CN117624151A - Preparation method of losartan potassium degradation impurity - Google Patents
Preparation method of losartan potassium degradation impurity Download PDFInfo
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- CN117624151A CN117624151A CN202210984434.4A CN202210984434A CN117624151A CN 117624151 A CN117624151 A CN 117624151A CN 202210984434 A CN202210984434 A CN 202210984434A CN 117624151 A CN117624151 A CN 117624151A
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- 239000012535 impurity Substances 0.000 title claims abstract description 37
- 239000002083 C09CA01 - Losartan Substances 0.000 title claims abstract description 26
- 229960000519 losartan potassium Drugs 0.000 title claims abstract description 26
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 230000015556 catabolic process Effects 0.000 title claims abstract description 22
- 238000006731 degradation reaction Methods 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 claims abstract description 22
- -1 iodide ions Chemical class 0.000 claims abstract description 14
- 239000005485 Azilsartan Substances 0.000 claims abstract description 13
- KGSXMPPBFPAXLY-UHFFFAOYSA-N azilsartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NOC(=O)N1 KGSXMPPBFPAXLY-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229960002731 azilsartan Drugs 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 6
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 5
- 239000011591 potassium Substances 0.000 claims abstract description 5
- 238000004440 column chromatography Methods 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 30
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 18
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- NALMPLUMOWIVJC-UHFFFAOYSA-N n,n,4-trimethylbenzeneamine oxide Chemical compound CC1=CC=C([N+](C)(C)[O-])C=C1 NALMPLUMOWIVJC-UHFFFAOYSA-N 0.000 claims description 6
- 239000002798 polar solvent Substances 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 239000011697 sodium iodate Substances 0.000 claims description 6
- 235000015281 sodium iodate Nutrition 0.000 claims description 6
- 229940032753 sodium iodate Drugs 0.000 claims description 6
- 235000009518 sodium iodide Nutrition 0.000 claims description 6
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 4
- 238000007259 addition reaction Methods 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 claims description 2
- 229940005633 iodate ion Drugs 0.000 claims description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000006467 substitution reaction Methods 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 3
- 238000003908 quality control method Methods 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 10
- 238000003756 stirring Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 235000010265 sodium sulphite Nutrition 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 150000007942 carboxylates Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- JLVIHQCWASNXCK-UHFFFAOYSA-N 2-butyl-5-chloro-1h-imidazole-4-carbaldehyde Chemical class CCCCC1=NC(C=O)=C(Cl)N1 JLVIHQCWASNXCK-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Abstract
The invention discloses a preparation method of a losartan potassium degradation impurity, which adopts low-cost butenone which can be purchased in the market as a starting material, synthesizes 4-iodine-3-hydroxy-2-butanone under the double catalysis of acid and iodide ions, directly performs substitution reaction with azilsartan under the catalysis of inorganic base without purification, and synthesizes the non-asartan potassium degradation impurity G with higher purity. The preparation method disclosed by the invention has the advantages of easily available raw materials and simple operation, and the prepared impurity G has high purity, and the purity of the impurity G is up to 99.6% after column chromatography purification, so that the method is suitable for the quality control research of the losartan potassium.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a losartan potassium degradation impurity.
Background
The losartan potassium is an angiotensin II receptor blocker independently developed by the Wuta-tsu corporation of Japan, is an oral prodrug, is mainly used for treating primary hypertension of adults, and is approved by the FDA in the United states in the earliest 2 months of 2011.
The research on the impurities is beneficial to the optimization and quality control of the synthesis process of the medicine, and the research on the impurities of the losartan potassium provides a better detection method for evaluating the synthesis quality of the losartan potassium and intermediates thereof, also provides a technical basis for optimizing the synthesis process of the losartan potassium, and has great significance for determining adverse reactions caused by related substances of the losartan potassium.
The related substances of the original research registration standard comprise a degradation impurity G of the ring opening of the losartan potassium, the impurity is a key impurity in the losartan potassium bulk drug, is easy to degrade and generate in an API, has a small limit and is controlled to be not more than 0.15%, and the structure is shown as follows:
by reference, a preparation method for efficiently preparing high-purity impurity G has not been found. The thought of forced destruction experiments of the prior art through the metartan potassium is that the impurity G cannot be obtained or the destroyed amount is very small, the requirement of the amount and purity of a reference substance cannot be met, the method can only be used for directional synthesis, the raw material of 4-halogen-3-hydroxy-2-butanone on the market is not supplied, the 4-halogen-3-hydroxy-2-butanone is difficult to confirm, and great difficulty is brought to directional synthesis. The invention adopts cheap butenone available in the market as the initial raw material to synthesize 4-iodo-3-hydroxy-2-butanone, and directly substitutes azilsartan for synthesizing impurity G without purification.
Disclosure of Invention
The invention aims to overcome the defect of lack of a preparation method of the losartan potassium degradation impurity in the prior art, and provides a preparation method which is simple to operate and can obtain high-purity losartan potassium degradation impurity G.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of a degradation impurity of a ring-opening of losartan potassium, which comprises the following two steps:
step 1: dissolving butenone in water, adding proper amount of organic solvent with relatively high polarity (to promote polar reaction), adding iodine and catalyst, and reacting at 50-60 deg.c; the reaction is complete, quenching, extraction and concentration are carried out to obtain the product 4-iodo-3-hydroxy-2-butanone with reddish brown oily substance.
Step 2: dissolving azilsartan in an organic polar solvent, adding inorganic base and a catalyst, forming carboxylate by the inorganic base and the azilsartan, controlling the temperature to be 20-30 ℃ to perform substitution reaction with 4-iodo-3-hydroxy-2-butanone under the action of the catalyst, completely reacting, extracting, concentrating to obtain deep red oily matter, and performing column chromatography to obtain a pure product.
The process route is as follows:
according to an embodiment of the present invention, step 1 may prepare intermediate 4-iodo-3-hydroxy-2-butanone in one step by a double catalytic reaction, namely catalytic addition and forward catalytic reaction: firstly, butenone needs to form a carbonium ion active intermediate under the catalysis of acid, and then 4-iodo-3-hydroxy-2-butanone is formed under the action of a nucleophile. The reaction belongs to SN1 reaction, and the solvent with larger polarity is favorable for the reaction. The inventors have found through extensive studies that the polar solvent is preferably one or more of methanol, ethanol, acetonitrile and propionitrile.
In addition, the acid can effectively promote the addition of olefin bonds to form a carbonium ion active intermediate, and according to the embodiment of the invention, the catalyst of the catalytic addition reaction in the double catalytic reaction is acid, preferably one or more of hydrochloric acid, sulfuric acid and perchloric acid; in order to better promote the addition reaction, the research shows that one or more of iodide ions or iodate ions can be selected to promote the hydroxide concentration in the reaction system, so that the forward catalytic reaction is effectively promoted, and the iodide ions or iodate ion reagents are preferably sodium iodide and sodium iodate.
According to an embodiment of the present invention, step 2 is a nucleophilic substitution reaction, and the polar solvent is effective to promote dissociation of the nucleophile, so that the present invention selects the polar solvent as the solvent in step 2, preferably one or more solvents selected from DMF, DMAC, DMSO.
According to the embodiment of the invention, the impurity G is prepared by adopting a simple mechanism of direct substitution of carboxylate and halogenated hydrocarbon in the step 2, and the inorganic base is preferably one or two of sodium carbonate and potassium carbonate; the catalyst is preferably one or two of potassium iodide and sodium iodide. The beneficial effects of the invention are as follows:
compared with the prior art, the invention adopts butenone to synthesize 4-halogen-3-hydroxy-2-butanone, and then substitutes azilsartan to obtain the impurity G raw material, thus the preparation method has the advantages of easy acquisition and simple operation, and the prepared key degradation impurity of the azilsartan potassium has high purity and is suitable for quality control research of the azilsartan potassium.
In the synthesis of 4-halogen-3-hydroxy-2-butanone in the step 1, iodide anions and acid double catalysis are adopted, so that the reaction can be smoothly carried out; the addition of a proper amount of nucleophilic solvent increases the concentration of hydroxyl in the system, is easy to carry out addition, and the product in the step 1 is directly subjected to the next reaction without post-treatment.
In the step 2, the impurity G is prepared by adopting a simple mechanism of direct substitution of carboxylate and halogenated hydrocarbon, the operation is simple, the reaction can be carried out at room temperature and the reaction is rapid, the purity of the prepared impurity G can reach 90%, and the purity of the prepared impurity G can reach 99.6% at most through column chromatography.
Drawings
Fig. 1 is a liquid chromatogram of the losartan potassium degradation impurity G, showing that the impurity G is peaked at 18.5min, and the chromatographic purity is 99.6%.
Fig. 2 is a mass spectrum of the losartan potassium degradation impurity G.
Fig. 3 is a nuclear magnetic hydrogen spectrum of the losartan potassium degradation impurity G.
Detailed Description
Example 1
450ml of water, 90ml of methanol are added into a reaction bottle, 3.00g of butenone, 1.34g of sodium iodide and 6.90g of iodine are added under stirring, 3.67g of concentrated hydrochloric acid is added dropwise, the temperature is raised to 55 ℃, the reaction is completed, sodium sulfite is quenched, acetonitrile is removed by concentration at 50 ℃, extraction is performed by ethyl acetate, and concentration is performed, so that 2.90g of reddish brown oily matter is obtained.
In a reaction flask6.80g of azilsartan, 150ml of DMAC are added, stirred, 2.80g of potassium carbonate and 3.40g of potassium iodide are added, 2.90g of reddish brown oil are added dropwise and reacted at 30 ℃. After the reaction, 500ml of water was added, extracted with DCM and concentrated to give 5.00g of a dark red oil, which was chromatographed on an EA/PE=1/5 column to give a product with a purity of 99.4%. MS: m/z 541.1 (M-); m/z 543.2 (m+); 1 H-NMR(600MHz,d-DMSO):δ12.38(s,2H),δ7.75~7.64(s,2H),δ7.57~7.53(t,1H),δ7.48~7.46(d,1H),δ7.28~7.21(q,3H),δ7.03~7.01(s,2H),δ5.63~5,52(q,2H),δ5.24~5.22(t,1H),δ4.62~4.57(q,2H),δ3.94~3.75(m,2H),δ2.13(s,3H),δ1.41~1.37(t,3H)。
example 2
450ml of water, 90ml of methanol are added into a reaction bottle, 3.00g of butenone, 1.98g of sodium iodate and 6.90g of iodine are added under stirring, 3.67g of concentrated hydrochloric acid is added dropwise, the temperature is raised to 55 ℃, after the reaction is finished, sodium sulfite is quenched, acetonitrile is removed by concentration at 50 ℃, extraction is performed by ethyl acetate, and concentration is performed, so that 2.86g of reddish brown oily matter is obtained.
6.80g of azilsartan, 150ml of DMAC, stirring, adding 2.80g of potassium carbonate and 3.40g of potassium iodide, dropwise adding 2.86g of reddish brown oily matter and reacting at 30 ℃. After the reaction, 500ml of water was added, extracted with DCM and concentrated to give 4.93g of a dark red oil, which was chromatographed on EA/pe=1/5 column to give a product with a purity of 99.6%.
Example 3 to a reaction flask was added 450ml of water, 90ml of acetonitrile, 3.00g of butenone, 1.98g of sodium iodate, 6.90g of iodine, 1.80g of concentrated sulfuric acid were added dropwise, the temperature was raised to 55 c, the reaction was completed, sodium sulfite was quenched, acetonitrile was removed by concentration at 50 c, extraction was performed with ethyl acetate, and concentration was performed to obtain 2.95g of a reddish brown oily substance.
6.80g of azilsartan, 150ml of DMAC, stirring, adding 2.80g of potassium carbonate and 3.40g of potassium iodide, dropwise adding 2.95g of reddish brown oily matter and reacting at 30 ℃. After the reaction, 500ml of water was added, extracted with DCM and concentrated to give 5.20g of a dark red oil, which was chromatographed on EA/pe=1/5 column to give the product with a purity of 99.2%.
Example 4
450ml of water, 90ml of acetonitrile are added into a reaction bottle, 3.00g of butenone, 1.98g of sodium iodate and 6.90g of iodine are added under stirring, 1.80g of concentrated sulfuric acid is added dropwise, the temperature is raised to 55 ℃, after the reaction is finished, sodium sulfite is quenched, acetonitrile is removed by concentration at 50 ℃, extraction is performed by ethyl acetate, and concentration is performed, so that 2.92g of reddish brown oily matter is obtained.
6.80g of azilsartan, 150ml of DMSO, stirring, adding 2.80g of potassium carbonate and 3.40g of potassium iodide, dropwise adding 2.92g of reddish brown oily matter, and reacting at 30 ℃. After the reaction, 500ml of water was added, extracted with DCM and concentrated to give 5.15g of a dark red oil, which was chromatographed on EA/pe=1/5 column to give the product with a purity of 99.2%.
Example 5
450ml of water, 90ml of acetonitrile are added into a reaction bottle, 3.00g of butenone, 1.98g of sodium iodate and 6.90g of iodine are added under stirring, 1.80g of concentrated sulfuric acid is added dropwise, the temperature is raised to 55 ℃, after the reaction is finished, sodium sulfite is quenched, acetonitrile is removed by concentration at 50 ℃, extraction is performed by ethyl acetate, and concentration is performed, so that 2.88g of reddish brown oily matter is obtained.
6.80g of azilsartan, 150ml of DMSO, stirring, adding 2.15g of sodium carbonate and 3.07g of sodium iodide, dropwise adding 2.88g of reddish brown oily matter, and reacting at 30 ℃. After the reaction, 500ml of water was added, extracted with DCM and concentrated to give 4.85g of a dark red oil, which was chromatographed on EA/pe=1/5 column to give the product with a purity of 99.5%.
Claims (9)
1. The preparation method of the losartan potassium degradation impurity is characterized by comprising the following steps:
step 1: dissolving butenone in water, adding an organic solvent, adding an iodine reagent and a catalyst for catalysis, and reacting at 50-60 ℃; the reaction is complete, quenching, extraction and concentration are carried out to obtain the product 4-iodo-3-hydroxy-2-butanone with reddish brown oily matter;
step 2: firstly, azilsartan is dissolved in an organic solvent, and inorganic base and a catalyst are added; finally adding the 4-iodine-3-hydroxy-2-butanone in the step 1 to react at 20-30 ℃; the reaction is complete, extraction and concentration are carried out to obtain deep red oily matter, and the pure product is obtained through column chromatography.
2. The method for preparing the losartan potassium degradation impurity according to claim 1, wherein the organic solvent in the step 1 is a polar solvent selected from one or more of methanol, ethanol, acetonitrile and propionitrile.
3. The method for preparing the losartan potassium degradation impurity according to claim 1, wherein the catalysis in the step 1 is a double catalytic reaction of catalytic addition and forward catalysis.
4. The method for preparing the losartan potassium degradation impurity according to claim 3, wherein the catalyst for catalyzing the addition reaction is an acid selected from one or more of hydrochloric acid, sulfuric acid and perchloric acid.
5. The method for preparing the losartan potassium degradation impurity according to claim 3, wherein the catalyst for the forward reaction is one or more of iodide ions and iodate ion reagents.
6. The method for preparing the losartan potassium degradation impurity according to claim 5, wherein the catalyst for the forward reaction is one or more of sodium iodide and sodium iodate.
7. The method for preparing the losartan potassium degradation impurity according to claim 1, wherein the organic solvent in the step 2 is a polar solvent selected from one or more of DMF, DMAC, DMSO.
8. The method for preparing the metartan potassium degradation impurity according to claim 1, wherein the inorganic base in the step 2 is one or two selected from sodium carbonate and potassium carbonate.
9. The method for preparing the losartan potassium degradation impurity according to claim 1, wherein the catalyst in the step 2 is one or two selected from potassium iodide and sodium iodide.
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