CN113968841B - Preparation method of fasudil hydrochloride hemihydrate - Google Patents
Preparation method of fasudil hydrochloride hemihydrate Download PDFInfo
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Abstract
The invention discloses a preparation method of fasudil hydrochloride hemihydrate, which comprises the following steps: s1, synthesizing fasudil alkali in a hydrophobic aprotic solvent to obtain fasudil alkali reaction liquid; washing fasudil alkali reaction liquid with water, and then extracting with hydrochloric acid aqueous solution to obtain an acid water extraction layer; washing the acid extraction water layer with dichloromethane, then adjusting the pH to 10-11, and crystallizing to obtain fasudil alkali wet product; s2, carrying out salt formation reaction on the fasudil alkali wet product and hydrochloric acid in water, crystallizing and drying to obtain fasudil hydrochloride hemihydrate. The method has the advantages of simple process operation, short production period, environmental protection, low cost, high yield and pure product, and is more suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of fasudil hydrochloride hemihydrate.
Background
Fasudil hydrochloride (Fasudil Hydrochloride) with chemical name of hexahydro-1- (5-sulfonyl isoquinoline) -1 (H) -1, 4-diazaHydrochloride hemihydrate, an isoquinoline sulfonamide derivative developed by the japanese Asahi chemical Co., ltd., is a Rho kinase inhibitor, which can inhibit not only the activity of intracellular free calcium ions but also the phosphorylation of smooth muscle myosin light chain, thereby dilating vascular smooth muscle and dilating blood vessels. Clinically used for improving and preventing cerebral vasospasm after subarachnoid hemorrhage and cerebral ischemia caused by cerebral vasospasm.
Fasudil hydrochloride has more synthetic patents, such as: the synthesis method of the novel compound is that isoquinoline-5-sulfonyl chloride or hydrochloride thereof is condensed with homopiperazine to obtain fasudil alkali, and then salified.
The fasudil alkali has good solubility in common organic solvents, low crystallization yield, and large differences in physicochemical properties of impurities and pigments generated in the fasudil alkali synthesis process, and is difficult to purify by adopting a conventional extraction and washing method. Therefore, the effective improvement of the purity of fasudil alkali is a key for preparing high-purity fasudil hydrochloride. At present, the common method is to extract and wash fasudil alkali synthesis reaction liquid for multiple times or separate the fasudil alkali synthesis reaction liquid by column chromatography, concentrate the fasudil alkali synthesis reaction liquid into salt and crystallize the salt to obtain the fasudil hydrochloride which can be used for medicines. US4678783 and US5942505 adopt silica gel column separation, so that the operation is complex, the time consumption is long, and the production efficiency is low; the purification method is improved by domestic researchers, and the products with different purities are obtained by combining the methods of water washing, dichloromethane washing, acid-base conversion, decoloration, crystallization and the like. Such as: CN102070612 adopts acid extraction, alkalization extraction, water washing and salifying crystallization to obtain fasudil hydrochloride with purity not lower than 98%; CN102020635 is decolorized by active carbon and crystallized to obtain fasudil hydrochloride with purity not lower than 99.5%; CN103450157 is prepared by water washing, acid extraction, dichloromethane washing, alkalization extraction and salifying crystallization to obtain fasudil hydrochloride with purity not lower than 99.9%.
In summary, the prior art for synthesizing fasudil hydrochloride does not obtain the crystalline fasudil alkali from the solvent, and the purity of the fasudil alkali is improved only by common extraction and washing or column chromatography, so that the quality of the fasudil hydrochloride cannot be expected. In addition, the prior art has solution phase inversion and concentration operations, such as: US4678783, CN102020635, CN103450157, US5942505 concentrate the reaction solvent dichloromethane or chloroform, CN102070612 concentrate the dichloromethane extract. The methylene dichloride and the chloroform have low boiling points, the concentration recovery rate is low, and the environmental pollution is unavoidable.
Fasudil hydrochloride has three crystal forms of anhydrate, hemihydrate and trihydrate, and the stable crystal form is the hemihydrate. Patent US5942505 dries crystalline hydrate of fasudil hydrochloride in water at 25 ℃ for 6 hours to obtain fasudil hydrochloride trihydrate, and then dries the crystalline hydrate of fasudil hydrochloride in 25 ℃ (humidity 75%) for 10 hours to obtain fasudil hydrochloride hemihydrate (water content is 2.5-3.1%), which is complex in operation and unfavorable for production.
Disclosure of Invention
Based on the technical problems existing in the background technology, the invention provides a preparation method of high-purity fasudil hydrochloride hemihydrate, and in addition, the invention also provides a crystallization method of high-purity fasudil alkali, and the method is applied to the synthesis of fasudil hydrochloride, so that the purity of fasudil hydrochloride can be obviously improved. The method has the advantages of simple process operation, short production period, environmental protection, low cost, high yield and pure product, and is more suitable for industrial production.
In the process of preparing fasudil alkali by using ginseng according to patent US4678783, patent US5942505, patent CN103450157, patent CN102020635 and patent CN102070612, the reaction liquid of the fasudil alkali is found to be solidified after washing and concentrating, and the concentrate is cooled to room temperature and is white solid blocks, and microscopic examination shows crystallinity; further studies have found that the solid is readily soluble in methylene chloride, chloroform, methanol, in ethyl acetate, ethanol, and slightly soluble in water.
The inventor carries out water washing on a reaction solution of the fasudil alkali according to the solubility difference of the fasudil alkali and the fasudil hydrochloride in dichloromethane, chloroform and water, so as to remove inorganic salt, excessive homopiperazine and water-soluble impurities, then uses dilute hydrochloric acid to extract, salifies the fasudil alkali into a water layer, alkalizes the water layer, stirs and cools the water layer to below 10 ℃ to separate out a large amount of solids, and filters the solid to obtain white fasudil alkali with the purity of more than 99.5%; the fasudil alkali is salified and crystallized to obtain fasudil hydrochloride, and the purity is more than 99.95 percent. It can be obtained from this that the preparation method of fasudil hydrochloride hemihydrate of the present invention comprises the processes of water washing, acidification, alkalization crystallization, salification and crystallization.
The inventor selects a drying method according to the crystalline hydrate (the water content is 28-32%) of fasudil hydrochloride prepared by patent US5942505, and the experiment shows that:
when the initial drying temperature is higher than 55 ℃, the crystalline hydrate is melted and agglomerated.
The crystal hydrate is dried by blowing at 25-35 ℃ for 12-18h, and then dried under reduced pressure at 50 ℃ for 12h to obtain white powder with the water content of 6-7%.
Drying the crystal hydrate for 6-12h at 55-65 ℃ under reduced pressure to obtain white solid, wherein the moisture is 2.6-3.0%, and the powder X-ray diffraction characteristics (2 theta) are as follows: 8.4.+ -. 0.2, 12.4.+ -. 0.2, 14.0.+ -. 0.2, 16.2.+ -. 0.2, 16.8.+ -. 0.2, 18.2.+ -. 0.2, 19.6.+ -. 0.2, 22.4.+ -. 0.2 and 25.6.+ -. 0.2 (as shown in FIG. 1) are consistent with the fasudil hydrochloride hemihydrate powder X-diffraction profile (2. Theta.) disclosed in patent US 5942505.
Drying the crystal hydrate at 66-70deg.C under reduced pressure for 6-12 hr to obtain white solid with water content less than 2.0%.
The moisture detection was performed according to Fei Xiushi.
The above results illustrate: the crystalline hydrate of fasudil hydrochloride in water (the water content is 28-32%) is dried under reduced pressure at 55-65 ℃ for at least 6 hours, and the fasudil hydrochloride hemihydrate can be prepared. It can be seen from this: the drying of the crystalline hydrate of fasudil hydrochloride comprises a dissolution and crystal transformation process.
The preparation method of fasudil hydrochloride hemihydrate provided by the invention comprises the following steps:
S1, synthesizing fasudil alkali in a hydrophobic aprotic solvent to obtain fasudil alkali reaction liquid; washing fasudil alkali reaction liquid with water, and then extracting with hydrochloric acid aqueous solution to obtain an acid water extraction layer; washing the acid extraction water layer with dichloromethane, then adjusting the pH to 10-11, and crystallizing to obtain fasudil alkali wet product;
S2, carrying out salt formation reaction on the fasudil alkali wet product and hydrochloric acid in water, crystallizing and drying to obtain fasudil hydrochloride hemihydrate.
The above "synthesis of sulodipine in hydrophobic aprotic solvent" may be carried out according to a method conventional in the art, or may be carried out by referring to methods disclosed in US4678783, US5942505, CN103450157, CN102020635, CN102070612, etc., i.e., isoquinoline-5-sulfonyl chloride or its hydrochloride, homopiperazine is reacted in dichloromethane or chloroform to obtain a reaction solution of sulodipine, and an inorganic base may be further contained during the reaction.
Preferably, in S1, the hydrophobic aprotic solvent is at least one of dichloromethane, chloroform, 1, 2-dichloroethane, ethyl acetate, isopropyl acetate, methyl tert-butyl ester.
Preferably, in S1, the molar ratio of HCl in hydrochloric acid to fasudil base is 1:0.90-0.95.
The molar quantity of the fasudil alkali is the theoretical molar quantity of the fasudil alkali generated by reaction, and can be obtained by calculation according to raw materials for preparing the fasudil alkali, and the calculation method is a well-known method for calculating the theoretical molar quantity of a product in a reaction solution by a person skilled in the art.
Preferably, in S1, the concentration of the aqueous hydrochloric acid solution is 0.35 to 0.45mol/L.
Preferably, in S1, the crystallization temperature is-3 to 3 ℃ and the crystallization time is 1 to 2 hours.
Preferably, in S1, the volume ratio of the washing water to the fasudil alkali reaction solution is 0.5-2:1.
Preferably, in S1, the volume ratio of the washing dichloromethane to the acid extraction layer is 1-2:1.
Preferably, in S1, the pH is adjusted with sodium hydroxide or sodium carbonate.
Preferably, in S2, the crystallization temperature is-1 to 3 ℃ and the crystallization time is 6-10h.
Preferably, in S2, the drying is reduced pressure drying, the drying temperature is 55-65 ℃, and the drying time is not less than 6 hours.
Preferably, in S2, the pH of the salt forming reaction is controlled between 5.8 and 6.2.
Preferably, in S2, the weight to volume ratio of fasudil base to water is 1g:2.5-3.0ml, wherein the water comprises water added alone, water in wet fasudil base and water in hydrochloric acid.
The inventors carried out the detection of fasudil base and fasudil hydrochloride prepared according to the methods described in US4678783, US5942505, CN103450157, CN102020635, CN102070612 and the present invention according to the impurity detection method disclosed in patent CN103450157, and the results are shown in tables 1-2.
TABLE 1 detection results of related substances of fasudil base prepared by different methods
TABLE 2 detection results of related substances of fasudil hydrochloride prepared by different methods
As can be seen from tables 1-2, the purity of the fasudil alkali and the fasudil hydrochloride prepared by the method is highest, the purity of the fasudil alkali is more than 99.5 percent (HPLC method), and the purity of the fasudil hydrochloride is more than 99.95 percent (HPLC method, chromatogram is shown in figure 3).
Compared with the prior art, the invention has the beneficial effects that:
The method obtains the fasudil alkali crystal by a water crystallization method, adopts the water crystallization method to prepare the high-purity fasudil alkali, has the purity of more than 99.5 percent, and can expect the purity of the fasudil hydrochloride according to the purity of the fasudil alkali crystal; the fasudil alkali and the fasudil hydrochloride are crystallized by water, so that the product has no organic solvent residue, and is environment-friendly; improving the drying condition of the crystalline hydrate of fasudil hydrochloride in water, improving the drying efficiency, and obtaining the crystalline form of fasudil hydrochloride hemihydrate through drying and crystal transformation, wherein the water content is 2.6-3.0%, and the purity is more than 99.95%.
Drawings
FIG. 1 is a powder X-ray diffraction pattern of fasudil hydrochloride hemihydrate prepared in example 1.
FIG. 2 is an infrared absorption diagram of fasudil hydrochloride hemihydrate prepared in example 1.
FIG. 3 is a HPLC chromatogram of fasudil hydrochloride hemihydrate prepared in example 1.
Detailed Description
The technical scheme of the invention is described in detail through specific embodiments.
Example 1
The preparation method of fasudil hydrochloride hemihydrate comprises the following steps:
Referring to example 3 of US4678783, 55g of isoquinoline-5-sulfonyl chloride hydrochloride is dissolved in 500ml of ice water, the pH value is adjusted to 6 by using saturated sodium bicarbonate aqueous solution, 1000ml of dichloromethane is used for extraction, the extracted solution is dripped into 500ml of dichloromethane solution containing 50g of homopiperazine within 20min, the temperature is reduced by ice bath, and the reaction solution is stirred for 2 hours at 15-20 ℃ after the addition, so as to obtain fasudil alkali reaction solution;
stirring and washing fasudil alkali reaction liquid twice with water, wherein the water consumption is 1500ml each time; then taking an organic layer, extracting with 660ml of 0.35mol/L hydrochloric acid aqueous solution, and taking an acid extraction layer; washing the acid-extracted water layer by stirring with 660ml of dichloromethane, regulating the pH=10 of the acid-extracted water layer by using 5mol/L sodium hydroxide aqueous solution, cooling to-3 ℃, stirring and crystallizing for 1h, filtering, washing a filter cake by using 100ml of water, and filtering to obtain 104.7g of fasudil wet product, wherein the water content is 49.38%, and the purity is 99.77%;
taking a fasudil alkali wet product, adding 40ml of water and 40ml of 4mol/L hydrochloric acid aqueous solution, stirring and dissolving, dropwise adding the 4mol/L hydrochloric acid aqueous solution until the pH value is=5.8, filtering, taking filtrate, cooling to-1-3 ℃, stirring and crystallizing for 6 hours, filtering, and drying a filter cake at 55-65 ℃ under reduced pressure for 8 hours to obtain 56.9g of fasudil hydrochloride hemihydrate, wherein the water content is 2.85%, the yield is 81.0%, and the purity is 100%.
The fasudil hydrochloride hemihydrate prepared in example 1 was tested, and the results are shown in fig. 1-3, and fig. 1 is a powder X-ray diffraction diagram of the fasudil hydrochloride hemihydrate prepared in example 1; FIG. 2 is an infrared absorption diagram of fasudil hydrochloride hemihydrate prepared in example 1; FIG. 3 is a HPLC chromatogram of fasudil hydrochloride hemihydrate prepared in example 1.
As can be seen from fig. 1-3: the fasudil hydrochloride hemihydrate is successfully prepared, and the purity is very high; the crystalline form is consistent with fasudil hydrochloride hemihydrate disclosed in patent US 5942505.
Example 2
The preparation method of fasudil hydrochloride hemihydrate comprises the following steps:
referring to example 1 of US5942505, 88g of homopiperazine was dissolved in 400ml of chloroform, cooled in an ice bath, and a chloroform solution of isoquinoline-5-sulfonyl chloride (50 g of isoquinoline-5-sulfonyl chloride was dissolved in 400ml of chloroform) was added dropwise over 1 hour, and after the addition, stirring was continued in an ice bath for 1 hour to obtain a fasudil base reaction solution;
stirring and washing fasudil alkali reaction liquid with water for two times, wherein the water consumption is 800ml each time; then taking organic layer, extracting with 580ml of 0.4mol/L hydrochloric acid aqueous solution, and taking acid extraction layer; washing the acid-extracted water layer with 580ml of dichloromethane under stirring, regulating the pH value of the acid-extracted water layer to be 11 with 10mol/L sodium hydroxide aqueous solution, cooling to-3 ℃, stirring and crystallizing for 2h, filtering, washing a filter cake with 100ml of water, and filtering to obtain 117.5g of fasudil wet product, wherein the water content is 51.06%, and the purity is 99.86%;
Taking a fasudil alkali wet product, adding 40ml of water and 40ml of 4mol/L hydrochloric acid aqueous solution, stirring and dissolving, dropwise adding the 4mol/L hydrochloric acid aqueous solution until the pH value is=6.0, filtering, taking filtrate, cooling to-1-3 ℃, stirring and crystallizing for 8 hours, filtering, and drying a filter cake at 55-65 ℃ under reduced pressure for 10 hours to obtain 62.2g of fasudil hydrochloride hemihydrate, wherein the water content is 2.91%, the yield is 83.9%, and the purity is 100%.
Example 3
The preparation method of fasudil hydrochloride hemihydrate comprises the following steps:
referring to example 2 of CN103450157, adding 7g of potassium carbonate and 25g of homopiperazine into 440ml of dichloromethane, stirring and dissolving, slowly and continuously adding 22g of 5-isoquinoline sulfonyl chloride hydrochloride at a temperature below 0 ℃, and stirring for 3 hours at a temperature of between 0 and 15 ℃ after adding to obtain fasudil alkali reaction solution;
Stirring and washing fasudil alkali reaction liquid with water for two times, wherein the water consumption is 220ml each time; then, the organic layer is extracted by 200ml of 0.45mol/L hydrochloric acid aqueous solution, and the acid extraction layer is taken; washing the acid-extracted water layer with 200ml of dichloromethane under stirring, regulating the pH=10 of the acid-extracted water layer with 10mol/L sodium hydroxide aqueous solution, cooling to-3 ℃, stirring and crystallizing for 2h, filtering, washing the filter cake with 40ml of water, and filtering to obtain 44.6g of fasudil wet product, wherein the water content is 51.03%, and the purity is 99.73%;
Taking a fasudil alkali wet product, adding 20ml of water and 20ml of 4mol/L hydrochloric acid aqueous solution, stirring and dissolving, dropwise adding the 4mol/L hydrochloric acid aqueous solution until the pH value is=6.2, filtering, taking filtrate, cooling to-1-3 ℃, stirring and crystallizing for 10 hours, filtering, and drying a filter cake at 55-65 ℃ under reduced pressure for 12 hours to obtain 24.2g of fasudil hydrochloride hemihydrate, wherein the water content is 2.63%, the yield is 86.3% and the purity is 100%.
Example 4
The preparation method of fasudil hydrochloride hemihydrate comprises the following steps:
Referring to example 1 of CN102020635, 50g of isoquinoline-5-sulfonyl chloride hydrochloride, 500ml of water, adjusting pH to 6 with saturated sodium bicarbonate at below 5 ℃, then extracting twice with 600ml of dichloromethane, combining the extracts, drying over anhydrous magnesium sulfate, filtering to obtain isoquinoline-5-sulfonyl chloride solution; 45g of homopiperazine and 350ml of dichloromethane are added into another reaction bottle, isoquinoline-5-sulfonyl chloride solution is dripped below 5 ℃, and the reaction liquid reacts for 2 hours at 15-20 ℃ after the addition, so as to obtain fasudil alkali reaction liquid;
stirring and washing fasudil alkali reaction liquid with water for two times, wherein the water consumption is 1000ml each time; then extracting the organic layer with 500ml of 0.4mol/L hydrochloric acid aqueous solution, and taking an acid extraction layer; washing an acid extraction water layer by using 500ml of dichloromethane under stirring, then regulating the pH value of the acid extraction water layer to be 11 by using 10mol/L sodium hydroxide aqueous solution, cooling to-3 ℃, stirring and crystallizing for 1.5h, filtering, washing a filter cake by using 100ml of water, and filtering to obtain 103.8g of fasudil alkali wet product, wherein the water content is 51.64%, and the purity is 99.65%;
And (3) taking a fasudil alkali wet product, adding 35ml of water and 35ml of 4mol/L hydrochloric acid aqueous solution, stirring and dissolving, dropwise adding the 4mol/L hydrochloric acid aqueous solution until the pH value is=6.0, filtering, taking filtrate, cooling to-1-3 ℃, stirring and crystallizing for 7h, filtering, and drying a filter cake at 55-65 ℃ under reduced pressure for 12h to obtain 51.8g of fasudil hydrochloride hemihydrate, wherein the water content is 2.75%, the yield is 81.2%, and the purity is 100%.
Example 5
The preparation method of fasudil hydrochloride hemihydrate comprises the following steps:
Referring to example 1 of CN102070612, 100g of isoquinoline-5-sulfonyl chloride hydrochloride, 50g of sodium bicarbonate and 700ml of methylene dichloride are added into a 2L three-mouth bottle, cooled to-12 ℃, 600ml of water is dripped at-8 to-12 ℃, stirring is continued for 15min after dripping, standing and layering are carried out, and an organic layer is separated for later use; adding 100g of homopiperazine and 200ml of dichloromethane into a 2L three-mouth bottle, mechanically stirring and dissolving to form a uniform solution, cooling to 0 ℃, dropwise adding a dichloromethane solution of isoquinoline-5-sulfonyl chloride at 0-5 ℃, and continuing stirring for 5 hours after the addition to obtain fasudil alkali reaction solution;
Stirring and washing fasudil alkali reaction liquid with water for two times, wherein the water consumption is 1000ml each time; then extracting the organic layer with 1000ml of 0.4mol/L hydrochloric acid aqueous solution, and taking an acid extraction layer; washing the acid-extracted water layer by using 1000ml of dichloromethane under stirring, then regulating the pH=10 of the acid-extracted water layer by using 10mol/L sodium hydroxide aqueous solution, cooling to-3 ℃, stirring and crystallizing for 1h, filtering, washing a filter cake by using 200ml of water, and filtering to obtain 203.2g of fasudil alkali wet product, wherein the water content is 49.40%, and the purity is 99.58%;
Taking a fasudil alkali wet product, adding 70ml of water and 70ml of 4mol/L hydrochloric acid aqueous solution, stirring and dissolving, dropwise adding the 4mol/L hydrochloric acid aqueous solution until the pH value is=6.0, filtering, taking filtrate, cooling to-1-3 ℃, stirring and crystallizing for 10 hours, filtering, and drying a filter cake at 55-65 ℃ under reduced pressure for 12 hours to obtain 105.6g of fasudil hydrochloride hemihydrate, wherein the water content is 2.81%, the yield is 82.7%, and the purity is 99.98%.
Example 6
The preparation method of fasudil hydrochloride hemihydrate comprises the following steps:
Adding 600g of potassium carbonate and 2500g of homopiperazine into 44L of dichloromethane, stirring and dissolving, controlling the temperature below 0 ℃, slowly and continuously adding 2200g of isoquinoline-5-sulfonyl chloride hydrochloride, and stirring for 2-3 hours at 0-15 ℃ after adding to obtain fasudil alkali reaction solution;
Stirring and washing fasudil alkali reaction liquid twice by using water, wherein the water consumption is 22L each time; then the organic layer is extracted by using 0.4mol/L hydrochloric acid aqueous solution 22L, and an acid water extraction layer is taken; stirring and washing an acid-extracted water layer by using 22L of dichloromethane, then regulating the pH value=11 of the acid-extracted water layer by using 6mol/L sodium hydroxide aqueous solution, cooling to-3 ℃, stirring and crystallizing for 2 hours, filtering, washing a filter cake by using 2000ml of water, and filtering to obtain 4120g of fasudil alkali wet product, wherein the water content is 45.35%, and the purity is 99.91%;
Taking a fasudil alkali wet product, adding 1600ml of water and 1600ml of 4mol/L hydrochloric acid aqueous solution, stirring and dissolving, dripping the 4mol/L hydrochloric acid aqueous solution until the pH value is=6.1, filtering, taking filtrate, cooling to-1-3 ℃, stirring and crystallizing for 9 hours, filtering, and drying a filter cake at 55-65 ℃ under reduced pressure for 12 hours to obtain 2360g of fasudil hydrochloride hemihydrate, wherein the water content is 2.77%, the yield is 84.0% and the purity is 100%.
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should make equivalent substitutions or modifications according to the technical scheme of the present invention and the inventive concept thereof, and should be covered by the scope of the present invention.
Claims (4)
1. The preparation method of fasudil hydrochloride hemihydrate is characterized by comprising the following steps of:
S1, synthesizing fasudil alkali in a hydrophobic aprotic solvent to obtain fasudil alkali reaction liquid; washing the fasudil alkali reaction solution with water, and extracting with hydrochloric acid aqueous solution to obtain an acid water extraction layer, wherein the molar ratio of HCl in the hydrochloric acid aqueous solution to fasudil alkali is 1:0.90-0.95, and the concentration of the hydrochloric acid aqueous solution is 0.35-0.45mol/L; washing the acid extraction water layer with dichloromethane, regulating pH to 10-11, stirring and crystallizing to obtain fasudil alkali wet product, wherein the crystallization temperature is-3 ℃ and the crystallization time is 1-2h;
The hydrophobic aprotic solvent is at least one of dichloromethane, chloroform, 1, 2-dichloroethane, ethyl acetate, isopropyl acetate and methyl tertiary butyl ester;
S2, carrying out salt formation reaction on fasudil alkali wet product and hydrochloric acid in water, stirring for crystallization, and drying to obtain fasudil hydrochloride hemihydrate, wherein the pH value of the salt formation reaction is controlled to be 5.8-6.2, the weight-volume ratio of fasudil alkali to water is 1g:2.5-3.0ml, the crystallization temperature is-1 to 3 ℃, and the crystallization time is 6-10h.
2. The method for preparing fasudil hydrochloride hemihydrate according to claim 1, wherein in S1, the volume ratio of the washing water to the fasudil alkali reaction solution is 0.5-2:1; in S1, the volume ratio of the dichloromethane for washing to the acid extraction layer is 1-2:1.
3. The process for the preparation of fasudil hydrochloride hemihydrate according to claim 1, characterized in that in S1 the pH is adjusted with sodium hydroxide or sodium carbonate.
4. The method for preparing fasudil hydrochloride hemihydrate according to claim 1, wherein in S2, the drying is reduced pressure drying, the drying temperature is 55-65 ℃, and the drying time is not less than 6 hours.
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| US5942505A (en) * | 1995-07-03 | 1999-08-24 | Asahi Kasei Kogyo Kabushiki Kaisha | 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride hydrates |
| CN102020635A (en) * | 2009-09-10 | 2011-04-20 | 河北凯盛医药科技有限公司 | Preparation method of hydrochloride Fasudil hemihydrate |
| CN103450157A (en) * | 2013-08-28 | 2013-12-18 | 合肥久诺医药科技有限公司 | Preparation method for high-purity hydroxyfasudil semihydrate |
| CN109776497A (en) * | 2019-03-07 | 2019-05-21 | 山东新华制药股份有限公司 | A kind of preparation method of hydrochloride Fasudil hemihydrate |
| CN112010805A (en) * | 2020-08-26 | 2020-12-01 | 山东威高药业股份有限公司 | Method for refining fasudil hydrochloride |
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2020
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