CN111170922A - Impurity generated in indapamide production, and synthetic method and application thereof - Google Patents
Impurity generated in indapamide production, and synthetic method and application thereof Download PDFInfo
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- CN111170922A CN111170922A CN202010019840.8A CN202010019840A CN111170922A CN 111170922 A CN111170922 A CN 111170922A CN 202010019840 A CN202010019840 A CN 202010019840A CN 111170922 A CN111170922 A CN 111170922A
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- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 title abstract description 33
- 229960004569 indapamide Drugs 0.000 title abstract description 33
- 239000012535 impurity Substances 0.000 title abstract description 22
- 238000010189 synthetic method Methods 0.000 title abstract description 9
- 238000004519 manufacturing process Methods 0.000 title abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 39
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- SCYSJFKWFQZRJW-UHFFFAOYSA-N 4-chloro-3-sulfamoylbenzoyl chloride Chemical compound NS(=O)(=O)C1=CC(C(Cl)=O)=CC=C1Cl SCYSJFKWFQZRJW-UHFFFAOYSA-N 0.000 claims abstract description 21
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims abstract description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000007858 starting material Substances 0.000 claims abstract description 6
- 238000005917 acylation reaction Methods 0.000 claims abstract description 5
- 239000003208 petroleum Substances 0.000 claims abstract description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 229940126062 Compound A Drugs 0.000 claims description 4
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 20
- 238000001308 synthesis method Methods 0.000 abstract description 9
- 238000012544 monitoring process Methods 0.000 abstract description 7
- 238000004458 analytical method Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 206010020772 Hypertension Diseases 0.000 description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 5
- 230000036772 blood pressure Effects 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000002220 antihypertensive agent Substances 0.000 description 4
- 229940127088 antihypertensive drug Drugs 0.000 description 4
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- 239000003451 thiazide diuretic agent Substances 0.000 description 4
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910001424 calcium ion Inorganic materials 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
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- 241000282414 Homo sapiens Species 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 206010042957 Systolic hypertension Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 206010047139 Vasoconstriction Diseases 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000003907 kidney function Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
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- 210000002464 muscle smooth vascular Anatomy 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
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- 238000010992 reflux Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000025033 vasoconstriction Effects 0.000 description 2
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HFFXLYHRNRKAPM-UHFFFAOYSA-N 2,4,5-trichloro-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C(=CC(Cl)=C(Cl)C=2)Cl)=N1 HFFXLYHRNRKAPM-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000005223 Alkalosis Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 208000007177 Left Ventricular Hypertrophy Diseases 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 208000003450 Neurogenic Diabetes Insipidus Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010031127 Orthostatic hypotension Diseases 0.000 description 1
- 206010033557 Palpitations Diseases 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010067171 Regurgitation Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
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- 208000022531 anorexia Diseases 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
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- 208000028235 central diabetes insipidus Diseases 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000027288 circadian rhythm Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010064 diabetes insipidus Diseases 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
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- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
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- 206010022437 insomnia Diseases 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
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- 230000027939 micturition Effects 0.000 description 1
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- 230000007935 neutral effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000003836 peripheral circulation Effects 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
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- 230000035807 sensation Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- -1 thiazide indole derivative Chemical class 0.000 description 1
- 150000004897 thiazines Chemical class 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an impurity generated in indapamide production, a synthetic method and application. The synthetic method of the indapamide impurity D comprises the following steps: reacting the starting material A with thionyl chloride, and distilling under reduced pressure to obtain a compound B; and (3) carrying out acylation reaction on the compound B and the compound C, and recrystallizing petroleum ether and ethyl acetate to obtain a compound D. The invention provides a simple synthesis method of indapamide impurity D. The synthesized indapamide impurity D can provide impurity control monitoring for the reaction, and the problem of impurity analysis and control of the indapamide is solved. Provides a powerful support for large-scale industrial production of indapamide.
Description
Technical Field
The invention relates to the technical field of chemical substance preparation, in particular to an impurity generated in indapamide production, a synthetic method and application.
Background
Hypertension is a common disease and a frequently encountered disease, and simultaneously can cause the pathological changes of heart, cerebral vessels, kidneys and the like, and is one of the diseases causing the highest human mortality in the world at present. Since 1948, the use of diuretics for lowering blood pressure in human beings begins, thiazide diuretics have been one of the major forces of antihypertensive drugs for a long time, and have definite curative effects no matter used singly or combined with other antihypertensive drugs. The results of international large-scale clinical trials have further established its position in the treatment of hypotension for decades. Several European and American council of hypertension treatment principles recommend diuretics as the first choice for patients with uncomplicated hypertension. Thiazide diuretics are also considered to have a unique position in the U.S. JNC7 directive. In 2010, the Chinese guidelines for hypertension prevention and treatment recommend diuretics (thiazines) and dihydropyridine calcium ion antagonists (DHP) to be ideal antihypertensive drugs for treating senile hypertension and isolated systolic hypertension. In 2009, diuretics account for about 3.22% of all antihypertensive drugs in our country, and are on the rise.
Indapamide (Indapamide), having the molecular formula of C16H16ClN3O3S, is a sulfonamide derivative having an indole ring structure, is pharmacologically related to thiazide diuretics, achieves a diuretic effect by inhibiting sodium reabsorption in the renal cortex dilution stage, binds to plasma proteins after oral absorption, selectively concentrates on vascular smooth muscle, inhibits intracellular calcium ion flux, reduces vasoconstriction, and reduces the responsiveness of blood vessels to a pressure-boosting substance, thereby reducing vascular resistance and producing hypotensive activity. Indapamide is a non-thiazide indole derivative with dual functions of reducing blood pressure and promoting urination, and can be selectively concentrated on vascular smooth muscle after being absorbed, inhibit the inward calcium ion flow of cells, reduce vasoconstriction and the reactivity of blood vessels to a pressure boosting substance, thereby improving the compliance of arteries, reducing the resistance of arterioles and the whole peripheral circulation and reversing the hypertrophy of the left ventricle caused by hypertension. The indapamide can also improve other atherosclerosis risk factors accompanied with hypertension, such as dyslipidemia, diabetes, obesity, hyperuricemia, renal function reduction, left ventricular hypertrophy and the like. After the indapamide is taken by a patient with a history of stroke or transient cerebral ischemia attack, the blood pressure can be reduced, the occurrence of fatal and non-fatal stroke is reduced, and the intelligence of the patient is not obviously reduced. The indapamide has the effect of repairing the injury of the proximal renal tubules of a hypertensive patient, can increase the creatinine clearance rate of the patient, reduce the excretion rate of urine microalbumin, and improve and repair the damaged renal function. The observation of a group of old patients with simple systolic hypertension taking indapamide shows that the medicine has good control effect on the dynamic blood pressure, can recover the disordered circadian rhythm of the patients and effectively reduces the early morning blood pressure peak value. Research shows that indapamide also has an effect on central diabetes insipidus. However, the indapamide has the following adverse reactions: 1. the digestive system is rarely suffered from diarrhea, anorexia, regurgitation and the like, and occasionally suffered from dry mouth, nausea, constipation and the like; 2. cardiovascular system, rarely seen postural hypotension, palpitation, arrhythmia, etc.; 3. the nervous system, headache, insomnia, dizziness, abnormal sensation and the like are rarely seen; 4. metabolism, low blood sodium, low blood potassium, low chlorine alkalosis; 5. skin allergic reactions such as rash and itching are rare.
In order to improve the quality of the indapamide and reduce the risk of clinical medication, the impurities in the raw material drug of the indapamide need to be researched and monitored. At present, an impurity reference substance is usually selected, and the content of impurities in the indapamide is strictly controlled by a high performance liquid chromatography and an external standard method, so that the synthesis method for quickly, simply and efficiently obtaining the impurity reference substance is urgent.
The main synthetic route mainly comprises the following methods: 1) CN100422146C, which reports that indapamide is prepared by using N-amido-2-methylindoline hydrochloride as a raw material; wherein the reaction equation is as follows:
indapamide D is an impurity occurring in the production process of indapamide, and MS is [ M = H ] + = 351.1. However, no effective synthetic methods have been reported so far.
Disclosure of Invention
The invention provides a simple synthetic method for synthesizing the impurity D. The synthesized indapamide impurity D can provide impurity control monitoring for the reaction, and the problem of impurity analysis and control of the indapamide is solved.
In order to achieve the purpose, the invention provides the following technical scheme:
an indapamide impurity D characterized in that it has the following structure:
the invention further discloses a synthesis method of the indapamide impurity D, which is characterized by comprising the following steps:
1) reacting the starting material A with thionyl chloride under the conditions of 80 ℃ and 2 hours; carrying out reduced pressure distillation to obtain a compound B; the compound A: the mol ratio of the thionyl chloride is 1: 5-10;
2) carrying out acylation reaction on the compound B and the compound C, and recrystallizing to obtain a compound D; the molar ratio of the compound B to the compound C is 1: 1- -1.2.
The recrystallization solvent is as follows: petroleum ether, ethyl acetate, n-hexane, and mixtures thereof; the mixture is characterized in that: the volume ratio of ethyl acetate to n-hexane is 1: 1.
the invention further discloses application of the indapamide impurity D in preparation of a reference substance for detecting the indapamide impurity. Experimental results show that the synthetic method is simple and effective. The synthesized indapamide impurity D can effectively provide impurity contrast monitoring for the reaction, and the problem of impurity analysis and control of the indapamide is solved.
The synthesis method of the indapamide impurity D is described in more detail as follows:
1) sequentially taking A, N as a starting material, reacting N-dimethylformamide with thionyl chloride, distilling, and baking to obtain an intermediate B; the starting material A: the mol ratio of the thionyl chloride is 1: 10;
2) and sequentially adding the compound B and triethylamine into tetrahydrofuran, adding the compound C, and reacting. Quenching, extraction, and recrystallization to obtain impurity D.
The molar ratio of the compound B to the compound C is 1: 1.05.
the synthetic route of the synthetic method of the indapamide impurity D disclosed by the invention is as follows:
1) sequentially taking A, N as a starting material, reacting N-dimethylformamide with thionyl chloride, distilling, and baking to obtain an intermediate B;
2) and sequentially adding the compound B and triethylamine into tetrahydrofuran, adding the compound C, and reacting. Quenching, extraction, and recrystallization to obtain impurity D.
In the synthesis method of the present invention, compound a: the ratio of thionyl chloride is 1: 10.
in the synthesis method of the present invention, the ratio of compound C to compound B is preferably 1: 1.2.
in the synthesis method, the reaction condition temperature in the step 1) is preferably 80 ℃ and the time is preferably 4 hours.
In the synthesis method of the invention, the solvent used in the recrystallization in the step 2) is preferably ethyl acetate: petroleum ether = 1: 1; or ethyl acetate/n-hexane = 1: 1.
the method for synthesizing impurities generated in the production of indapamide SUO has the positive effects that:
the invention provides a simple synthesis method of indapamide impurity D. The synthesized indapamide impurity D can provide impurity control monitoring for the reaction, and the problem of impurity analysis and control of the indapamide is solved. Provides a powerful support for large-scale industrial production of indapamide.
Detailed Description
For the sake of simplicity and clarity, descriptions of well-known techniques are omitted appropriately below to avoid unnecessary detail affecting the description of the present solution. The synthesis of indapamide impurity D according to the present invention is further illustrated below with reference to preferred examples, in particular, compound a is commercially available; the thionyl chloride, N, N-dimethylformamide and triethylamine used are commercially available.
Example 1
A method for synthesizing impurity D generated in the production of indapamide, comprising the steps of:
1) 10.00 g (0.042 mol) of compound A, 25.4 g (0.0.21 mol) of thionyl chloride and 0.05 mL of N, N-dimethylformamide are sequentially added into a 250 mL three-necked flask provided with a thermometer, a reflux pipe and a mechanical stirrer, the temperature is kept at 80 ℃, the reaction is kept for 4 hours, the reaction is monitored by TLC, after the reaction is finished, the thionyl chloride in the reaction solution is evaporated, the material is placed in a tray and placed in an oven, and the temperature is raised to 80 ℃ after the oven is opened for 8 hours. Compound B10.3 g was obtained in 95.52% yield.
2) 5.00 g (0.37mol) of Compound C, 9.50 g (0.93 mol) of triethylamine and 100mL of dry tetrahydrofuran were added to a 250 mL three-necked flask equipped with a thermometer and mechanically stirred under nitrogen atmosphere, 10 g (0.39 mol) of Compound B was dissolved in 50mL of tetrahydrofuran and added dropwise to the reaction over 30 minutes for 2 hours, followed by monitoring the reaction by TLC, and after completion of the reaction, the reaction mixture was quenched with an aqueous solution. And extracted with ethyl acetate. The organic phase was washed twice with saturated aqueous citric acid solution and once with saturated aqueous sodium bicarbonate solution and the organic phase was evaporated to dryness. The material was dissolved in 5mL of ethyl acetate, and 5mL of n-hexane was added dropwise with stirring and stirred for 30 minutes. Filtration and cake rinsed with a small amount of ethyl acetate/hexanes = 1/1. The indapamide impurity D10.3 g, yield 78.2%, purity HPLC 92.3% was obtained.
According to the formula, the indapamide D can be efficiently synthesized. However, in the acylation process, a part of the compound B is not reacted completely, so that raw materials are not completely treated in the post-treatment purification process, and the purification is difficult.
Example 2
1) 15.00 g (0.042 mol) of compound A, 50.4 g (0.42 mol) of thionyl chloride and 0.05 mL of N, N-dimethylformamide are sequentially added into a 250 mL three-necked flask provided with a thermometer, a reflux pipe and a mechanical stirrer, the temperature is kept at 80 ℃, the reaction is kept at 4 hours, the TLC is used for monitoring the reaction, after the reaction is finished, the thionyl chloride in the reaction liquid is evaporated, the material is placed in a tray and placed in an oven, and the temperature is raised to 80 ℃ after the oven is opened for 8 hours. 15.2 g of Compound B was obtained in 95.52% yield.
2) 5.00 g (0.37mol) of Compound C, 9.50 g (0.93 mol) of triethylamine and 100mL of dry tetrahydrofuran were added to a 250 mL three-necked flask equipped with a thermometer and mechanically stirred under nitrogen atmosphere, 10.5 g (0.39 mol) of Compound B was dissolved in 50mL of tetrahydrofuran and added dropwise to the reaction over 30 minutes for 2 hours, followed by monitoring the reaction by TLC, and after completion of the reaction, the reaction mixture was quenched with an aqueous solution. And extracted with ethyl acetate. The organic phase was washed twice with saturated aqueous citric acid solution and once with saturated aqueous sodium bicarbonate solution and the organic phase was evaporated to dryness. The material was dissolved in 5mL of ethyl acetate, and 5mL of n-hexane was added dropwise with stirring and stirred for 30 minutes. Filtration and cake rinsed with a small amount of ethyl acetate/hexanes = 1/1. Obtain indapamide impurity D11.3 g, yield 85.8%, purity HPLC 98.87%.
1H NMR(CDCl3)δ8.29(s,1H),7.64-7.68(m,2H),7.25(s,1H), 7.08(d,2H), 5.23(s,2H), 4.70(s, 1H), 3.44-3.50(m,1H), 1.28(s,3H). [M+H]+=351.1.
According to the formula, the indapamide impurity D can be synthesized efficiently and high-quality. The acylation reaction process has few impurities, the reaction is fast, the purification is simple, and the synthetic impurity D is easily obtained.
Example 3
An Agilent 1200 high performance liquid chromatograph, octadecylsilane chemically bonded silica as a filler, methanol-water-glacial acetic acid (volume ratio is 45: 55: 0.5) as a mobile phase, 20 mg of indapamide reference substance is precisely weighed and placed in a 100mL measuring flask, 5mL of methanol is added for dissolution, the mobile phase is diluted to a scale, the solution is shaken up, 5mL is measured, 2mL of 1mol/L sodium hydroxide solution is added, the solution is placed in a water bath pot for heating for one hour, the solution is cooled and adjusted to be neutral by 1mol/L hydrochloric acid solution. Dilute to 50mL with mobile phase. The sample introduction amount is 100 mu l, the flow rate is 1-3 ml/min, the detection wavelength is 246nm, and the column temperature is 30 ℃. Under the chromatographic conditions, indapamide peaked about 12 minutes, and impurities peaked about 24.8 minutes.
Taking a proper amount of the impurity monomer, preparing a solution of 0.5mg/ml by using a diluent, determining according to an indapamide related substance inspection method, and calculating the purity of a main peak to be 98.87% by using an area normalization method. No peak was observed at 12 minutes. For further verification, a test solution is added into an indapamide sample solution to be used as a mixed solution for HPLC determination, a peak is generated at 24.81 minutes, and a chromatogram proves that the indapamide sample has no target impurity peak.
It will be apparent to those skilled in the art that various changes and modifications can be made in the above embodiments without departing from the spirit and scope of the invention, and it is intended that all such changes and modifications as fall within the true spirit and scope of the invention be interpreted in accordance with the principles of the invention. And the invention is not limited to the example embodiments set forth in the description.
Claims (3)
1. An indapamide impurity D characterized in that it has the following structure:
2. a method for synthesizing the indapamide impurity D as described in claim 1, characterized in that:
1) reacting the starting material A with thionyl chloride under the conditions of 80 ℃ and 2 hours; carrying out reduced pressure distillation to obtain a compound B; the compound A: the weight portion ratio of the thionyl chloride is 1: 10;
2) carrying out acylation reaction on the compound B and the compound C, and crystallizing to obtain a compound D; the weight part ratio of the compound B to the compound C is 1: 1.05; the recrystallization solvent is as follows: petroleum ether, ethyl acetate, n-hexane, and mixtures thereof; the mixture is characterized in that: the volume ratio of ethyl acetate to n-hexane is 1: 1.
3. the use of the indapamide impurity D as described in claim 1 for the preparation of a control for detecting indapamide impurity.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060182803A1 (en) * | 2005-02-17 | 2006-08-17 | Standard Chem. & Pharm. Co., Ltd. | Oral sustained-release pharmaceutical composition of indapamide, production and use thereof |
| CN106316916A (en) * | 2015-06-29 | 2017-01-11 | 天津市亨必达化学合成物有限公司 | Purification method of indapamide |
| CN107082757A (en) * | 2017-05-26 | 2017-08-22 | 合肥华方医药科技有限公司 | A kind of preparation method of indapamide impurity |
| CN109705016A (en) * | 2019-01-23 | 2019-05-03 | 济南同路医药科技发展有限公司 | A kind of preparation method of the indapamide in relation to substance B |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060182803A1 (en) * | 2005-02-17 | 2006-08-17 | Standard Chem. & Pharm. Co., Ltd. | Oral sustained-release pharmaceutical composition of indapamide, production and use thereof |
| CN106316916A (en) * | 2015-06-29 | 2017-01-11 | 天津市亨必达化学合成物有限公司 | Purification method of indapamide |
| CN107082757A (en) * | 2017-05-26 | 2017-08-22 | 合肥华方医药科技有限公司 | A kind of preparation method of indapamide impurity |
| CN109705016A (en) * | 2019-01-23 | 2019-05-03 | 济南同路医药科技发展有限公司 | A kind of preparation method of the indapamide in relation to substance B |
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