
Adding 2L acetonitrile and 85.1g pyrrolidone into a 5L reaction bottle, adding 68.0g sodium ethoxide in batches, stirring at room temperature for 1h, adding 220.7g of the intermediate N- [ (2- (diisopropylamino) ethyl) -chloroacetamide, heating and refluxing for 10h, pouring the mixture into 2L ice water after the reaction is finished, carrying out layering, extracting a water layer by using dichloromethane, combining organic layers, drying by anhydrous sodium sulfate, and carrying out reduced pressure evaporation to dryness to obtain 242.0g of oily matter with the yield of 90%.
(3) Preparation of crystalline pramipexole dihydrate
Dissolving 242.0g of the pramipexole oily substance in 500mL of ethanol, adding 40g of pure water, slowly dropwise adding 2.5L of petroleum ether at room temperature for 3h, slowly separating out crystals, cooling to below 20 ℃, stirring for 5h, performing suction filtration, washing a filter cake with petroleum ether, and performing vacuum drying to obtain the pramipexole dihydrate which is 245.0g of white flaky crystals with the yield of 90%.
Example 10
A method for preparing a crystalline pramipexole monohydrate comprising the steps of:
the pramipexole dihydrate obtained in example 9 was placed in an oven and dried in vacuo for 12h to obtain pramipexole monohydrate as a white flaky crystal with a yield of 100%.
Examples of the experiments
XRPD (X-ray Diffraction) pattern testing was performed on the pramipexole dihydrate obtained in example 1 and the pramipexole monohydrate obtained in example 2, under both Cu-Ka radiation and equipment model: x-ray diffractometer model X' Pert3 from PANALYTICAL (PANACEAE). Approximately 10 mg of the sample was uniformly spread on a single crystal silicon sample pan and XRD testing was performed with the parameters described in table 1 below.
Table 1: XRD scanning parameters
The XRD pattern of the pramipexole monohydrate crystal is shown in fig. 1, and the results are shown in table 2.
Table 2: diffraction peak data for pramipexole monohydrate crystals
As can be seen from fig. 1 and table 2 above, the crystal of this monohydrate has diffraction peaks at 2 θ of 4.5 °, 4.9 °, 8.9 °, 9.6 °, 9.7 °, 13.3 °, 13.9 °, 14.5 °, 14.8 °, 15.1 °, 15.4 °, 16.8 °, 17.2 °, 17.7 °, 19.0 °, 19.3 °, 20.4 °, 22.2 °, 23.7 °, 24.1 °, 24.9 °, 25.2 °, 25.3 °, 26.2 °, 26.8 °, 27.4 °, 27.9 °, 29.0 °, 29.9 °, 31.3 °, 32.9 °, 33.9 °, 34.6 °, 37.0 °, and 39.0 ° (the error range of each diffraction peak is ± 0.2).
The XRD pattern of pramipexole dihydrate is shown in fig. 2, and the results are shown in table 3. As can be seen from fig. 2 and table 3, the crystal of the dihydrate shows diffraction peaks at 2 θ of 4.5 °, 4.8 °, 9.6 °, 13.3 °, 13.8 °, 14.3 °, 15.1 °, 15.3 °, 16.6 °, 16.8 °, 17.0 °, 17.7 °, 18.9 °, 19.1 °, 19.9 °, 20.4 °, 22.4 °, 23.2 °, 23.6 °, 24.0 °, 24.8 °, 25.2 °, 26.1 °, 26.7 °, 27.4 °, 28.1 °, 28.7 °, 28.9 °, 29.6 °, 30.0 °, 31.2 °, 32.6 °, 33.8 °, 34.5 °, 35.0 °, 36.1 °, 37.1 °, 38.8 ° (error range of each diffraction peak is ± 0.2).
Table 3: diffraction peak data for pramipexole dihydrate crystals
A comparison of XRD patterns of the pramipexole monohydrate crystals and the pramipexole dihydrate crystals is shown in fig. 5. Referring to fig. 1, table 2, fig. 2, and table 3, it is seen that the dihydrate crystal has more diffraction peaks (error range of each diffraction peak is ± 0.2) at 2 θ of 8.9 °, 9.7 °, 14.8 °, and 25.3 ° compared with the pramiperacetam compound.
In addition, in order to verify the phase change of the two crystals, Differential Scanning Calorimetry (DSC) test was performed. Wherein figure 3 is a TGA/DSC profile of the crystalline pramipexole monohydrate having an endothermic peak at 46.1 ℃ to 50.1 ℃; figure 4 is a TGA/DSC profile of crystalline pramipexole dihydrate with an endothermic peak at 45.5 ℃.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. A preparation method of a pramipexole dihydrate crystal is characterized by comprising the following steps:
(a) dropwise adding a mixed solution of N- [ (2- (diisopropylamino) ethyl) -chloroacetamide and a second organic solvent into a mixed solution of pyrrolidone, alkali and a first organic solvent for reaction, separating to obtain an organic phase, and drying to obtain a crude product of the pramipexole;
(b) and (3) dropwise adding a fourth organic solvent into the mixture of the crude product of pramipexole, the third organic solvent and water, cooling, stirring, collecting solids, and drying until the water content of the crystals is 10-12%.
2. The method of preparing crystalline pramipexole dihydrate according to claim 1, wherein the first organic solvent comprises at least one of dichloromethane, acetonitrile, toluene, chloroform, N-dimethylformamide, and tetrahydrofuran;
preferably, the second organic solvent comprises dichloromethane and/or ethyl acetate;
preferably, the base comprises at least one of sodium hydride, potassium tert-butoxide, sodium methoxide, sodium hydroxide and sodium ethoxide;
preferably, the third organic solvent comprises at least one of tetrahydrofuran, methanol, ethanol, isopropanol, acetone, dioxane, toluene, dichloromethane, ethyl acetate, methyl tert-butyl ether, and acetonitrile;
preferably, the fourth organic solvent includes at least one of petroleum ether, diethyl ether, methyl tert-butyl ether, n-pentane, n-hexane, and n-heptane.
3. The preparation method of pramipexole dihydrate crystals according to claim 1, wherein the temperature of the mixed system is 10-20 ℃ during the dropwise addition in step (a), and the dropwise addition time is 0.5-2 hours;
preferably, after the dropwise adding is completed, heating and carrying out a reflux reaction, wherein the time of the reflux reaction is 6-12 h.
4. The preparation method of pramipexole dihydrate crystals according to claim 1, wherein the temperature of the mixed system is 8 to 10 ℃ during the dropwise addition in step (b), and the dropwise addition time is 1 to 5 hours.
5. The method for preparing crystalline pramipexole dihydrate according to claim 1, wherein the ratio of the mass of the crude pramipexole to the volume of the third organic solvent is 1 g: (2-30) mL;
preferably, the volume ratio of the third organic solvent to water is (10-15): 1.
6. the method for preparing pramipexole dihydrate crystals according to claim 1, wherein the temperature reduction is carried out to a temperature of 10 to 20 ℃;
preferably, the stirring time is 1-5 h;
preferably, in the step (b), the drying temperature is 25-50 ℃;
preferably, the means of collecting the solids comprises filtration;
preferably, the filtered solid is rinsed and then dried;
preferably, the rinsing is performed with the third organic solvent.
7. Process for the preparation of pramipexole according to claim 1, characterised in that said process for the preparation of N- [ (2- (diisopropylamino) ethyl) -chloroacetamide comprises the following steps:
reacting the mixture of N, N-diisopropyl ethylenediamine, chloroacetyl chloride, the first organic solvent and alkali, collecting an organic phase, and drying;
preferably, the collecting the organic phase comprises: mixing the reacted system with water, separating to obtain an organic phase and a water phase, extracting the water phase with the second organic solvent, and combining the organic phases;
preferably, the reaction temperature of the mixture of the N, N-diisopropyl ethylenediamine, the chloroacetyl chloride, the first organic solvent and the base is 20-40 ℃, and the reaction time is 2-10 h;
preferably, in the reacting the mixture of N, N-diisopropylethylenediamine, chloroacetyl chloride, the first organic solvent and the base, the base comprises at least one of triethylamine, sodium bicarbonate, sodium carbonate, sodium hydroxide and diisopropylamine.
8. Crystalline pramipexole dihydrate obtained by the method for producing crystalline pramipexole dihydrate according to any one of claims 1 to 7;
preferably, the crystalline pramipexole dihydrate has an X-powder diffraction pattern by Cu-ka radiation showing diffraction peaks at least diffraction angles 2 θ ± 0.2 ° of 4.5 °, 4.8 °, 9.6 °, 13.3 °, 13.8 °, 14.3 °, 15.1 °, 15.3 °, 16.6 °, 16.8 °, 17.0 °, 17.7 °, 18.9 °, 19.1 °, 19.9 °, 20.4 °, 22.4 °, 23.2 °, 23.6 °, 24.0 °, 24.8 °, 25.2 °, 26.1 °, 26.7 °, 27.4 °, 28.1 °, 28.7 °, 28.9 °, 29.6 °, 30.0 °, 31.2 °, 32.6 °, 33.8 °, 34.5 °, 35.0 °, 36.1 °, 37.1 °, 38.8 °.
9. A preparation method of a pramipexole monohydrate crystal is characterized by comprising the following steps:
preparing crystalline pramipexole dihydrate by a process according to any one of claims 1 to 8;
drying the pramipexole dihydrate crystal until the water content is 5-7%;
preferably, the drying temperature is 30-50 ℃.
10. Crystalline pramipexole monohydrate obtained by the process for the preparation of crystalline pramipexole monohydrate according to claim 9;
preferably, the crystalline pramipexole monohydrate has an X-powder diffraction pattern with Cu-ka radiation showing diffraction peaks at least diffraction angles 2 θ ± 0.2 ° of 4.5 °, 4.9 °, 8.9 °, 9.6 °, 9.7 °, 13.3 °, 13.9 °, 14.5 °, 14.8 °, 15.1 °, 15.4 °, 16.8 °, 17.2 °, 17.7 °, 19.0 °, 19.3 °, 20.4 °, 22.2 °, 23.7 °, 24.1 °, 24.9 °, 25.2 °, 25.3 °, 26.2 °, 26.8 °, 27.4 °, 27.9 °, 29.0 °, 29.9 °, 31.3 °, 32.9 °, 33.9 °, 34.6 °, 37.0 °, 39.0 °.
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| CN104341333A (en) * | 2014-10-29 | 2015-02-11 | 北京华睿鼎信科技有限公司 | Preparation method of Pramiracetam sulfate |
| CN111875530A (en) * | 2020-08-17 | 2020-11-03 | 浙江朗华制药有限公司 | Pramipexole hydrate crystal and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104341333A (en) * | 2014-10-29 | 2015-02-11 | 北京华睿鼎信科技有限公司 | Preparation method of Pramiracetam sulfate |
| CN111875530A (en) * | 2020-08-17 | 2020-11-03 | 浙江朗华制药有限公司 | Pramipexole hydrate crystal and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 卢丽霞 等: "促智药普拉西坦的合成", 《化工时刊》 * |
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