CN111004232B - Purification of 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine and preparation method of penehyclidine hydrochloride - Google Patents
Purification of 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine and preparation method of penehyclidine hydrochloride Download PDFInfo
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- DDTVVMRZNVIVQM-UHFFFAOYSA-N 2-(1-azabicyclo[2.2.2]octan-3-yloxy)-1-cyclopentyl-1-phenylethanol;hydrochloride Chemical compound Cl.C1N(CC2)CCC2C1OCC(O)(C=1C=CC=CC=1)C1CCCC1 DDTVVMRZNVIVQM-UHFFFAOYSA-N 0.000 title claims abstract description 44
- GTKRIWMDLNOSLI-UHFFFAOYSA-N 2-(1-azabicyclo[2.2.2]octan-3-yloxy)-1-cyclopentyl-1-phenylethanol Chemical compound C1N(CC2)CCC2C1OCC(O)(C=1C=CC=CC=1)C1CCCC1 GTKRIWMDLNOSLI-UHFFFAOYSA-N 0.000 title claims abstract description 38
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a purification method of 3- (2-cyclopentyl-2-hydroxy-2-phenyl ethoxy) quinuclidine and a preparation method of penehyclidine hydrochloride, which comprises the steps of (1) mixing 3-quinuclidine alcohol with a dimethyl sulfoxide solution, and reacting with a sodium hydride solution and a 1, 1-phenylpentyl ethylene oxide solution; (2) adding purified water and ethyl acetate for extraction, and collecting an organic phase; washing, back-extracting by using a hydrochloric acid solution, and collecting a water layer; (3) adjusting the pH value of the water layer to 5-7, washing with ethyl acetate, adjusting the pH value to 9-12 again, extracting with ethyl acetate, and collecting an organic phase; (4) filtering, and concentrating under reduced pressure to obtain 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine oily substance. According to the invention, the 3- (2-cyclopentyl-2-hydroxy-2-phenyl ethoxy) quinuclidine is separated and purified, so that the yield and quality of a target product are improved, and a finished product of the penehyclidine hydrochloride with high yield and high purity is obtained through one-step salifying crystallization.
Description
Technical Field
The invention relates to the technical field of medical chemistry, and particularly relates to a method for purifying 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine and preparing penehyclidine hydrochloride.
Background
Penehyclidine hydrochloride (hydrochloride) is a new anticholinergic drug developed by the academy of military medical sciences in China. The chemical name is 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine hydrochloride, which is a bioisostere analogue of diphenylglycolic acid-3-quinuclidine alcohol. The research considers that the penehyclidine hydrochloride has an anticholinergic drug with a selective effect. At present, vardenafil hydrochloride has been successfully used for clinically treating organophosphorus pesticide poisoning, and has high antitoxic potency, long-lasting antitoxic effect and small adverse effect. Meanwhile, the choline resisting effect of the penehyclidine hydrochloride has new medical clinical application value on gastrointestinal diseases, ophthalmic diseases, respiratory diseases, central nervous system diseases, anesthesia, urogenital diseases, renal colic and bladder irritation, anti-infective shock, choline resisting colic and the like. Research shows that animal experiments and clinical observation of the penehyclidine hydrochloride show that the penehyclidine hydrochloride has obvious curative effect on new indications, and the medicinal application and the application field of the penehyclidine hydrochloride are further expanded.
The 4 optical isomers of penehyclidine hydrochloride have certain pharmacological effects on medical performance, but the effects on antimuscarinic (M-type cholinergic receptor) and anti-smoke (N-cholinergic receptor) are different.
3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine
The molecular formula is as follows: 315.45
The compound is an important intermediate of 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine hydrochloride. However, the existing preparation of the intermediate often lacks a good impurity removal and purification process for a target product, so that the product has the problems of complex operation, low purity and yield, high cost and the like.
With the increasingly strict and definite requirements of impurities research in drug development in China, the research on drug byproducts and degradation products especially enters a brand new research stage, so that the research on the impurities of the products is controlled within a safe and reasonable limit range, and the method has important significance for improving the quality and safety of the penehyclidine hydrochloride.
Disclosure of Invention
Therefore, the invention provides a method for purifying 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine and preparing penehyclidine hydrochloride, which improves the yield of a target product by effectively purifying the 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine and can obtain a finished product of penehyclidine hydrochloride with high yield and high purity by one-step salifying crystallization.
The technical scheme of the invention is realized as follows:
a process for the purification of 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine comprising the steps of:
(1) mixing 3-quinuclidinol and a dimethyl sulfoxide solution, sequentially adding sodium hydride, stirring for reaction, dropwise adding a 1, 1-phenylpentyl ethylene oxide solution for reaction, and dropwise adding a saturated sodium chloride solution for terminating the reaction to obtain a reaction solution; wherein the molar ratio of the 1, 1-phenylpentyl oxirane solution to the 3-quinuclidinol to the sodium hydride is 1: (1-2.5): (1-1.5);
(2) adding purified water into the reaction solution, stirring, adding ethyl acetate for extraction, separating an ethyl acetate layer, and collecting an organic phase; washing the organic phase with pure water and saturated sodium chloride solution in sequence, and then carrying out back extraction with hydrochloric acid solution to collect a water layer;
(3) adjusting the pH value of the water layer to 5-7 by using an alkaline solution, washing by using ethyl acetate, adjusting the pH value to 9-12 by using the alkaline solution again, extracting by using ethyl acetate, collecting an organic phase, washing and drying to obtain an initial product;
(4) filtering the primary product, collecting the filtrate, decolorizing, filtering with heat, and concentrating under reduced pressure to obtain 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine oil. The invention provides a purification method of 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine, which carries out a series of preparation and purification processes on a target product, namely the 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine. Firstly, extracting by adopting pure water and ethyl acetate, dissolving a target product in an organic phase according to a similar compatibility principle, reducing water-soluble impurities, and collecting the organic phase; secondly, washing the organic phase by adopting a saturated sodium chloride solution to remove salt-soluble impurities in the organic phase, further reducing the existence of the impurities, re-extracting the organic phase by using strong acid, transferring a target product into an acidic aqueous solution according to the property that free alkali forms salt in the acidic aqueous solution and is dissolved in water, removing the organic impurities, collecting a water layer, and preventing the target product from remaining in the organic phase. On the basis, the pH value of the water layer is secondarily adjusted and the water layer is repeatedly extracted by adopting an alkaline reagent, so that impurities in the target product are effectively removed, namely, when the pH value of the water layer is adjusted to 5-7, according to the acid solubility characteristic of the target product, the pH value of the solution is adjusted to be in a neutral state of weak acid, most of the target product is dissolved in a weak acid aqueous solution, the water layer is washed by ethyl acetate, organic impurities are dissolved in the ethyl acetate as far as possible, and the impurities dissolved in an organic phase are further removed; adjusting the pH value of the water layer to 9-12, extracting the water layer by using ethyl acetate, transferring the target product to an organic phase, and removing water-soluble impurities; thereby greatly reducing the content of impurities and ensuring the yield of the target product to the maximum extent, thereby improving the quality standard of the target product. The method for purifying the target product is simple, the generation of impurities is fully reduced at the source, the yield of the target product is ensured, the quality standard of the target product is further improved, and the method is easy for industrial production.
The synthetic route of the invention is as follows:
further, in the step (1), stirring and mixing the 3-quinuclidinol and the dimethyl sulfoxide solution at 145-155 r/min for 5-10 min at room temperature; adding sodium hydride at room temperature, stirring for reacting for 25-35 min, heating to 60 ℃, continuously stirring for 1-1.5 h at constant temperature, controlling the temperature below 20 ℃, dropwise adding a 1, 1-phenylpentyl oxirane solution, heating to 70 ℃ after dropwise adding is completed within 25-35 min, reacting for 3.5-4.5 h, finally cooling to below 20 ℃, and dropwise adding a saturated sodium chloride solution to terminate the reaction.
Further explaining, in the step (2), after ethyl acetate is added for extraction, an ethyl acetate layer is separated, an organic phase is collected, a water layer is extracted for 2-3 times by using ethyl acetate, and the organic phases are combined.
Further, in the step (2), washing the organic phase for 1-2 times by pure water and washing the organic phase for 1-2 times by saturated sodium chloride solution, back-extracting by using 0.8-1.2 mol/L hydrochloric acid solution, collecting a water layer, extracting the organic phase for 2-3 times by using 0.08-0.12 mol/L hydrochloric acid solution, and combining the water layers.
Further, in the step (3), the alkaline aqueous solution is any one of sodium carbonate, sodium bicarbonate or sodium hydroxide solution. The alkaline solution is adopted to adjust the pH value of the water layer, so that the yield and the purity of the target product are improved.
Further explaining, in the step (3), the pH value of a water layer is adjusted to 5-7 by 8-12% sodium hydroxide solution, the water layer is washed by ethyl acetate for 2-3 times, then the pH value is adjusted to 9-12 by 28-32% sodium hydroxide solution, the ethyl acetate is added for extraction for 3-4 times, an organic phase is collected, and after the water layer is washed by saturated sodium chloride solution, the organic phase is dried by anhydrous sodium sulfate or magnesium sulfate.
Further explaining, in the step (4), filtering the primary product, washing a filter cake with ethyl acetate, collecting filtrate, adding the filtrate into active carbon with the liquid volume of 2-3% to stir and reflux for 20-25 min at 60 ℃ for decolorization, performing thermal filtration, and performing reduced pressure rotary evaporation on the filtrate at 60 ℃ for 2-4 hours to obtain the oily substance of the 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine.
A preparation method of penehyclidine hydrochloride comprises the following steps:
(1) adding tert-butyl methyl ether into the prepared oily matter of the 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine, heating to dissolve, cooling, dropwise adding a hydrogen chloride ethyl acetate solution until the pH value of the solution is 2-3, slowly adding the tert-butyl methyl ether in a supplementing manner, and stirring at normal temperature to separate out a solid;
(2) and filtering the precipitated solid, washing, and drying in vacuum to obtain the penehyclidine hydrochloride. The invention provides a preparation method of penehyclidine hydrochloride, which optimizes the preparation process of 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine in the synthesis process of penehyclidine hydrochloride, purifies the penehyclidine hydrochloride, directly processes the target product in a solution state after synthesis to remove most impurities, and then obtains a penehyclidine hydrochloride finished product with high yield and high purity by one-step salifying crystallization, thereby reducing the component loss, greatly increasing the yield of 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine hydrochloride, improving the quality standard of the penehyclidine hydrochloride Low pollution and the like, and is easy for industrial production.
Further explaining, in the step (1), the heating and dissolving temperature is 55-65 ℃, the temperature is reduced to-5-0 ℃, and the ethyl acetate solution of hydrogen chloride is dropwise added under the stirring condition.
Further explaining, in the step (2), washing the precipitated solid with tert-butyl methyl ether, and performing vacuum drying at 65-75 ℃ for 2-3 h to obtain the penehyclidine hydrochloride.
Compared with the prior art, the invention has the beneficial effects that: according to the invention, a series of preparation and purification processes are carried out on the target product 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine, and on the basis of adopting pure water and ethyl acetate for extraction, saturated sodium chloride solution for washing and strong acid back extraction of an organic phase, the treatment of secondary adjustment of the pH value of a water layer and repeated extraction is carried out by adopting an alkaline reagent, so that the impurities in the target product are effectively removed, the impurity content is greatly reduced, the yield of the target product can be ensured to the maximum extent, and the quality standard of the target product is improved. The method for purifying the target product is simple, the generation of impurities is fully reduced at the source, the yield of the target product is ensured, and the quality standard of the target product is improved.
Meanwhile, the target product of the 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine is directly treated in a solution state after being synthesized, most impurities can be removed, and then a finished product of the penehyclidine hydrochloride with high yield and high purity can be obtained only by one-step salifying crystallization, so that the component loss is reduced, the yield of the 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine hydrochloride is increased, and the quality standard of the penehyclidine hydrochloride is improved.
Drawings
FIG. 1 is a liquid chromatogram of a self-made sample of penehyclidine hydrochloride in an embodiment of the invention;
FIG. 2 is an infrared scan of a homemade sample of penehyclidine hydrochloride according to an embodiment of the present invention.
Detailed Description
In order to better understand the technical content of the invention, specific examples are provided below to further illustrate the invention.
The experimental methods used in the examples of the present invention are all conventional methods unless otherwise specified.
The materials, reagents and the like used in the examples of the present invention can be obtained commercially without specific description.
Example 1-a process for the purification of 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine comprising the steps of:
(1) mixing 3-quinuclidinol and a dimethyl sulfoxide solution, sequentially adding sodium hydride, stirring for reaction, dropwise adding a 1, 1-phenylpentyl ethylene oxide solution for reaction, and dropwise adding a saturated sodium chloride solution for terminating the reaction to obtain a reaction solution; wherein the molar ratio of the 1, 1-phenylpentyl oxirane solution to the 3-quinuclidinol to the sodium hydride is 1:1: 1;
(2) adding purified water into the reaction solution, stirring, adding ethyl acetate for extraction, separating an ethyl acetate layer, and collecting an organic phase; washing the organic phase with pure water and saturated sodium chloride solution in sequence, and then carrying out back extraction with hydrochloric acid solution to collect a water layer;
(3) adjusting the pH value of a water layer to 5-7 by using an alkaline solution, washing by using ethyl acetate, adjusting the pH value to 9-12 by using the alkaline solution again, extracting by using the ethyl acetate, collecting an organic phase, washing and drying to obtain an initial product;
(4) filtering the primary product, collecting the filtrate, decolorizing, filtering with heat, and concentrating under reduced pressure to obtain 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine oil.
Example 2-a process for the purification of 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine comprising the steps of:
(1) stirring and mixing 3-quinuclidinol and dimethyl sulfoxide solution at 145-155 r/min for 5-10 min at room temperature, adding sodium hydride at room temperature, stirring and reacting for 25-35 min, heating to 60 ℃, and continuing stirring at constant temperature for 1-1.5 h; controlling the temperature below 20 ℃, dropwise adding a 1, 1-phenylpentyl oxirane solution, after dropwise adding within 25-35 min, heating to 70 ℃ and reacting for 3.5-4.5 h; cooling to below 20 ℃, and dropwise adding a saturated sodium chloride solution to terminate the reaction to obtain a reaction solution; wherein the molar ratio of the 1, 1-phenylpentyl oxirane solution to the 3-quinuclidinol to the sodium hydride is 1: 2.5: 1.5;
(2) adding purified water into the reaction solution, stirring, adding ethyl acetate for extraction, separating an ethyl acetate layer, collecting an organic phase, extracting a water layer with ethyl acetate for 2-3 times, and combining the organic phases; washing the organic phase for 1-2 times by pure water and washing the organic phase for 1-2 times by a saturated sodium chloride solution, back-extracting by a 0.8-1.2 mol/L hydrochloric acid solution, collecting a water layer, extracting the organic phase for 2-3 times by a 0.08-0.12 mol/L hydrochloric acid solution, and combining the water layers;
(3) adjusting the pH value of a water layer to 5-7 by using 8-12% sodium hydroxide solution, washing with ethyl acetate for 2-3 times, adjusting the pH value to 9-12 by using 28-32% sodium hydroxide solution, extracting with ethyl acetate for 3-4 times, collecting an organic phase, washing with saturated sodium chloride solution, and drying with anhydrous sodium sulfate or magnesium sulfate to obtain a primary product;
(4) filtering the primary product, washing a filter cake with ethyl acetate, collecting filtrate, adding the filtrate into active carbon with the liquid volume of 2-3% for decoloring treatment at 60 ℃ by stirring and refluxing for 20-25 min, carrying out heat filtration, and carrying out rotary evaporation on the filtrate at 60 ℃ under reduced pressure for 2-4 hours to obtain the oily substance of the 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine.
Example 3-a process for the preparation of penehyclidine hydrochloride comprising the steps of:
(1) adding tert-butyl methyl ether into the oily substance of the 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine prepared in the example 2, heating to 55-65 ℃ for dissolution, cooling to-5-0 ℃, dropwise adding a hydrogen chloride ethyl acetate solution under stirring to the pH value of the solution of 2-3, slowly adding the tert-butyl methyl ether, and stirring at normal temperature to separate out a solid;
(2) and filtering the precipitated solid, washing with tert-butyl methyl ether, and vacuum-drying at 65-75 ℃ for 2-3 h to obtain penehyclidine hydrochloride.
Example 4-a process for the preparation of penehyclidine hydrochloride comprising the steps of:
(1) adding 640g of 3-quinuclidinol and 3000ml of dimethyl sulfoxide into a 20L reaction kettle, and stirring and mixing at room temperature at 150 revolutions per minute for 8 min; adding 200g sodium hydride, and stirring at room temperature for 30 min; heating to 60 ℃, and stirring for reaction for 1 h;
(2) controlling the temperature to be below 20 ℃, dissolving 520g of 1, 1-phenylpentyl oxirane solution by using 700ml of dimethyl sulfoxide, dropwise adding the dissolved 1, 1-phenylpentyl oxirane solution into the solution, completing dropwise adding within 30min, and heating to 70 ℃ for reaction for 4 h;
(3) cooling to below 20 ℃, and dropwise adding 2400ml of saturated sodium chloride solution to terminate the reaction;
(4) adding 2200ml of purified water at room temperature, fully stirring, adding 2800ml of ethyl acetate, shaking, mixing uniformly, and extracting; transferring the sample solution into a knockout, mixing the sample solution with the water layer after extraction if emulsification exists, separating out an ethyl acetate layer, collecting an organic phase, extracting the water layer for 2 times (1400 ml/time) by using ethyl acetate, and combining the organic phases;
(5) washing the organic phase 1 times with 1700ml pure water, washing 1 time (1700 ml/time) with saturated sodium chloride solution, back-extracting the organic phase with 1700ml prepared 1mol/L hydrochloric acid solution, collecting the water layer (the pH of the water layer is strong acid), extracting the organic phase 2 times (800 ml/time) with 0.1mol/L hydrochloric acid solution, and combining the water layers;
(6) adjusting the pH of the aqueous layer to 5.56 with 10% sodium hydroxide solution, washing the aqueous layer 2 times with ethyl acetate (1400 ml/time); the pH of the aqueous layer was adjusted to 9 with 30% sodium hydroxide solution, and extracted 3 times with ethyl acetate (2100ml, 1000ml, 1000ml), and the organic phase was collected, washed 1 time with saturated sodium chloride solution, and dried over 300g of anhydrous sodium sulfate to give an initial product.
(7) The crude product was filtered, the filter cake was washed with 500ml of ethyl acetate, the filtrate was collected, 2% by volume of liquid activated carbon was added to the filtrate, the mixture was stirred and refluxed at 60 ℃ for 20min, the mixture was filtered hot, and the filtrate was rotary-evaporated at 60 ℃ under reduced pressure for 3 hours to give 570.5g of 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine oily substance in a molar yield of 70%.
(8) 570.5g of the oil are dissolved by heating to 60 ℃ with 1000ml of tert-butyl methyl ether; cooling to-3 ℃, dropwise adding an ethyl acetate hydrochloride solution (about 5L) while stirring until the pH value of the solution is 2-3, slowly adding 5L of tert-butyl methyl ether, stirring at normal temperature for at least 3h, and separating out a solid;
(9) and filtering the precipitated solid, washing the solid with 500ml of tert-butyl methyl ether, and drying the solid at 70 ℃ for 2-3 h in vacuum to obtain 611.2g of penehyclidine hydrochloride, wherein the molar yield of the step is about 96%, and the purity of the step is 100%.
Example 5-a process for the preparation of penehyclidine hydrochloride, following the procedure of example 4, with the exception that: in the step (1), 600g of 3-quinuclidinol and 3000ml of dimethyl sulfoxide are stirred and mixed for 8min at room temperature at the speed of 150 revolutions per minute; adding 190g of sodium hydride, and stirring at room temperature for 30 min; heating to 60 ℃, and stirring for reaction for 1 h; the remaining steps and parameters were the same as in example 4.
540.5g of 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine oily matter is prepared, the molar yield is about 71 percent, and the purity of a crude product is 98.9 percent; 580.2g of penehyclidine hydrochloride is obtained, the molar yield of the step is about 95%, and the purity is 100%.
The invention adopts some common reagents to prepare 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine, such as dimethyl sulfoxide, sodium hydride, saturated sodium chloride, ethyl acetate, hydrochloric acid solution and sodium hydroxide solution, and effectively reduces the impurity content by acid treatment and adjustment of the pH value of the 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine solution according to the water solubility and the difficult solubility in organic reagents such as ether and the like of the 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine hydrochloride, thereby improving the yield and the quality of the 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine hydrochloride and providing a basis for the preparation of the pentaethylquinether hydrochloride, provides important guiding significance for safe medication of the 3- (2-cyclopentyl-2-hydroxy-2-phenyl ethoxy) quinuclidine hydrochloride and has high practical value.
Comparative example-a study of the washing effect of ethyl acetate at different acidity was carried out:
according to the dissolution property of a target product, the product is easily soluble in water under an acidic condition, is soluble in organic reagents such as diethyl ether and the like under a neutral or alkaline condition, is presumed to generate by-products with similar structures according to a similar compatibility principle, is similar to the product in solubility, and is used for adjusting the pH value of a reaction liquid by adopting an alkaline solution when the reaction liquid is subjected to post-treatment, and researching the washing and impurity removal effects of ethyl acetate under different acidity conditions, wherein the method specifically comprises the following steps:
1. adjusting the pH of the water layer to 4.85 (4.5-5.0) by using a 10% sodium hydroxide solution, eluting the water layer for 2 times by using ethyl acetate, and carrying out the rest steps to be the same as the step in the example 4;
2. adjusting the pH of the water layer to 5.25 (5.0-5.5) by using a 10% sodium hydroxide solution, eluting the water layer for 2 times by using ethyl acetate, and carrying out the rest steps to be the same as the step in the example 4;
3. adjusting the pH of the water layer to 5.67 (5.5-6.0) by using a 10% sodium hydroxide solution, eluting the water layer for 2 times by using ethyl acetate, and carrying out the rest steps to be the same as the step in the example 4;
4. adjusting the pH of the water layer to 6.33 (6.0-6.5) by using a 10% sodium hydroxide solution, eluting the water layer for 2 times by using ethyl acetate, and carrying out the rest steps to be the same as the step in the example 4;
5. adjusting the pH of the water layer to 6.33 (6.5-7.0) by using a 10% sodium hydroxide solution, eluting the water layer for 2 times by using ethyl acetate, and carrying out the rest steps to be the same as the step in the example 4;
the results of the study are given in the following table:
TABLE 1 washing effect of ethyl acetate at different acidity table (area normalization method)
According to the table, the reaction solution is adjusted to have a pH value under a weak acid neutral condition, and is washed by ethyl acetate, so that the effects of obvious impurity removal and decoloration are achieved, the yield is greatly improved, namely, when the pH value of a water layer is adjusted to 5.5-6.0, the optimal selection is that a good impurity removal effect can be achieved, and the yield is improved.
Example 6 HPLC detection methods for 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine and 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine hydrochloride
The method comprises the following steps: referring to the Chinese pharmacopoeia 2015 year version 0512 high performance liquid chromatography
A detector: ultraviolet detector
A chromatographic column: c18, 4.6mm X250 mm, 5 μm or equivalent performance column
Mobile phase: acetonitrile-0.02 mol/L potassium dihydrogen phosphate solution-triethylamine (30:70:0.2) (pH adjusted to 4.0 with phosphoric acid) as mobile phase A, acetonitrile-0.02 mol/L potassium dihydrogen phosphate solution-triethylamine (65:35:0.2) (pH adjusted to 4.5 with phosphoric acid) as mobile phase B
Detection wavelength: 220nm
Flow rate: 1.5ml/min
Column temperature: 30 deg.C
Gradient program:
20. mu.l of the sample solution (example 4) was precisely measured and injected into a liquid chromatograph, and the chromatogram was recorded. If an impurity peak exists in the chromatogram of the test solution, the result is shown in figure 1 according to the calculation of a peak area normalization method, and the purity is 100%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. A method for purifying 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine, which is characterized by comprising the following steps: the method comprises the following steps:
(1) mixing 3-quinuclidinol and a dimethyl sulfoxide solution, sequentially adding sodium hydride, stirring for reaction, dropwise adding a 1, 1-phenylpentyl ethylene oxide solution for reaction, and dropwise adding a saturated sodium chloride solution for terminating the reaction to obtain a reaction solution; wherein the molar ratio of the 1, 1-phenylpentyl oxirane solution to the 3-quinuclidinol to the sodium hydride is 1: (1-2.5): (1-1.5);
(2) adding purified water into the reaction solution, stirring, adding ethyl acetate for extraction, separating an ethyl acetate layer, and collecting an organic phase; washing the organic phase with pure water and saturated sodium chloride solution in sequence, and then carrying out back extraction with hydrochloric acid solution to collect a water layer;
(3) adjusting the pH value of the water layer to 5.5-6.0 by using an alkaline solution, washing by using ethyl acetate, adjusting the pH value to 9-12 by using the alkaline solution again, extracting by using ethyl acetate, collecting an organic phase, washing and drying to obtain a primary product;
(4) filtering the primary product, collecting the filtrate, decolorizing, filtering with heat, and concentrating under reduced pressure to obtain 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine oil.
2. The process for purifying 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine as claimed in claim 1, wherein: in the step (1), stirring and mixing 3-quinuclidinol and a dimethyl sulfoxide solution at 145-155 r/min for 5-10 min at room temperature; adding sodium hydride at room temperature, stirring for reacting for 25-35 min, heating to 60 ℃, continuously stirring for 1-1.5 h at constant temperature, controlling the temperature below 20 ℃, dropwise adding a 1, 1-phenylpentyl oxirane solution, heating to 70 ℃ after dropwise adding is completed within 25-35 min, reacting for 3.5-4.5 h, finally cooling to below 20 ℃, and dropwise adding a saturated sodium chloride solution to terminate the reaction.
3. The process for purifying 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine as claimed in claim 1, wherein: and (3) adding ethyl acetate to extract, separating an ethyl acetate layer, collecting an organic phase, extracting a water layer with ethyl acetate for 2-3 times, and combining the organic phases.
4. The process of claim 3, wherein the purification process of 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine is carried out by: in the step (2), washing the organic phase for 1-2 times by pure water and washing the organic phase for 1-2 times by a saturated sodium chloride solution, back-extracting by a 0.8-1.2 mol/L hydrochloric acid solution, collecting a water layer, extracting the organic phase for 2-3 times by a 0.08-0.12 mol/L hydrochloric acid solution, and combining the water layers.
5. The process for purifying 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine as claimed in claim 1, wherein: in the step (3), the alkaline aqueous solution is any one of sodium carbonate, sodium bicarbonate or sodium hydroxide solution.
6. The process of claim 5, wherein the purification process of 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine is carried out by: in the step (3), the pH value of a water layer is adjusted to 5.5-6.0 by 8-12% sodium hydroxide solution, the water layer is washed by ethyl acetate for 2-3 times, then the pH value is adjusted to 9-12 by 28-32% sodium hydroxide solution, the ethyl acetate is added for extraction for 3-4 times, an organic phase is collected, and the organic phase is washed by saturated sodium chloride solution and dried by anhydrous sodium sulfate or magnesium sulfate.
7. The process for purifying 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine as claimed in claim 1, wherein: in the step (4), the primary product is filtered, ethyl acetate is used for washing a filter cake, filtrate is collected, the filtrate is added into active carbon with the liquid volume of 2-3% and stirred and refluxed for 20-25 min at 60 ℃ for decolorization treatment, heat filtration is carried out, and the filtrate is subjected to reduced pressure rotary evaporation for 2-4 hours at 60 ℃ to obtain the oily substance of the 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine.
8. A preparation method of penehyclidine hydrochloride is characterized by comprising the following steps: the method comprises the following steps:
(1) adding tert-butyl methyl ether into the oily substance of the 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine prepared according to any one of the claims l to 7, heating to dissolve, cooling, dropwise adding a hydrogen chloride ethyl acetate solution to the solution until the pH value is 2-3, slowly adding the tert-butyl methyl ether, and stirring at normal temperature to separate out a solid;
(2) and filtering the precipitated solid, washing, and drying in vacuum to obtain the penehyclidine hydrochloride.
9. The process of claim 8, wherein the reaction mixture comprises: in the step (1), the heating and dissolving temperature is 55-65 ℃, the temperature is reduced to-5-0 ℃, and the ethyl acetate solution of hydrogen chloride is dropwise added under the stirring condition.
10. The process of claim 8, wherein the reaction mixture comprises: in the step (2), washing the precipitated solid with tert-butyl methyl ether, and vacuum-drying at 65-75 ℃ for 2-3 h to obtain penehyclidine hydrochloride.
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