CN117209387B - Salifying and purifying process of esmolol hydrochloride - Google Patents
Salifying and purifying process of esmolol hydrochloride Download PDFInfo
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- CN117209387B CN117209387B CN202311193197.0A CN202311193197A CN117209387B CN 117209387 B CN117209387 B CN 117209387B CN 202311193197 A CN202311193197 A CN 202311193197A CN 117209387 B CN117209387 B CN 117209387B
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- esmolol
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- VZTMYLWJKCAXMZ-UHFFFAOYSA-N 2-[(2-chloroquinazolin-4-yl)amino]ethanol Chemical compound C1=CC=C2C(NCCO)=NC(Cl)=NC2=C1 VZTMYLWJKCAXMZ-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 229960001015 esmolol hydrochloride Drugs 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 title claims abstract description 15
- 238000003756 stirring Methods 0.000 claims abstract description 35
- 229960003745 esmolol Drugs 0.000 claims abstract description 33
- AQNDDEOPVVGCPG-UHFFFAOYSA-N esmolol Chemical compound COC(=O)CCC1=CC=C(OCC(O)CNC(C)C)C=C1 AQNDDEOPVVGCPG-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000002904 solvent Substances 0.000 claims abstract description 32
- 238000001914 filtration Methods 0.000 claims abstract description 19
- 239000012043 crude product Substances 0.000 claims abstract description 18
- 239000007787 solid Substances 0.000 claims abstract description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 12
- 238000001816 cooling Methods 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 239000002245 particle Substances 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 12
- 229940011051 isopropyl acetate Drugs 0.000 claims description 12
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims description 3
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims 1
- 230000008023 solidification Effects 0.000 claims 1
- 238000007711 solidification Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 59
- 238000001953 recrystallisation Methods 0.000 abstract description 11
- 238000009776 industrial production Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 239000000047 product Substances 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 9
- 230000001376 precipitating effect Effects 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000002386 leaching Methods 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- -1 odorless Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical group CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 description 1
- LQZJCKURBAMINH-UHFFFAOYSA-N 2-methoxy-2-methylpropane;hydrochloride Chemical compound Cl.COC(C)(C)C LQZJCKURBAMINH-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a salifying and purifying process of esmolol hydrochloride, which comprises the steps of dissolving esmolol alkali oily matter in a poor solvent A, then dripping hydrogen chloride organic solvent solution, stirring at a low temperature until white solid is separated out, adding a benign solvent A to obtain particles, obtaining esmolol hydrochloride crude product, adding the crude product into a benign solvent B to dissolve, filtering, adding the poor solvent B, cooling and crystallizing to prepare the salt. The invention confirms the structure and the generation mechanism of new impurities, provides a solution for the difficulty in salification and recrystallization caused by the existence of the impurities, and the purity of the crude product obtained by the technical scheme of the invention is more than 98%, the recrystallized API accords with pharmacopoeia of various countries, the purity is more than or equal to 99.0%, and the impurity A is less than or equal to 0.2%; b is less than or equal to 0.25 percent; c is less than or equal to 0.15 percent; d is less than or equal to 0.5%, the impurity E and other single impurities are less than or equal to 0.1%, and the quality controllability is high, so that the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to salifying and purifying processes of esmolol hydrochloride.
Background
Esmolol hydrochloride (Esmolol hydrochloride, API), which is a white or off-white crystalline powder, odorless, chemical name: methyl 4- [ 2-hydroxy-3- (isopropylamino) propoxy ] phenylpropionate hydrochloride having the formula:
the main industrial flow preparation method comprises the following steps:
The preparation method comprises the steps of taking parahydroxy phenylpropionic acid as a starting material, firstly carrying out esterification reaction with methanol to generate methyl parahydroxy phenylpropionate, then carrying out etherification reaction with epoxy chloropropane to generate an epoxy compound with electrophilic activity, then carrying out ring opening reaction with tert-butylamine to generate esmolol base, finally forming salt with hydrogen chloride gas in ethyl acetate, and then carrying out continuous repeated recrystallization in an ethyl acetate system to obtain esmolol hydrochloride.
The above route has mainly 4 known impurities named impurities A (1), B (2), C (3), D (4), and the limit standards and structural formulas are shown in the following tables 1 and 2.
Table 1: comparison table of self-fitting quality standard and pharmacopoeia standard
Table 2: impurity list
The related patents to esmolol hydrochloride synthesis, publication CN113651706A, CN113480438A, CN115260045A, all use large amounts of ethyl acetate during salt formation or recrystallization of esmolol, thus creating an impurity of exchange of ethanol with the molecular structural methyl ester of esmolol. The impurity E is named temporarily because the pharmacopoeia of the impurity is not recorded.
The mechanism of this impurity formation is as follows:
The impurity is extremely similar to esmolol in nature, and causes great trouble to subsequent purification when synthesizing a crude esmolol hydrochloride product; if ethyl acetate is used continuously, there is a risk of exceeding the standard for the impurity. The use of methanol hydrochloride and methyl tertiary butyl ether systems in the synthesis of esmolol hydrochloride has been reported to produce crude esmolol hydrochloride. However, the system used in the method is difficult to crystallize, and the system is layered and becomes heterogeneous after the methyl alcohol hydrochloride and the methyl tertiary butyl ether are added. Patent CN115260045A uses isopropanol hydrochloride in salification and uses a large amount of isopropanol to crystallize, but the system can hardly crystallize in a single solvent, and cannot be produced in large scale. Although methanol/diethyl ether hydrochloride system is used in the synthesis of beta blocker esmolol hydrochloride, such as Yuxin red, the solid eluted by the system is sticky, and diethyl ether cannot be used in large scale in mass production.
Disclosure of Invention
Aiming at the problems, the invention provides a salifying and purifying process of esmolol hydrochloride, which can reduce the generation of impurity E as much as possible.
The salt forming and purifying process of esmolol hydrochloride includes dissolving esmolol alkali oil in poor solvent A, dropping organic solvent solution of hydrogen chloride, stirring at low temperature until white solid is separated out, adding benign solvent A to obtain coarse esmolol hydrochloride product, dissolving coarse esmolol hydrochloride product in benign solvent B, filtering, adding poor solvent B, cooling and crystallizing to obtain salt.
The esmolol alkali oil is characterized in that the purity of esmolol alkali is 60-80%;
the poor solvent A is methyl tertiary butyl ether, diethyl ether, n-heptane or isopropyl acetate;
further, the volume-to-mass ratio (ml: g) of the poor solvent A to the esmolol alkali oil is 2:1;
the benign solvent A is acetone, acetonitrile or methanol; preferably acetone;
the hydrogen chloride organic solvent is hydrogen chloride methyl tertiary butyl ether, hydrogen chloride methanol, hydrogen chloride diethyl ether or hydrogen chloride isopropanol, preferably hydrogen chloride methyl tertiary butyl ether;
the benign solvent B is methanol, isopropanol or water, and the solvent ratio is 0.5V/W.
The poor solvent B is acetone, isopropyl acetate or acetonitrile, preferably acetone.
More preferably, the salifying and purifying process of esmolol hydrochloride provided by the invention comprises the steps of dissolving esmolol alkali by using poor solvent methyl tertiary butyl ether, adding hydrogen chloride methyl tertiary butyl ether to form salt for curing, adding benign solvent acetone, stirring and dispersing particles at high speed, and carrying out suction filtration to obtain a crude product; after the crude product is dissolved, the benign solvent methanol is used for dissolving, and the poor solvent isopropyl acetate is added for crystallization, thus obtaining the esmolol hydrochloride API.
The invention confirms the structure and the generation mechanism of new impurities, provides a solution for the difficulty in salification and recrystallization caused by the existence of the impurities, and the purity of the crude product obtained by the technical scheme of the invention is more than 98%, the recrystallized API accords with pharmacopoeia of various countries, the purity is more than or equal to 99.0%, and the impurity A is less than or equal to 0.2%; b is less than or equal to 0.25 percent; c is less than or equal to 0.15 percent; d is less than or equal to 0.5%, the impurity E and other single impurities are less than or equal to 0.1%, and the quality controllability is high, so that the method is suitable for industrial production.
Detailed Description
The present invention will be described in detail with reference to examples.
Example 1:
Salt formation operation of esmolol base: adding 10g of esmolol oily matter (the content is about 60% -70%) and 15mL of methyl tertiary butyl ether into a 250mL three-port bottle, stirring until the esmolol oily matter is fully dissolved, dripping 4M methyl tertiary butyl ether hydrochloride into the system after the esmolol oily matter is fully dissolved, adjusting the pH to be less than 2, gradually precipitating white solid in the system, wherein the solid is relatively sticky, continuously dripping 15mL of acetone, stirring at a high speed to enable particles to be dispersed, crystallizing for 3-4h at 0-10 ℃, carrying out suction filtration, leaching a filter cake with a little tertiary butyl ether, and drying at 40-45 ℃ to obtain 4.20g of a product, wherein the salification yield is 60-70%, the purity is 98.01%, and the hydrolyzed impurity A is 0.23%; b,0.26%; c,0.26%, D,0.91%; e,0.08%.
And (3) carrying out esmolol hydrochloride recrystallization operation: adding 4.2g of esmolol hydrochloride crude product, 2.6mL of methanol and 10.4mL of acetone into a 250mL three-port bottle in sequence, stirring and dissolving at 40 ℃, adding active carbon, stirring for 30min, filtering, slowly cooling to 0-10 ℃ and gradually separating out solids, stirring at a controlled temperature for 3-4h, filtering to obtain qualified API (application program interface) 3.5g, yield of 83.3%, purity of more than 99.08%, impurity A and impurity A of 0.16%; b,0.12%, C,0.10%, D < 0.32%, impurity E and other single impurities < 0.1%. The quality standard is tightened according to the pharmacopoeia of esmolol hydrochloride of various countries: the purity is more than or equal to 99.0 percent, and the impurity A is less than or equal to 0.2 percent; b is less than or equal to 0.25 percent; c is less than or equal to 0.15 percent; d is less than or equal to 0.5 percent, and impurity E is less than or equal to 0.1 percent. The related substances are measured according to high performance liquid chromatography (general rule 0512).
Example 2:
Salt formation operation of esmolol base: adding 10g of esmolol oily matter (the content is about 60% -70%) and 15mL of isopropyl acetate into a 250mL three-port bottle, stirring until the esmolol oily matter is fully dissolved, dripping 4M isopropyl hydrochloride into a system after the esmolol oily matter is fully dissolved, adjusting the pH to be less than 2, gradually precipitating white solid in the system, dripping 15mL of acetonitrile, stirring to enable particles to be dispersed, crystallizing at 0-10 ℃ for 24 hours, filtering, leaching a filter cake with a little isopropyl acetate, drying at 40-45 ℃ to obtain 4.50g of a product, obtaining 60-70% of salified yield, 98.33% of purity, and hydrolyzing impurities A and 0.18%; b,0.08%; c,0.06%, D,0.31%; e,0.02%.
And (3) carrying out esmolol hydrochloride recrystallization operation: sequentially adding 4.5g of esmolol hydrochloride crude product, 2.7mL of methanol and 9.0mL of isopropyl acetate into a 250mL three-port bottle, stirring and dissolving at 40 ℃, adding active carbon, stirring for 30min, filtering, slowly cooling to 0-10 ℃ and gradually precipitating solids, stirring at a controlled temperature for 3-4h, filtering to obtain qualified API, drying and totaling 3.6g, yield 80%, purity more than 99.4%, impurity A and 0.11%; b,0.06%; c,0.07%; d,0.13%; impurity E and other single impurities are less than 0.1 percent. The quality standard is tightened according to the pharmacopoeia of esmolol hydrochloride of various countries: the purity is more than or equal to 99.0 percent, and the impurity A is less than or equal to 0.2 percent; b is less than or equal to 0.25 percent; c is less than or equal to 0.15 percent; d is less than or equal to 0.5 percent, and impurity E is less than or equal to 0.1 percent. The related substances are measured according to high performance liquid chromatography (general rule 0512).
Example 3:
salt formation operation of esmolol base: adding 10g of esmolol oily matter (the content is about 60% -70%) and 15mL of isopropyl acetate into a 250mL three-port bottle, stirring until the esmolol oily matter is fully dissolved, dripping 2M isopropyl hydrochloride into a system after the esmolol oily matter is fully dissolved, adjusting the pH value to be less than 2, gradually precipitating white solid in the system, dripping 15mL of acetonitrile, stirring to enable particles to be dispersed, crystallizing at 0-10 ℃ for 2-4 h, filtering, leaching a filter cake by using a little isopropyl acetate, drying at 40-45 ℃ to obtain 4.50g of a product, obtaining 60-70% of salified yield, 98.73% of purity, and hydrolyzing impurities A and 0.14%; b,0.09%; c,0.11%, D,0.21%; e,0.05%.
And (3) carrying out esmolol hydrochloride recrystallization operation: sequentially adding 4.5g of esmolol hydrochloride crude product, 2.7mL of methanol and 9.0mL of isopropyl acetate into a 250mL three-port bottle, stirring and dissolving at 40 ℃, adding active carbon, stirring for 30min, filtering, slowly cooling to 0-10 ℃ and gradually precipitating solids, stirring at a controlled temperature for 3-4h, filtering to obtain qualified API, drying and totaling 3.6g, yield 80%, purity more than 99.2%, impurity A and 0.10%; b,0.07%, C,0.08%; d,0.12%, impurity E and other single impurities are less than 0.1%. The quality standard is tightened according to the pharmacopoeia of esmolol hydrochloride of various countries: the purity is more than or equal to 99.0 percent, and the impurity A is less than or equal to 0.2 percent; b is less than or equal to 0.25 percent; c is less than or equal to 0.15 percent; d is less than or equal to 0.5 percent, and impurity E is less than or equal to 0.1 percent. The related substances are measured according to high performance liquid chromatography (general rule 0512).
Comparative example 1:
Salt formation operation of esmolol base: adding 10g of esmolol oily matter (the content is about 60% -70%) and 15mL of ethyl acetate into a 250mL three-necked flask, stirring until the esmolol oily matter is fully dissolved, dripping 4M ethyl acetate hydrochloride into a system after the esmolol oily matter is fully dissolved, adjusting the pH to be less than 2, gradually precipitating white solid in the system, crystallizing for 2 hours at 0-10 ℃, carrying out suction filtration, leaching a filter cake by using a little cold ethyl acetate, drying at 40-45 ℃ to obtain 4.10g of a product, wherein the salifying yield is 65-75%, the purity is 98.62%, the hydrolyzed impurity A is less than 0.3%, and the impurity E is 1.3%.
First recrystallization operation of esmolol hydrochloride: adding 4.1g of esmolol hydrochloride crude product, 2.1mL of methanol and 8.2mL of ethyl acetate into a 250mL three-port bottle in sequence, stirring and dissolving at 40 ℃, adding active carbon, stirring for 30min, filtering, slowly cooling to 0-10 ℃ and gradually precipitating solids, stirring at a controlled temperature for 3-4h, filtering, and obtaining a total of 3.4g of recrystallized primary product after drying, wherein the yield is 83%, the impurity E is 0.87%, and the product is unqualified. Secondary recrystallization operation of esmolol hydrochloride: adding 3.4g of esmolol hydrochloride crude product, 1.7mL of methanol and 3.4mL of ethyl acetate into a 250mL three-port bottle in sequence, stirring and dissolving at 40 ℃, adding active carbon, stirring for 30min, filtering, slowly cooling to 0-10 ℃ and gradually precipitating solids, stirring at a controlled temperature for 3-4h, filtering, and obtaining a recrystallized product, wherein the total weight of the recrystallized product is 2.78g, the yield is 82%, the impurity E is 0.57%, and the recrystallized product is unqualified. The quality standard is tightened according to the pharmacopoeia of esmolol hydrochloride of various countries: the purity is more than or equal to 99.0 percent, and the impurity A is less than or equal to 0.2 percent; b is less than or equal to 0.25 percent; c is less than or equal to 0.15 percent; d is less than or equal to 0.5 percent, and the impurity E and other single impurities are less than or equal to 0.1 percent. The related substances are measured according to high performance liquid chromatography (general rule 0512).
Comparative example 2:
salt formation operation of esmolol base: adding 10g of esmolol oily substance (the content is about 60% -70%) and 30mL of ethyl acetate into a 250mL three-port bottle, stirring until the esmolol oily substance is fully dissolved, introducing hydrogen chloride gas into the system after the esmolol oily substance is fully dissolved, regulating the pH to be less than 2, gradually precipitating white solid in the system, stirring to enable particles to be dispersed, crystallizing at 0-10 ℃ for 2-4h, carrying out suction filtration, leaching a filter cake by using a little cold ethyl acetate, drying at 40-45 ℃ to obtain 4.30g of a product, wherein the salifying yield is 60-70%, the purity is 98.59%, the hydrolyzed impurity A is less than 0.3%, and the impurity E is 1.1%.
First recrystallization operation of esmolol hydrochloride: adding 4.3g of esmolol hydrochloride crude product and 43mL of ethyl acetate into a 1000mL three-port bottle in sequence, stirring and dissolving at 40-50 ℃, adding active carbon, stirring for 30min, filtering, slowly cooling to 0-10 ℃ to gradually precipitate solids, stirring at a controlled temperature for 2-4h, filtering, and obtaining 3.6g of first recrystallized crude product, yield of 83%, impurity E and 0.77%, and failing.
Secondary recrystallization operation of esmolol hydrochloride: adding 3.6g of esmolol hydrochloride crude product and 36mL of ethyl acetate into a 1000mL three-port bottle in sequence, stirring and dissolving at 40-50 ℃, adding active carbon, stirring for 30min, filtering, slowly cooling to 0-10 ℃ to gradually precipitate solids, stirring at a controlled temperature for 2-4h, and filtering to obtain a secondary refined product, wherein the yield is 81%, the impurity E is 0.45%, and the secondary refined product is unqualified. The quality standard is tightened according to the pharmacopoeia of esmolol hydrochloride of various countries: the purity is more than or equal to 99.0 percent, and the impurity A is less than or equal to 0.2 percent; b is less than or equal to 0.25 percent; c is less than or equal to 0.15 percent; d is less than or equal to 0.5 percent, and the impurity E and other single impurities are less than or equal to 0.1 percent. The related substances are measured according to high performance liquid chromatography (general rule 0512).
The above examples and comparative examples reflect the great possibility of the presence of impurity E and the difficulty of removal after the addition of ethyl acetate, especially ethyl acetate hydrochloride, and the overrun of impurity E has an effect on the efficacy of esmolol hydrochloride to some extent, but the limitation is still strictly controlled while existing as a known impurity, ensuring the quality of the product.
In conclusion, the esmolol hydrochloride prepared by the method accords with the regulations of pharmacopoeia of various countries, particularly sources of the impurity E are traced, the structure of the impurity E is confirmed, and the impurity mass spectrum of the esmolol hydrochloride is supplemented.
Claims (3)
1. The salifying and purifying process of esmolol hydrochloride is characterized in that esmolol alkali oily matter is dissolved in a poor solvent A, then hydrogen chloride organic solvent solution is dripped into the poor solvent A, stirring is carried out at a low temperature until white solid is separated out, and benign solvent A is added to obtain particles, thus obtaining esmolol hydrochloride crude product; adding the crude product into the benign solvent B for dissolution, decoloring, filtering, adding the poor solvent B, cooling and crystallizing to prepare salt;
the poor solvent A is methyl tertiary butyl ether, diethyl ether, n-heptane or isopropyl acetate;
The benign solvent A is acetone, acetonitrile or methanol;
the hydrogen chloride organic solvent is hydrogen chloride methyl tertiary butyl ether, hydrogen chloride methanol, hydrogen chloride diethyl ether or hydrogen chloride isopropanol;
the benign solvent B is methanol, isopropanol or water;
The poor solvent B is acetone, isopropyl acetate or acetonitrile.
2. The process for salifying and purifying esmolol hydrochloride according to claim 1, wherein the purity of esmolol alkali oil is 60-80%.
3. The salifying and purifying process of esmolol hydrochloride according to claim 1, wherein the salifying and purifying process is to dissolve esmolol alkali with poor solvent methyl tertiary butyl ether, then add hydrogen chloride methyl tertiary butyl ether to form salt for solidification, add benign solvent acetone to stir and disperse particles at high speed, and suction-filter to obtain crude product; after the crude product is dissolved, the solution is dissolved by benign solvent methanol, and the poor solvent isopropyl acetate is added for crystallization, thus obtaining esmolol hydrochloride.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1217320A (en) * | 1997-11-13 | 1999-05-26 | 山东省医药工业研究所 | Process for synthesizing and refining esmolol hydrochloride |
| CN101891636A (en) * | 2009-05-21 | 2010-11-24 | 南京海辰药业有限公司 | Novel method for preparing esmolol hydrochloride optical isomer |
| CN103087048A (en) * | 2013-02-26 | 2013-05-08 | 四川尚锐生物医药有限公司 | Method for purifying esomeprazole sodium |
| CN111848420A (en) * | 2020-07-22 | 2020-10-30 | 杭州煌森生物科技有限公司 | Novel crystal form of esmolol hydrochloride and preparation method thereof |
| CN113480438A (en) * | 2021-07-19 | 2021-10-08 | 山东安弘制药有限公司 | Preparation method of esmolol hydrochloride |
| CN113651706A (en) * | 2021-07-16 | 2021-11-16 | 湖州展望药业有限公司 | Preparation process of high-purity esmolol hydrochloride |
| CN115260045A (en) * | 2022-07-11 | 2022-11-01 | 山东科源制药股份有限公司 | Preparation process of high-purity esmolol hydrochloride |
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| CN117304043A (en) * | 2023-09-25 | 2023-12-29 | 杭州沐源生物医药科技有限公司 | Esmolol hydrochloride and preparation of preparation thereof |
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Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1217320A (en) * | 1997-11-13 | 1999-05-26 | 山东省医药工业研究所 | Process for synthesizing and refining esmolol hydrochloride |
| CN101891636A (en) * | 2009-05-21 | 2010-11-24 | 南京海辰药业有限公司 | Novel method for preparing esmolol hydrochloride optical isomer |
| CN103087048A (en) * | 2013-02-26 | 2013-05-08 | 四川尚锐生物医药有限公司 | Method for purifying esomeprazole sodium |
| CN111848420A (en) * | 2020-07-22 | 2020-10-30 | 杭州煌森生物科技有限公司 | Novel crystal form of esmolol hydrochloride and preparation method thereof |
| CN113651706A (en) * | 2021-07-16 | 2021-11-16 | 湖州展望药业有限公司 | Preparation process of high-purity esmolol hydrochloride |
| CN113480438A (en) * | 2021-07-19 | 2021-10-08 | 山东安弘制药有限公司 | Preparation method of esmolol hydrochloride |
| CN115260045A (en) * | 2022-07-11 | 2022-11-01 | 山东科源制药股份有限公司 | Preparation process of high-purity esmolol hydrochloride |
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