CN114671836A - Synthesis method of amiodarone impurity C - Google Patents
Synthesis method of amiodarone impurity C Download PDFInfo
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- 229960005260 amiodarone Drugs 0.000 title claims abstract description 29
- 239000012535 impurity Substances 0.000 title claims abstract description 28
- IYIKLHRQXLHMJQ-UHFFFAOYSA-N amiodarone Chemical compound CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCCN(CC)CC)C(I)=C1 IYIKLHRQXLHMJQ-UHFFFAOYSA-N 0.000 title claims abstract 16
- 238000001308 synthesis method Methods 0.000 title abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 13
- 239000011630 iodine Substances 0.000 claims abstract description 13
- RAGSWDIQBBZLLL-UHFFFAOYSA-N 2-chloroethyl(diethyl)azanium;chloride Chemical compound Cl.CCN(CC)CCCl RAGSWDIQBBZLLL-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000010189 synthetic method Methods 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000013558 reference substance Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 238000003908 quality control method Methods 0.000 abstract 1
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 9
- 238000005086 pumping Methods 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 229960003234 amiodarone hydrochloride Drugs 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- -1 preferably Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- RTGDFNSFWBGLEC-TVPGTPATSA-N 2-morpholin-4-ylethyl (z)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(\C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-TVPGTPATSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 206010042600 Supraventricular arrhythmias Diseases 0.000 description 1
- 206010047281 Ventricular arrhythmia Diseases 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- RVIQSSNDHKQZHH-UHFFFAOYSA-N carbonyl diiodide Chemical compound IC(I)=O RVIQSSNDHKQZHH-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthesis method of amiodarone impurity C, which comprises the following steps: (1) dissolving a compound I in a solvent, and carrying out substitution reaction with N, N-diethyl-beta-chloroethyl amine hydrochloride under the action of alkali to obtain an intermediate 1; (2) dissolving the intermediate 1 in a solvent, and reacting with an iodine simple substance under the action of alkali to obtain an amiodarone impurity C; the method is simple to operate and low in cost, and the amiodarone impurity C synthesized according to the method is used as an impurity reference substance, so that a qualified, low-cost and easily-obtained reference substance is provided for the quality control of amiodarone, and an important guiding significance is provided for the production and safe medication of amiodarone medicines.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of amiodarone hydrochloride impurity C.
Background
Amiodarone (Amiodarone), also known as Amiodarone, Amiodarone (or its hydrochloride CAS:19774-82-4) is a third class of antiarrhythmic drugs that is widely used in the treatment and prevention of ventricular and supraventricular arrhythmias. Patients with cardiovascular diseases in modern society are greatly rising, and the demand of the medicines is increasing day by day. The market share of amiodarone hydrochloride is continuously expanding on the basis of stable curative effect and lower side effect. The research on the amiodarone impurity and the synthetic method are widely reported correspondingly, and few documents are found for the conventional method for synthesizing the amiodarone European pharmacopoeia EP impurity C. Therefore, the synthesis method of the amiodarone impurity C, which is simple to operate, low in cost, easy to separate and purify and high in yield, is significant. The invention is particularly proposed as follows:
Amiodarone hydrochloride having the following structural formula:
amiodarone hydrochloride impurity C has the following structural formula:
bioorganic & Medicinal Chemistry Letters 18(2008) 5920-:
and (2) adding methanol into the compound I to dissolve the compound I, adding sodium iodide and sodium hydroxide, cooling to-5 ℃, dropwise adding sodium hypochlorite, quenching reaction by using dilute hydrochloric acid after the reaction is finished, and performing aftertreatment purification to obtain an intermediate 1 with the yield of 25% and the yield of the byproducts of the two last iodides of 11%. And in the second step, under the action of alkali, N-diethyl-beta-chloroethyl amine hydrochloride is butted and reacted to obtain the target product. In the literature, the first-step reaction yield is low, impurities are more, the polarity of the generated intermediate 1 and the polarity of the two iodine byproducts are similar, and the separation and purification are difficult. Therefore, the method for synthesizing the amiodarone impurity C is necessary to find a method which has high yield, low cost, simple operation and easy separation and purification, and has important significance for improving the quality standard of the medicine.
Disclosure of Invention
In order to solve the problems, the invention discloses a synthesis method of an amine iodoketone impurity C, which has the advantages of low cost, simple operation, high yield and easy separation and purification.
In order to achieve the purpose, the technical scheme of the invention is as follows:
A synthetic method of amiodarone impurity C comprises the following steps:
(1) dissolving a compound I in a solvent, and carrying out substitution reaction with N, N-diethyl-beta-chloroethyl amine hydrochloride under the action of alkali to obtain an intermediate 1;
(2) the intermediate 1 is dissolved in a solvent and reacts with iodine simple substance under the action of alkali to obtain amiodarone impurity C.
The specific synthetic process route of the amiodarone impurity C is as follows:
further, in the step (1), the molar ratio of the compound I to the N, N-diethyl-beta-chloroethyl amine hydrochloride is 1:1.0-4.0, and preferably, the molar ratio of the compound I to the N, N-diethyl-beta-chloroethyl amine hydrochloride is 1: 1.2.
Further, in the step (1), the molar ratio of the base to the compound I is 1.0-4.0:1.0, preferably, the molar ratio of the base to the compound I is 2.0: 1.0; the volume ratio of the solvent to the compound I is 1.0-100.0:1.0, and preferably the volume ratio of the solvent to the compound I is 30.0: 1.0.
Further, in the step (1), the base is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide, preferably, the base is potassium carbonate; the solvent is one or more of toluene, water, acetonitrile, acetone, tetrahydrofuran, N-dimethylformamide and dimethyl sulfoxide, and preferably, the solvent is a mixture of water and toluene.
Further, in the step (1), the temperature of the substitution reaction is 30-90 ℃, preferably, the temperature of the substitution reaction is 80-85 ℃, and the reaction time is 1-6 hours, preferably, the reaction time is 1 hour.
Further, in the step (2), the molar ratio of the intermediate 1 to the iodine is 1:0.5-3.0, and preferably, the molar ratio of the intermediate to the iodine is 1: 0.9.
Further, in the step (2), the molar ratio of the base to the intermediate 1 is 1.0-5.0:1.0, preferably, the molar ratio of the base to the intermediate 1 is 1.0: 1.0; the volume ratio of the solvent to the intermediate 1 is 1.0-100.0:1.0, and preferably, the volume ratio of the solvent to the intermediate 1 is 20.0: 1.0.
Further, in the step (2), the base is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide, preferably, the base is sodium hydroxide; the solvent is one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran and ethyl acetate, and preferably, the solvent is methanol.
Further, in the step (2), the temperature of the reaction is 0-30 ℃, preferably, the temperature of the reaction is 0-5 ℃; the reaction time is 2 to 12 hours, and preferably, the reaction time is 6 hours.
The invention has the beneficial effects that:
the synthesis method of the amiodarone impurity C changes the synthetic route of firstly adding iodine and then butting N, N-diethyl-beta-chloroethylamine hydrochloride in the original reported literature, and changes the synthetic route of firstly butting N, N-diethyl-beta-chloroethylamine hydrochloride and then adding iodine by reacting with iodine monomers at low temperature. The method has the advantages of high yield, simple operation, low cost and easy separation and purification. Provides a qualified and low-cost impurity reference substance for controlling the quality of amiodarone hydrochloride.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of a product obtained in example 4 of the present invention;
FIG. 2 is a mass spectrum of the product obtained in example 4 of the present invention;
FIG. 3 is an HPLC chromatogram of the product obtained in example 4 of the present invention;
FIG. 4 shows a synthetic process route of the present invention.
Detailed Description
The present invention will be further illustrated with reference to the accompanying drawings and detailed description, which will be understood to be illustrative only and not to limit the scope of the invention.
Example 1
In a 500ml three-necked flask, 10.0g (0.034mol) of Compound I, 100ml of water and 200ml of toluene are added; adding 9.4g (0.068mol) of potassium carbonate to obtain turbid white system, heating to 50-55 ℃, adding 7.0g (0.041mol) of N, N-diethyl-beta-chloroethylamine hydrochloride in batches, and gradually dissolving the system to be clear in the process. The temperature is increased to 80-85 ℃ for reaction for 1 hour. TLC detecting reaction completely, cooling reaction liquid, adding 50ml water, separating organic phase by layer, adding 100ml of 2 ethyl acetate into water phase for extraction, combining organic phase, adding 50ml of saturated saline solution for washing, adding 20g of anhydrous sodium sulfate for drying, filtering to remove salt, and concentrating to remove solvent; column chromatography (pure EA) afforded 11.5g of intermediate 1 in 85% yield and 95% HPLC purity.
Example 2
In a 500ml three-necked flask, 10.0g (0.034mol) of Compound I and 100ml of acetone are added; 1.4g (0.034mol) of sodium hydroxide is added to obtain a turbid white system, the temperature is raised to 50-55 ℃, 11.7g (0.068mol) of N, N-diethyl-beta-chloroethylamine hydrochloride is added in batches, and the system gradually dissolves and becomes clear in the process. The temperature is increased to 80-85 ℃ for reaction for 1.5 hours. TLC detecting reaction is complete, reaction liquid is cooled, 50ml of water is added, organic phase is separated by layers, 100ml of 2 ethyl acetate is added into water phase for extraction, organic phase is combined, 50ml of saturated saline solution is added for washing, 20g of anhydrous sodium sulfate is added for drying, salt is removed by filtration, and solvent is removed by concentration; column chromatography (pure EA) afforded 10.7g of intermediate 1 in 79.9% yield and 94% HPLC purity.
Example 3
In a 500ml three-necked flask, 10.0g (0.034mol) of Compound I is added, and 300ml of acetonitrile is added; 18.7g (0.136mol) of potassium carbonate is added to lead the system to be turbid white, the temperature is raised to 50-55 ℃, 23.4g (0.136mol) of N, N-diethyl-beta-chloroethylamine hydrochloride is added in batches, and the system gradually dissolves and becomes clear in the process. The temperature is increased to 80-85 ℃ for reaction for 2 hours. TLC detecting reaction, cooling reaction liquid, adding 50ml water, separating organic phase by layer, adding 100ml of 2 ethyl acetate into water phase for extraction, combining organic phase, adding 50ml saturated salt water for washing, adding 20g anhydrous sodium sulfate for drying, filtering to remove salt, concentrating to remove solvent; column chromatography (pure EA) afforded 10.2g of intermediate 1 in 76.1% yield and 90% HPLC purity.
Example 4
In a 500ml three-necked flask, 230ml of methanol was added, 11.5g (0.029mol) of intermediate 1 was added, and 1.2g (0.029mol) of sodium hydroxide was added thereto after cooling to 0 to 5 ℃ in an ice bath. Keeping the temperature at 0-5 ℃, and adding 6.6g (0.026mol) of elementary iodine into 10 batches. After the addition, the reaction is kept for 6 hours, HPLC detection reaction shows that 15 percent of raw material remains, 75 percent of monoiodine target product and 10 percent of diiodo byproduct. Adding 200ml of water into the system, stirring for 10 minutes, concentrating at low temperature to remove most of methanol solvent, adding 200ml of 2 ethyl acetate for extraction, layering and combining organic phases, adding 50ml of saturated saline solution to wash the organic phases, adding 20g of anhydrous sodium sulfate into the layered organic phases, drying and pumping filtration, concentrating the filtrate to dryness, performing column chromatography (pure EA) to obtain 12.3g of crude product, recrystallizing with 60ml of acetonitrile to obtain 10.2g of crude product, adding 100ml of methanol for dissolution, dropwise adding hydrochloric acid methanol to adjust the pH to 6, separating out a large amount of white solid, stirring for 0.5 hour, pumping filtration, adding a small amount of methanol into a filter cake for leaching, pumping to obtain 9.4g of target product, wherein the yield is 62.7 percent, and the HPLC purity is 98 percent.
Example 5
In a 500ml three-necked flask, 230ml of methanol was added, 11.5g (0.029mol) of intermediate 1 was added, the temperature was lowered to 5 to 10 ℃ in ice bath, and 8.0g (0.058mol) of potassium carbonate was added. Keeping the temperature at 5-10 ℃, adding 7.4g (0.029mol) of elementary iodine in 10 batches. After the addition, the reaction is kept for 12 hours, HPLC detection reaction shows that 6 percent of raw material is remained, the monoiodine target product accounts for 70 percent, and the diiodo byproduct accounts for 20 percent. Adding 200ml of water into the system, stirring for 10 minutes, concentrating at low temperature to remove most of methanol solvent, adding 200ml of 2 ethyl acetate for extraction, layering and combining organic phases, adding 50ml of saturated saline solution to wash the organic phases, adding 20g of anhydrous sodium sulfate into the layered organic phases, drying and pumping filtration, concentrating the filtrate to dryness, performing column chromatography (pure EA) to obtain 10.6g of crude product, recrystallizing with 60ml of acetonitrile to obtain 9.1g of crude product, adding 100ml of methanol for dissolution, dropwise adding hydrochloric acid methanol to adjust the pH to 6, separating out a large amount of white solid, stirring for 0.5 hour, pumping filtration, adding a small amount of methanol into a filter cake for leaching, pumping to obtain 8.6g of target product, wherein the yield is 57.3%, and the HPLC purity is 87%.
Example 6
In a 500ml three-necked flask, 230ml of methanol was added, 11.5g (0.029mol) of intermediate 1 was added, the temperature was lowered to 5 to 10 ℃ in an ice bath, and 2.8g (0.116mol) of lithium hydroxide was added. Keeping the temperature at 5-10 ℃, and adding 6.6g (0.026mol) of elementary iodine into 10 batches. After the addition, the reaction is kept for 6 hours, HPLC detection reaction shows that 30 percent of raw material remains, 60 percent of monoiodine target product and 10 percent of diiodo byproduct. Adding 200ml of water into the system, stirring for 10 minutes, concentrating at low temperature to remove most of methanol solvent, adding 200ml of 2 ethyl acetate for extraction, layering and combining organic phases, adding 50ml of saturated saline solution to wash the organic phases, adding 20g of anhydrous sodium sulfate into the layered organic phases, drying and pumping filtration, concentrating the filtrate to dryness, performing column chromatography (pure EA) to obtain 10.3g of crude product, recrystallizing with 60ml of acetonitrile to obtain 8.3g of crude product, adding 100ml of methanol for dissolution, dropwise adding hydrochloric acid methanol to adjust the pH to 6, separating out a large amount of white solid, stirring for 0.5 hour, pumping filtration, adding a small amount of methanol into a filter cake for leaching, pumping to obtain 8.1g of target product, wherein the yield is 54.0%, and the HPLC purity is 91%.
It should be noted that the above-mentioned contents only illustrate the technical idea of the present invention, and the protection scope of the present invention is not limited thereby, and it is obvious to those skilled in the art that several modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations fall within the protection scope of the claims of the present invention.
Claims (9)
1. A synthetic method of amiodarone impurity C is characterized by comprising the following steps:
(1) dissolving a compound I in a solvent, and carrying out substitution reaction with N, N-diethyl-beta-chloroethyl amine hydrochloride under the action of alkali to obtain an intermediate 1;
(2) dissolving the intermediate 1 in a solvent, and reacting with an iodine simple substance under the action of alkali to obtain an amiodarone impurity C;
2. the method for synthesizing amiodarone impurity C according to claim 1, wherein in the step (1), the molar ratio of the compound I to the N, N-diethyl-beta-chloroethylamine hydrochloride is 1: 1.0-4.0.
3. The method for synthesizing amiodarone impurity C according to claim 1, wherein in the step (1), the molar ratio of the base to the compound I is 1.0-4.0: 1.0; the volume ratio of the solvent to the compound I is 1.0-100: 1.0.
4. The method for synthesizing amiodarone impurity C as claimed in claim 1, wherein in step (1), the base is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide; the solvent is one or more of toluene, water, acetonitrile, acetone, tetrahydrofuran, N-dimethylformamide and dimethyl sulfoxide.
5. The method for synthesizing amiodarone impurity C according to claim 1, wherein in the step (1), the temperature of the substitution reaction is 30-90 ℃, and the reaction time is 1-6 hours.
6. The method for synthesizing amiodarone impurity C according to claim 1, wherein in the step (2), the molar ratio of the intermediate 1 to the iodine is 1: 0.5-5.0.
7. The method for synthesizing amiodarone EP impurity as claimed in claim 1, wherein in step (2), the molar ratio of the base to the intermediate 1 is 1.0-5.0: 1.0; the volume ratio of the solvent to the intermediate 1 is 1.0-100: 1.0.
8. The method for synthesizing amiodarone impurity C as claimed in claim 1, wherein in step (2), the base is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide; the solvent is one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran and ethyl acetate.
9. The method for synthesizing amiodarone impurity C as claimed in claim 1, wherein in the step (2), the reaction temperature is 0-30 ℃ and the reaction time is 2-12 hours.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4575513A (en) * | 1983-08-02 | 1986-03-11 | Sanofi | Pharmaceutical and veterinary compositions for the treatment of ischemic cardiac disorders |
| CN109053652A (en) * | 2018-09-04 | 2018-12-21 | 北京深蓝海生物医药科技有限公司 | A kind of preparation method of Amiodarone Hydrochloride intermediate |
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2021
- 2021-12-30 CN CN202111660207.8A patent/CN114671836A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4575513A (en) * | 1983-08-02 | 1986-03-11 | Sanofi | Pharmaceutical and veterinary compositions for the treatment of ischemic cardiac disorders |
| CN109053652A (en) * | 2018-09-04 | 2018-12-21 | 北京深蓝海生物医药科技有限公司 | A kind of preparation method of Amiodarone Hydrochloride intermediate |
Non-Patent Citations (2)
| Title |
|---|
| AARON N. SNEAD ET AL.: "Trace amine-associated receptor 1 (TAAR1) is activated by amiodarone metabolites", 《BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS》, vol. 18, 9 August 2008 (2008-08-09), pages 5920 - 5922, XP025627170, DOI: 10.1016/j.bmcl.2008.08.013 * |
| NICOLAS FAUCHER ET AL.: "Highly Chemoselective Hydrogenolysis of Iodoarenes", 《JOURNAL OF ORGANIC CHEMISTRY》, vol. 67, 15 January 2002 (2002-01-15), pages 932 - 934 * |
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