CN107033129A - The synthetic method of Irbesartan impurity - Google Patents
The synthetic method of Irbesartan impurity Download PDFInfo
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- CN107033129A CN107033129A CN201710112779.XA CN201710112779A CN107033129A CN 107033129 A CN107033129 A CN 107033129A CN 201710112779 A CN201710112779 A CN 201710112779A CN 107033129 A CN107033129 A CN 107033129A
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- bases
- diketone
- nonane
- diaza spiros
- biphenyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Irbesartan impurity (3 (base of (base of 2'(1H tetrazoles 5) biphenyl 4) methyl) 1, 3 diaza spiros [4, 4] nonane 2, 4 diketone) synthetic method, by adding 32% sodium hydroxide solution into 5 (base of 4 bromomethylbiphenyl 2) 1 trityl 1H tetrazoliums, TBAB and dichloromethane, under stirring, instill 1, 3 diaza spiros [4, 4] nonane 2, 4 diketone dichloromethane solutions, washed after reaction, dichloromethane is evaporated off, obtain 3 (base of (base of 2'(1 trityl 1H tetrazoles 5) biphenyl 4) methyl) 1, 3 diaza spiros [4, 4] nonane 2, 4 diketone, de- trityl group is carried out to it, obtain Irbesartan impurity crude product；Then pH value, extracting and demixing, anhydrous magnesium sulfate drying, stirring and crystallizing etc. are adjusted again and obtains white solid, are finally recrystallized again, are obtained target product Irbesartan impurity.Good effect：Reaction condition is gentle, and synthesis step is simple, is easy to experimental implementation, the advantages of product quality is stable.
Description
Technical field
The invention belongs to field of medicaments, and in particular to (((2'- (1H- tetrazole -5- bases) joins 3- the impurity in Irbesartan
Benzene -4- bases) methyl) -1,3- diaza spiros [4,4] nonane -2,4- diketone) and synthetic method.
Background technology
Irbesartan (irbesartan), its chemical entitled 3- butyl -3- [4- [3- (1H-TETRAZOLE -5- bases) phenyl] benzyl
Base] -1,3- diaza spiros-[4,4] nonyl- 1- alkene -4- ketone are a kind of non-peptideangiotensinⅱ receptor antagonists of high selectivity
Agent, the angiotensinⅡ is the octapeptide produced by the effect of angiotensin converting enzyme, and has relatively large to blood pressure
Influence, is a kind of clinical conventional medicine for treating essential hypertension.And Irbesartan is prepared and preserved in synthesis or preparation
During there may be catabolite impurity ((3- ((2'- (1H- tetrazole -5- bases) biphenyl -4- bases) methyl) -1,3- diazas
Spiral shell [4,4] nonane -2,4- diketone), its presence can directly affect the security and validity of medication.Its structural formula is：
Synthesis technique patent document now on Irbesartan is relatively more, such as CN102898420B, US5270317,
WO9906398 etc., these patents all describe in detail the synthesis technique of Irbesartan, but without point recorded on impurity
Analysis, detection, to realize the control to drug quality.Ester bond, ehter bond, methylene and tetrazole etc. are active in the structure of Irbesartan
The presence of group so that the compound is easily affected by the surrounding environment during synthesis, preparation, storage etc., occurring one is
The chemical reaction of row, generates corresponding impurity.
For impurity (3- ((2'- (1H- tetrazole -5- bases) biphenyl -4- bases) methyl) -1,3- diaza spiros [4,4] nonyl
Alkane -2,4- diketone) impurity is obtained typically by oxidative degradation, this method is simple to operate, but yield is relatively low.The application is led to
Chemical synthesis process is crossed, reaction raw materials simple and easy to get are chosen, simple synthetic method obtains the impurity.
The content of the invention
It is an object of the invention to provide a kind of Irbesartan impurity (3- ((2'- (1H- tetrazole -5- bases) biphenyl -4-
Base) methyl) -1,3- diaza spiros [4,4] nonane -2,4- diketone) and synthetic method, for obtaining as decompression class curative strategic point
The impurity of the high-purity of Bei Shatan impurity analysis, the above-mentioned deficiency for overcoming the preparation technology of the existing impurity to operate.
The synthetic method of the present invention comprises the following steps：
It is molten that 1. 32% sodium hydroxide is added into 5- (4- bromomethylbiphenyl -2- bases) -1- trityls -1H-TETRAZOLE (I)
Liquid, TBAB and dichloromethane, under stirring, then instill 1,3- diaza spiros [4,4] nonane -2,4- diketone (II)-two
Chloromethanes solution, 35~60 DEG C of 5~20h of reaction, washing is evaporated off dichloromethane, obtains the 3- ((2'- (nitrogen of 1- trityls 1H- tetra-
Azoles -5- bases) biphenyl -4- bases) methyl) -1,3- diaza spiros [4,4] nonane -2,4- diketone；
Wherein, the addition of 32% sodium hydroxide solution (m/v), TBAB, dichloromethane and compound (II)
Respectively 1-5 times (v/m), 0.01-0.1 times (v/m), 10-25 times (v/m), 0.4-1.2 times (m/m) of compound (I).
2. with 3- ((2'- (1- trityl 1H- tetrazole -5- bases) biphenyl -4- of the gained of tetrahydrofuran dissolving step 1
Base) methyl) -1,3- diaza spiros [4,4] nonane -2,4- diketone, under room temperature, 0~3% moisture condition, containing the low of C1~C5
In level alcohol, add chloroacetic chloride and slough obtained Irbesartan impurity (3- ((2'- (1H- tetrazole -5- bases) biphenyl -4- of trityl
Base) methyl) -1,3- diaza spiros [4,4] nonane -2,4- diketone), after reaction terminates, 10% potassium bicarbonate solution (m/v) is added dropwise
PH value is adjusted to neutrality, static, layering, water layer is extracted once with tetrahydrofuran, merge tetrahydrofuran layer, anhydrous magnesium sulfate is done
Dry, reduced under vacuum adds acetone and n-hexane into residue to dry, and stirring separates out crystallization, and suction filtration obtains white solid, will
Obtained white solid acetone, n-hexane recrystallization, obtains target product Irbesartan impurity of the present invention；
Wherein, the addition of tetrahydrofuran, lower alcohol and chloroacetic chloride is respectively the 3- ((2'- (nitrogen of 1- trityls 1H- tetra-
Azoles -5- bases) biphenyl -4- bases) methyl) and -1,3- diaza spiros [4,4] nonane -2,4- diketone 1.0-2.5 times (v/m), 3-5 times
(v/m), 0.1-0.5 times (v/m)；Acetone and n-hexane usage ratio are 1:1.5-1:3(v/v).
The positive effect of the present invention is to have obtained the higher impurity of purity, is used for Irbesartan as known impurities
In quality analysis, impurity position in sample is specified, impurity and sample room separating degree is investigated, makes analysis method more accurate；Simultaneously
Gentle with reaction condition, synthesis step is simple, is easy to experimental implementation, the advantages of product quality is stable.
Embodiment：
The present invention is expanded on further below by embodiment.
Embodiment one：
1. 5- (4- bromomethylbiphenyl -2- bases) -1- trityls -1H-TETRAZOLE 30g are weighed, dichloromethane 200ml, input
In 1000ml three-necked bottles, 32% sodium hydroxide solution 80ml is added dropwise in the lower room temperature of stirring, after dripping off, is cooled to less than 10 DEG C, addition
Four butyl bromation amine 1.0g, under stirring, then instills 1,3- diaza spiros [4,4] nonane -2,4- diketone (II) 15g and is dissolved in dichloromethane
In alkane 150ml), 20h is heated to reflux at 40 DEG C after dripping off, purifying water washing is used after the completion of reaction 2 times, each 400ml, organic phase
Vacuum distillation goes out dichloromethane, obtains object.
2. the object 8g obtained, plus tetrahydrofuran 15ml, methanol 25ml, stirring and dissolving, add chloroacetic chloride 2ml, stir
Reaction is mixed, after reaction terminates, 10% potassium bicarbonate solution is added dropwise and adjusts pH value to neutrality, static, layering, water layer tetrahydrofuran
20ml is extracted once, merges tetrahydrofuran layer, and anhydrous magnesium sulfate is dried, and reduced under vacuum adds 16ml into residue to dry
Acetone, 32ml n-hexanes, stirring separate out crystallization, and suction filtration obtains white solid, and obtained white solid is tied again with acetone, n-hexane
Crystalline substance, purity 99.6%.
Purity detecting
It is filler with octadecylsilane chemically bonded silica；With phosphoric acid solution (85% phosphoric acid 5.5ml is taken, is added water to
950ml, pH is adjusted to 3.2)-acetonitrile (62 with triethylamine：38)；Detection wavelength 220nm；Flow velocity 1.0ml/min, sample size is 10
μl。
Gains are assert
1H NMR(400MHz,d-DMSO)δ:1.26-1.31 (m, 2H, CH2), 1.46-1.52 (m, 2H, CH2), 1.69-
1.71 (m, 2H, CH2), 2.32 (t, J=7.2Hz, 2H, CH2), 4.71 (s, 1H, NCH), 5.54 (s, 1H, NH), 7.13 (s, 4H,
ArH), 7.54-7.63 (m, 2H, ArH), 7.68-7.71 (m, 2H, ArH)；
13C NMR(400MHz,d-DMSO)δ:27.3,28.2,37.2,42.8,76.5,124.1,126.6,128.3,
129.5,131.2,131.5,136.6,139.2,141.3,155.5,161.5,186.2,187.4；
IR (film, cm-1)2952,1700,1696,1661,1454,1185,765,710
Embodiment two：
1. 5- (4- bromomethylbiphenyl -2- bases) -1- trityls -1H-TETRAZOLE 30g are weighed, dichloromethane 200ml, input
Into 1000ml three-necked bottles, 32% sodium hydroxide solution 50ml is added dropwise in the lower room temperature of stirring, after dripping off, and is cooled to less than 10 DEG C, plus
Enter four butyl bromation amine 2.0g, under stirring, then instill 1,3- diaza spiros [4,4] nonane -2,4- diketone (II) 25g and be dissolved in dichloro
In methane 250ml), 10h is heated to reflux at 50 DEG C after dripping off, with water washing is purified 2 times after the completion of reaction, each 400ml is organic
Mutually decompression distills out dichloromethane, obtains object.
2. the object 8g obtained, plus tetrahydrofuran 10ml, ethanol 30ml, stirring and dissolving, add chloroacetic chloride 1ml, stir
Reaction is mixed, after reaction terminates, 10% potassium bicarbonate solution is added dropwise and adjusts pH value to neutrality, static, layering, water layer tetrahydrofuran
20ml is extracted once, merges tetrahydrofuran layer, and anhydrous magnesium sulfate is dried, and reduced under vacuum adds 16ml into residue to dry
Acetone, 26ml n-hexanes, stirring separate out crystallization, and suction filtration obtains white solid, and obtained white solid is tied again with acetone, n-hexane
Crystalline substance, purity 99.3%.
Purity detecting
It is filler with octadecylsilane chemically bonded silica；With phosphoric acid solution (85% phosphoric acid 5.5ml is taken, is added water to
950ml, pH is adjusted to 3.2)-acetonitrile (62 with triethylamine：38)；Detection wavelength 220nm；Flow velocity 1.0ml/min, sample size is 10
μl。
Gains are assert
1H NMR(400MHz,d-DMSO)δ:1.24-1.30 (m, 2H, CH2), 1.45-1.50 (m, 2H, CH2), 1.68-
1.72 (m, 2H, CH2), 2.33 (t, J=7.2Hz, 2H, CH2), 4.73 (s, 1H, NCH), 5.56 (s, 1H, NH), 7.15 (s, 4H,
ArH), 7.51-7.62 (m, 2H, ArH), 7.64-7.74 (m, 2H, ArH)；
13C NMR(400MHz,d-DMSO)δ:27.2,28.4,37.1,42.6,76.7,124.3,126.3,128.6,
129.2,131.0,131.2,136.8,139.4,141.1,155.2,161.4,186.3,187.5；
IR (film, cm-1)2947,1708,1691,1665,1463,1190,760,707
Embodiment three：
1. 5- (4- bromomethylbiphenyl -2- bases) -1- trityls -1H-TETRAZOLE 30g are weighed, dichloromethane 350ml, input
Into 1000ml three-necked bottles, 32% sodium hydroxide solution 150ml is added dropwise in the lower room temperature of stirring, after dripping off, and is cooled to less than 10 DEG C, plus
Enter four butyl bromation amine 3.0g, under stirring, then instill 1,3- diaza spiros [4,4] nonane -2,4- diketone (II) 35g and be dissolved in dichloro
In methane 350ml), 6h is heated to reflux at 60 DEG C after dripping off, with water washing is purified 2 times after the completion of reaction, each 400ml is organic
Mutually decompression distills out dichloromethane, obtains object.
2. the object 8g obtained, plus tetrahydrofuran 20ml, methanol 40ml, stirring and dissolving, add chloroacetic chloride 4ml, stir
Reaction is mixed, after reaction terminates, 10% potassium bicarbonate solution is added dropwise and adjusts pH value to neutrality, static, layering, water layer tetrahydrofuran
20ml is extracted once, merges tetrahydrofuran layer, and anhydrous magnesium sulfate is dried, and reduced under vacuum adds 16ml into residue to dry
Acetone, 45ml n-hexanes, stirring separate out crystallization, and suction filtration obtains white solid, and obtained white solid is tied again with acetone, n-hexane
Crystalline substance, purity 99.5%.
Purity detecting
It is filler with octadecylsilane chemically bonded silica；With phosphoric acid solution (85% phosphoric acid 5.5ml is taken, is added water to
950ml, pH is adjusted to 3.2)-acetonitrile (62 with triethylamine：38)；Detection wavelength 220nm；Flow velocity 1.0ml/min, sample size is 10
μl。
Gains are assert
1H NMR(400MHz,d-DMSO)δ:1.23-1.34 (m, 2H, CH2), 1.47-1.54 (m, 2H, CH2), 1.65-
1.73 (m, 2H, CH2), 2.35 (t, J=7.2Hz, 2H, CH2), 4.73 (s, 1H, NCH), 5.51 (s, 1H, NH), 7.15 (s, 4H,
ArH), 7.52-7.61 (m, 2H, ArH), 7.66-7.71 (m, 2H, ArH)；
13C NMR(400MHz,d-DMSO)δ:27.8,28.4,36.9,42.4,77.0,123.9,126.4,128.0,
129.7,131.4,131.5,136.2,139.4,141.6,155.9,162.1,185.8,187.7；
IR (film, cm-1)2959,1708,1691,1669,1461,1183,758,705。
Claims (1)
1. Irbesartan impurity (3- ((2'- (1H- tetrazole -5- bases) biphenyl -4- bases) methyl) -1,3- diaza spiros [4,4] nonyl
Alkane -2,4- diketone) synthetic method, comprise the following steps：
(1) 32% sodium hydroxide solution, four are added into 5- (4- bromomethylbiphenyl -2- bases) -1- trityls -1H-TETRAZOLE (I)
Butylammonium bromide and dichloromethane, under stirring, then instill 1,3- diaza spiros [4,4] nonane -2,4- diketone (II)-dichloromethane
Solution, 35~60 DEG C of 5~20h of reaction, washing is evaporated off dichloromethane, obtains 3- ((2'- (1- trityl 1H- tetrazole -5- bases)
Biphenyl -4- bases) methyl) -1,3- diaza spiros [4,4] nonane -2,4- diketone；
Wherein, the addition difference of 32% sodium hydroxide solution (m/v), TBAB, dichloromethane and compound (II)
For 1-5 times (v/m), 0.01-0.1 times (v/m), 10-25 times (v/m), 0.4-1.2 times (m/m) of compound (I)；
(2) with the 3- ((2'- (1- trityl 1H- tetrazole -5- bases) biphenyl -4- bases) obtained by tetrahydrofuran dissolving step (1)
Methyl) -1,3- diaza spiros [4,4] nonane -2,4- diketone, under room temperature, 0~3% moisture condition, the lower alcohol containing C1~C5
In, add chloroacetic chloride and slough obtained Irbesartan impurity (3- ((2'- (1H- tetrazole -5- bases) biphenyl -4- bases) first of trityl
Base) -1,3- diaza spiros [4,4] nonane -2,4- diketone), after reaction terminates, 10% potassium bicarbonate solution (m/v) regulation is added dropwise
PH value is static to neutrality, and layering, water layer is extracted once with tetrahydrofuran, merges tetrahydrofuran layer, and anhydrous magnesium sulfate is dried, very
It is concentrated to dryness under sky, acetone and n-hexane is added into residue, stirring separates out crystallization, and suction filtration obtains white solid, by what is obtained
White solid acetone, n-hexane recrystallization, obtain target product Irbesartan impurity of the present invention；
Wherein, the addition of tetrahydrofuran, lower alcohol and chloroacetic chloride is respectively 3- ((2'- (1- trityl 1H- tetrazoles -5-
Base) biphenyl -4- bases) methyl) and -1,3- diaza spiros [4,4] nonane -2,4- diketone 1.0-2.5 times (v/m), 3-5 times (v/m),
0.1-0.5 times (v/m)；Acetone and n-hexane usage ratio are 1:1.5-1:3(v/v).
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101433536A (en) * | 2007-11-12 | 2009-05-20 | 北京瑞康医药技术有限公司 | Therapeutic compositions containing amlodipine niacin and losartan medicament |
| WO2013186390A1 (en) * | 2012-06-15 | 2013-12-19 | Farma Grs, D.O.O. | Selective crystallization processes using reverse micelle and w/o microemulsion systems - multitask emulsion crystallization (mec) |
| CN103787999A (en) * | 2013-12-18 | 2014-05-14 | 吉林修正药业新药开发有限公司 | Synthesis method of irbesartan impurity |
| CN106083826A (en) * | 2016-06-22 | 2016-11-09 | 浙江华海药业股份有限公司 | A kind of irbesartan isomer and the preparation method of intermediate thereof |
-
2017
- 2017-02-28 CN CN201710112779.XA patent/CN107033129A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101433536A (en) * | 2007-11-12 | 2009-05-20 | 北京瑞康医药技术有限公司 | Therapeutic compositions containing amlodipine niacin and losartan medicament |
| WO2013186390A1 (en) * | 2012-06-15 | 2013-12-19 | Farma Grs, D.O.O. | Selective crystallization processes using reverse micelle and w/o microemulsion systems - multitask emulsion crystallization (mec) |
| CN103787999A (en) * | 2013-12-18 | 2014-05-14 | 吉林修正药业新药开发有限公司 | Synthesis method of irbesartan impurity |
| CN106083826A (en) * | 2016-06-22 | 2016-11-09 | 浙江华海药业股份有限公司 | A kind of irbesartan isomer and the preparation method of intermediate thereof |
Non-Patent Citations (1)
| Title |
|---|
| 惠芳 等: "厄贝沙坦氢氯噻嗪片的含量测定和有关物质研究", 《中国新药杂志》 * |
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