CN106866625B - Preparation method of ketanserin - Google Patents
Preparation method of ketanserin Download PDFInfo
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- CN106866625B CN106866625B CN201710029847.6A CN201710029847A CN106866625B CN 106866625 B CN106866625 B CN 106866625B CN 201710029847 A CN201710029847 A CN 201710029847A CN 106866625 B CN106866625 B CN 106866625B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention relates to a preparation method of a medicine raw material ketanserin, in particular to a preparation method of high-yield and high-purity ketanserin. The technical scheme adopted by the invention is as follows: a method for preparing high-purity high-yield ketanserin, which comprises the following steps: (1)3- (2-chloroethyl) -2,4(1H,3H) -quinazoline diketone and 4- (4-fluorobenzoyl) piperidine hydrochloride are subjected to condensation reaction to prepare a crude product of ketanserin; (2) recrystallizing the crude ketanserin prepared in the step (1) to obtain a pure ketanserin product, wherein the reaction formula is as follows:
Description
Technical Field
The invention relates to a preparation method of a medicine raw material ketanserin, in particular to a preparation method of high-yield and high-purity ketanserin.
Background
Ketanserin, having the chemical name 3- [2- [4- (4-fluorobenzolyl) -1-piperidinyl ] ethyl ] -2,4(1H,3H) -quinazoline, and the generic name Ketanserin, having the following structural formula:
。
It is an antihypertensive drug, but has no antihypertensive effect on normal persons. The clinical application is mainly used for mild, moderate or severe hypertension, and is also used for congestive heart failure and Raynaud's disease, and in addition, the research finds new application in myocardial infarction, inflammatory pain and sexual dysfunction.
Prior patent application EP0098499a1 discloses a process for the preparation of ketanserin, prepared by the reaction of the intermediate 4- (4-fluorobenzoyl) piperidine and 2, 3-dihydro-5H-oxazolo [2,3-B ] quinazolin-5-one, of the formula 1:
。
Or ketanserin as disclosed in US4335127, which is obtained by condensing intermediate 3- (2-chloroethyl) -2,4(1H,3H) -quinazolinedione and 4- (4-fluorobenzoyl) piperidine hydrochloride, and has the reaction formula shown in formula 2:
。
however, none of the above documents describes the purity of ketanserin, and the purity of ketanserin products in the market is 95 ~ 98%, which cannot meet the quality standard of pharmaceutical raw material drugs (the content of impurities is less than or equal to 0.10%), and moreover, the yield of products prepared by the process shown in formula 2 is low, which is only 27%, so that the preparation of high ~ yield and high ~ purity ketanserin is particularly important.
Disclosure of Invention
The invention aims to solve the technical problems of low yield and low purity of the obtained ketanserin product in the existing preparation method of ketanserin. The technical scheme adopted by the invention is as follows: a method for preparing high-purity high-yield ketanserin, which comprises the following steps:
(1)3- (2-chloroethyl) -2,4(1H,3H) -quinazoline diketone and 4- (4-fluorobenzoyl) piperidine hydrochloride are subjected to condensation reaction to prepare a crude product of ketanserin;
(2) Recrystallizing the crude ketanserin prepared in the step (1) to obtain a pure ketanserin product, wherein the reaction formula is as follows:
Preferably, in step (1), the base used in the reaction is anhydrous sodium carbonate, and the ratio of the addition amount of the base to the amount of the 4- (4-fluorobenzoyl) piperidine hydrochloride is 4: 1;
Preferably, in step (1), the reaction solvent is 4-methyl-2-pentanone;
Preferably, in the step (1), the reaction temperature is 100 +/-2 ℃, and the reaction time is 72 hours;
Preferably, in the step (2), the organic solvent used in the recrystallization step is a mixed solvent of methanol and dichloromethane;
Preferably, in the step (2), the volume ratio of the organic solvent methanol to dichloromethane used in the recrystallization step is 1: 2;
preferably, in the step (2), the ratio of the mass of the crude ketanserin to the volume of the organic solvent is 1:24 ~ 30 (g/mL).
in the preparation and synthesis process of ketanserin, the condensation reaction of two intermediates of 3- (2-chloroethyl) -2,4(1H,3H) -quinazolinedione and 4- (4-fluorobenzoyl) piperidine hydrochloride and the recrystallization of the crude product are key steps, and the two steps are specially researched and described in detail below:
regarding the step (1), the condensation reaction of two intermediates, namely 3- (2-chloroethyl) -2,4(1H,3H) -quinazolinedione and 4- (4-fluorobenzoyl) piperidine hydrochloride, has high requirements on a solvent and a base, and has a large influence on the quality of a product if the selection of the base and the solvent is not proper, so that detailed exploration is carried out on the selection of the base and the solvent in the process research process. Through a plurality of experiments, research personnel find that if the alkalinity is too strong, the content of impurities in the product is increased, so that the post-treatment operation of the process is complex, and therefore, the alkali is preferably sodium carbonate; if the solvent is not properly selected, the color of the reaction solution can be deepened, and the appearance and the quality of the product are seriously influenced, so that the solvent is preferably 4-methyl-2-pentanone. Through multiple experimental researches, the reaction time is 72 hours, the temperature is controlled at 100 +/-2 ℃, and the mass ratio of the 3- (2-chloroethyl) -2,4(1H,3H) -quinazolinedione to the 4- (4-fluorobenzoyl) piperidine hydrochloride is controlled to be 1.05: 1, the ratio of the addition amount of the alkali to the amount of the 4- (4-fluorobenzoyl) piperidine hydrochloride is 4:1, and by adopting the process condition, the yield of the crude ketanserin is 92.6 percent and is far better than 27 percent reported in the literature.
in the prior art, solvents used in the step of recrystallizing the crude ketanserin product are solvents used in the condensation reaction step of two intermediates of 3- (2-chloroethyl) -2,4(1H,3H) -quinazolinedione and 4- (4-fluorobenzoyl) piperidine hydrochloride, but no report is made on the purity of the ketanserin after recrystallization.
the invention prepares the ketanserin product with high yield and high purity by improving the technological conditions of the condensation reaction of the intermediate 3- (2-chloroethyl) -2,4(1H,3H) -quinazolinedione and 4- (4-fluorobenzoyl) piperidine hydrochloride and the recrystallization of the crude ketanserin product.
Drawings
FIG. 1 is a HPLC data chart of crude tetrodoterin in the example, wherein impurity A is 4- (4-fluorobenzoyl) piperidine hydrochloride and impurity B is 3- (2-chloroethyl) -2,4(1H,3H) -quinazolinedione.
FIG. 2 is a nuclear magnetic data plot of a pure sample of the example ketanserin.
FIG. 3 is a chart of HPLC data of pure tetraketotryptilin from example.
FIG. 4 is a chart of HPLC data for the crude product of pentaketanserin in example, in which impurity A refers to 4- (4-fluorobenzoyl) piperidine hydrochloride and impurity B refers to 3- (2-chloroethyl) -2,4(1H,3H) -quinazolinedione.
FIG. 5 is a chart of HPLC data for pure pentaketanserin of example, where impurity B refers to 3- (2-chloroethyl) -2,4(1H,3H) -quinazolinedione.
Detailed Description
Ketanserin related substance detection method
chromatographic conditions and system applicability test: using a C18 column; phosphate (3.4 g of monopotassium phosphate is taken and dissolved by 50ml of water, 10ml of triethylamine is added, and then the solution is diluted to 1000ml by water): methanol =1:1 (pH adjusted to 4.0 with phosphoric acid), detection wavelength 245 nm;
Test solution: precisely weighing 10mg of the product, placing the product in a 100ml measuring flask, adding a mobile phase for dissolving, and diluting to a scale;
control solution: precisely measuring 1ml of a test solution, placing the test solution into a 100ml measuring flask, and adding a mobile phase to dilute the test solution to a scale;
and (2) injecting 20 mu l of the control solution into a liquid chromatograph, adjusting the detection sensitivity to ensure that the peak height of the main component peak is 10-20% of the full range, precisely measuring 20 mu l of the test solution and 20 mu l of the control solution respectively, injecting the test solution and the control solution into the liquid chromatograph respectively, and recording the chromatogram until the retention time of the main component peak is 3 times that of the main component peak, wherein if an impurity peak exists in the chromatogram of the test solution, the peak area of a single impurity is not more than 1/5 (0.2%) of the main peak area of the control solution, and the sum of the peak areas of the impurities is not more than the main peak area (1.0%) of the control solution.
EXAMPLE one preparation of intermediate 4- (4-fluorobenzoyl) piperidine hydrochloride
Step one preparation of 1-acetyl-4-piperidinecarboxylic acid
300 g (2.3 mol) of 4-piperidinecarboxylic acid as a starting material were dispersed in 1.5L of acetic anhydride, refluxed and stirred overnight, and subjected to TLC (HSGF254 silica gel plate, developer: V)methanol:VEthyl acetate=1:6), recovering acetic anhydride after the reaction is finished, adding 500 mL of methyl tert ~ butyl ether into the residue, stirring and filtering, washing a filter cake with methyl tert ~ butyl ether (100 mL multiplied by 2), and drying to obtain 330 g of white solid, wherein the yield is 83%, and the temperature is mp 180 ~ 181 ℃.
Step II preparation of acetyl-4- (4-fluorobenzoyl) piperidine
slowly dissolving 200 g of 1 ~ acetyl ~ 4 ~ piperidinecarboxylic acid in 1.5L of thionyl chloride, stirring for 4h at room temperature, filtering by using a sand core funnel, filtering to protect the solution, slightly contacting with air, washing by using 500 mL of methyl tert ~ butyl ether, drying in vacuum (T =50 ℃) to obtain 213g of 1 ~ acetyl ~ 4 ~ piperidinecarbonyl chloride, dispersing 276g of anhydrous aluminum trichloride in 1L of fluorobenzene, slowly adding 213g of 1 ~ acetyl ~ 4 ~ piperidinecarbonyl chloride under stirring (temperature of 30 ~ 70 ℃), refluxing for 3h after the addition is finished, and performing TLC (HSGF254 silica gel plate, developing agent: V GF 254)Methylene dichloride:VMethanol=40:3) monitoring the reaction process, cooling to room temperature after the reaction is complete, pouring into ice water for quenching, extracting with 2L dichloromethane, concentrating to dryness to obtain 200 g of oily product, and obtaining yield of 68% (the product can be directly used for the next reaction).
Step three preparation of 4- (4-fluorobenzoyl) piperidine hydrochloride
Dissolving 1-acetyl-4- (4-fluorobenzoyl) piperidine 200 g in 600mL of 6mol/L HCl aqueous solution, refluxing and stirring for 8h, after the reaction is finished, concentrating and removing water, carrying water with toluene for more than 3 times until the water is completely evaporated, pulping with dichloromethane, cooling to 20 ℃, filtering, washing a filter cake with dichloromethane, and then washing with Vmethylene dichloride：VPetroleum ether=1: washing and drying to obtain 174 g of yellow solid with yield of 89% (which can be directly used for the next reaction).
EXAMPLE two preparation of the intermediate 3- (2-chloroethyl) -2,4(1H,3H) -quinazolinedione
Step one preparation of Ethyl 2- [ (ethoxycarbonyl) amino ] benzoate
870g of ethyl 2-aminobenzoate as a starting material was dissolved in 7L of toluene, and the mixture was heated to reflux, 626g of ethyl chloroformate was added dropwise thereto, and the mixture was stirred under reflux overnight, followed by TLC (HSGF254 silica gel plate, developing solvent: V)Ethyl acetate:VPetroleum ether=1:20) monitoring reaction progress, after reaction is completed, cooling toWashing with 5L saturated sodium carbonate to alkalinity at room temperature, concentrating to remove partial toluene, cooling, crystallizing, filtering to obtain 1.1kg product with 88% yield.
Step two preparation of 3- (2-hydroxyethyl) -2,4- (1H,3H) -quinazolinedione
1.1kg of 2- [ (ethoxycarbonyl) amino group was added to the reaction flask]Ethyl benzoate and 285g 2-aminoethanol were heated to 90 ℃ and stirred under reflux overnight, and the mixture was purified by TLC (HSGF254 silica gel plate, developing solvent: V)ethyl acetate:VMethanol=10:1) monitoring the reaction process, after the reaction is finished, cooling to 10 ℃, adding 2L dichloromethane, stirring for 30min, filtering, washing a filter cake with dichloromethane, and drying at 50 ℃ to obtain 800g of white solid with the yield of 83.7%.
Step three preparation of 3- (2-chloroethyl) -2,4(1H,3H) -quinazolinedione
670g of 3- (2-hydroxyethyl) -2,4- (1H,3H) -quinazolinedione, 423g of thionyl chloride and 7L of chloroform were added to the reaction flask, stirred at reflux overnight and applied to a TLC method (HSGF254 silica gel plate, developing solvent: V)Ethyl acetate:VPetroleum ether=1:1) monitoring the reaction process, after the reaction is completed, cooling to below 10 ℃, filtering, washing a filter cake by dichloromethane, and drying at 50 ℃ to obtain 650g of white solid with the yield of 89.0%.
EXAMPLE 3 Process study of the preparation method of the present invention
The condensation reaction of 3- (2-chloroethyl) -2,4(1H,3H) -quinazolinedione and 4- (4-fluorobenzoyl) piperidine hydrochloride is a key step for preparing ketanserin, and the step has great influence on the quality and yield of products. Based on the technical problem reported in document US4335127 that the yield of ketanserin synthesized by this step is low, we have studied and improved the process from the following three aspects.
firstly, a reaction solvent is screened, an experimental scheme using ketones or ethers as a solvent is explored, and the result shows that when anisole is used as the solvent, the color of a reaction solution is black, when diphenyl ether or cyclohexanone is used as the solvent, the color of the reaction solution is yellow, 4-methyl-2-pentanone is used as the solvent, the color of the reaction solution is white, and for the simplicity of a post-treatment process, the user determines that 4-methyl-2-pentanone is used as the solvent.
secondly, through multiple experiments, the technical problem of low yield of ketanserin reported in document US4335127 is that the reaction of raw materials is incomplete, so potassium carbonate with strong alkalinity is considered as an alkali reagent, however, when the experiment is carried out for 7 ~ 8h, the experimental result shows that impurities are more in spot during TLC detection, and sodium carbonate is still used as the alkali.
Finally, we have studied the reaction time and, based on document US4335127, we have determined the temperature as 100 ± 2 ℃, when the reaction has proceeded for 24 hours, TLC detection has not been completed; when the reaction is carried out for 48 hours, TLC detection is not completed, but the product is obviously more than 24 hours; when the reaction is carried out for 72 hours, the TLC detection reaction is complete, and the impurity spots are less; therefore, we set the time to 72 h.
In addition, the recrystallization step has great influence on the quality of the product, the selection of the crystallization solvent is the core content of the research of the refining process, and the proper crystallization solvent and the reasonable crystallization operation play an important role in removing impurities of the product.
according to the document U.S. Pat. No. 4,4335127, we first used 4-methyl-2-pentanone as a recrystallization solvent, but since ketanserin was not completely dissolved under heating reflux conditions, we also examined the case of using anisole, diphenyl ether, and cyclohexanone as recrystallization solvents, respectively, and none of the three solvents was completely dissolved under heating reflux conditions, so that the above solvents were not suitable for recrystallization of ketanserin.
according to a large number of experiments, a mixed solvent of methanol and dichloromethane is determined as a ketanserin crystallization solvent, and then the influence of the use amount of the solvent and the volume ratio of the solvent to the solvent on recrystallization is considered by taking the mixed solvent of the methanol and the dichloromethane as a recrystallization solvent, and the experimental result shows that the volume ratio of the methanol to the dichloromethane is 1:2 as a crystallization solvent system, and the volume ratio (mass ~ volume ratio, g/mL) of the crude product of the ketanserin to the crystallization solvent is 1:24 ~ 1:30, so that a product with high yield and high purity is obtained.
EXAMPLE 4 preparation of ketanserin
Step one preparation of crude ketanserin
10g of 4- (4-fluorobenzoyl) piperidine hydrochloride, 9.7g of 3- (2-chloroethyl) -2,4(1H,3H) -quinazolinedione, 17.5g of Na2CO3Adding into 150mL of 4-methyl-2-pentanone, heating and refluxing for 72h, detecting complete reaction by TLC, cooling to room temperature, pouring into 500 mL of water, filtering, washing the solid with 50mL of multiplied by 3 water, and drying to obtain 15g of white solid, the yield is 92.6%, and the purity (HPLC) is 98.43%.
Step two ketone tryptiline pure product preparation
Dissolving crude ketanserin 15g in mixed solution of 450mL methanol and dichloromethane (V)methanol：VMethylene dichloride=1:2), refluxing and stirring at 45 ~ 50 ℃ for 20min, filtering while hot, removing insoluble solids, concentrating the liquid to 150mL, and filtering to obtain 14g of pure ketanserin, wherein the total yield of the butting step is 86.4%, and the purity (HPLC) is 99.93%.
Example 5 comparative example
4.5 g of 4- (4-fluorobenzoyl) piperidine hydrochloride (0.02mol), 4.9 g of 3- (2-chloroethyl) -2,4(1H,3H) -quinazolinedione (0.02mol), 8 g of Na2CO3adding the obtained product into 80mL of 4 ~ methyl ~ 2 ~ pentanone, heating and stirring for 7 ~ 8h, cooling after the reaction is finished, pouring a proper amount of water, stirring, filtering, and drying to obtain 4.6 g of crude ketanserin, wherein the purity (HPLC) is 98.32%, and the crude ketanserin is recrystallized by using 4 ~ methyl ~ 2 ~ pentanone to obtain 2.2g of crystals, and the total yield of the butting step is 27% and the purity (HPLC) is 99.22%.
Claims (2)
1. A method for preparing ketanserin, which comprises the following steps:
(1)3- (2-chloroethane) -2,4(1H,3H) -quinazoline diketone and 4- (4-fluorobenzoyl) piperidine hydrochloride are subjected to condensation reaction to prepare a crude product of ketanserin;
(2) Recrystallizing the crude ketanserin prepared in the step (1) to obtain a pure ketanserin product;
Wherein, in the step (1), the alkali used for the reaction is anhydrous sodium carbonate, the mass ratio of the addition amount of the alkali to the substance of the 4- (4-fluorobenzoyl) piperidine hydrochloride is 4:1, the reaction solvent is 4-methyl-2-pentanone, the reaction temperature is 100 +/-2 ℃, and the reaction time is 72 hours; in the step (2), the organic solvent used in the recrystallization step is a mixed solvent of methanol and dichloromethane, and the volume ratio of methanol to dichloromethane is 1: 2.
2. the method of claim 1, wherein in step (2), the ratio of the mass of crude ketanserin to the volume of organic solvent is 1:24 ~ 30 g/mL.
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| CN112142760A (en) * | 2020-10-20 | 2020-12-29 | 江苏法安德医药科技有限公司 | Ketanserin intermediate and preparation method of ketanserin |
| WO2023133524A1 (en) * | 2022-01-06 | 2023-07-13 | Terran Biosciences, Inc. | A process for synthesizing ketanserin |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4335127A (en) * | 1979-01-08 | 1982-06-15 | Janssen Pharmaceutica, N.V. | Piperidinylalkyl quinazoline compounds, composition and method of use |
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- 2017-01-17 CN CN201710029847.6A patent/CN106866625B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4335127A (en) * | 1979-01-08 | 1982-06-15 | Janssen Pharmaceutica, N.V. | Piperidinylalkyl quinazoline compounds, composition and method of use |
Non-Patent Citations (2)
| Title |
|---|
| Ketanserin Analogues: Structure-Affinity Relationships for 5-HT2 and 5-HT1c Serotonin Receptor Binding;Jeff L. Herndon,et al.;《J. Med. Chem.》;19921231;4903-4910 * |
| Reinvestigation of the Synthesis of Ketanserin (5) and its Hydrochloride Salt (5.HCl) via 3-(2-Chloroethyl)-2,4-(1H,3H)-quinazolinedione (2) or Dihydro-5H-oxazole(2,3-b)quinazolin-5-one (1);Hossein Fakhraian，et al.;《J. Heterocyclic Chem.》;20131023;151-156 * |
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