CN115215813A - Method for controlling valsartan impurity - Google Patents
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- CN115215813A CN115215813A CN202210896314.9A CN202210896314A CN115215813A CN 115215813 A CN115215813 A CN 115215813A CN 202210896314 A CN202210896314 A CN 202210896314A CN 115215813 A CN115215813 A CN 115215813A
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- valsartan
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- 239000004072 C09CA03 - Valsartan Substances 0.000 title claims abstract description 144
- 229960004699 valsartan Drugs 0.000 title claims abstract description 144
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 title claims abstract description 140
- 239000012535 impurity Substances 0.000 title claims abstract description 96
- 238000000034 method Methods 0.000 title claims abstract description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 78
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 57
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 44
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 42
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims abstract description 34
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims abstract description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 28
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims abstract description 28
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 18
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims abstract description 17
- 235000019400 benzoyl peroxide Nutrition 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 16
- NHWQMJMIYICNBP-UHFFFAOYSA-N 2-chlorobenzonitrile Chemical compound ClC1=CC=CC=C1C#N NHWQMJMIYICNBP-UHFFFAOYSA-N 0.000 claims abstract description 14
- XEAFFUWADFEZGC-UHFFFAOYSA-M Cl[Ni](C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound Cl[Ni](C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 XEAFFUWADFEZGC-UHFFFAOYSA-M 0.000 claims abstract description 14
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims abstract description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 14
- 230000035484 reaction time Effects 0.000 claims abstract description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 38
- -1 (biphenyl-4-yl) monomethyl radical Chemical class 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 28
- 238000003756 stirring Methods 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 22
- 239000007787 solid Substances 0.000 claims description 19
- 238000010438 heat treatment Methods 0.000 claims description 17
- KUGLDBMQKZTXPW-JEDNCBNOSA-N methyl (2s)-2-amino-3-methylbutanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)C(C)C KUGLDBMQKZTXPW-JEDNCBNOSA-N 0.000 claims description 17
- ZGQVZLSNEBEHFN-UHFFFAOYSA-N 2-(4-methylphenyl)benzonitrile Chemical group C1=CC(C)=CC=C1C1=CC=CC=C1C#N ZGQVZLSNEBEHFN-UHFFFAOYSA-N 0.000 claims description 16
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 16
- 238000001704 evaporation Methods 0.000 claims description 16
- 239000008096 xylene Substances 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 14
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 claims description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 238000000967 suction filtration Methods 0.000 claims description 10
- 239000000843 powder Substances 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- LFFIEVAMVPCZNA-UHFFFAOYSA-N 2-[4-(bromomethyl)phenyl]benzonitrile Chemical group C1=CC(CBr)=CC=C1C1=CC=CC=C1C#N LFFIEVAMVPCZNA-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 229960004295 valine Drugs 0.000 claims description 8
- QOHGRBMFOXKPAJ-UHFFFAOYSA-M FC(F)(F)[Sn]Cl Chemical compound FC(F)(F)[Sn]Cl QOHGRBMFOXKPAJ-UHFFFAOYSA-M 0.000 claims description 7
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 7
- 238000001514 detection method Methods 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 claims description 5
- 238000007865 diluting Methods 0.000 claims description 5
- 235000019441 ethanol Nutrition 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 150000002894 organic compounds Chemical class 0.000 claims description 5
- 239000008213 purified water Substances 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 238000001647 drug administration Methods 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 4
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- 231100000446 genotoxin Toxicity 0.000 claims description 3
- 238000003860 storage Methods 0.000 claims description 3
- 239000012024 dehydrating agents Substances 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- GCTFWCDSFPMHHS-UHFFFAOYSA-M Tributyltin chloride Chemical compound CCCC[Sn](Cl)(CCCC)CCCC GCTFWCDSFPMHHS-UHFFFAOYSA-M 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 1
- 238000001542 size-exclusion chromatography Methods 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 abstract description 6
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 53
- 239000010410 layer Substances 0.000 description 10
- 239000003814 drug Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 206010020772 Hypertension Diseases 0.000 description 5
- AFYPFACVUDMOHA-UHFFFAOYSA-N chlorotrifluoromethane Chemical compound FC(F)(F)Cl AFYPFACVUDMOHA-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000002220 antihypertensive agent Substances 0.000 description 3
- VNWAZSKEPOODRR-UHFFFAOYSA-J chloro(trifluoro)stannane Chemical compound F[Sn](F)(F)Cl VNWAZSKEPOODRR-UHFFFAOYSA-J 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 102000005862 Angiotensin II Human genes 0.000 description 2
- 101800000733 Angiotensin-2 Proteins 0.000 description 2
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229950006323 angiotensin ii Drugs 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000002270 exclusion chromatography Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000004217 heart function Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000003907 kidney function Effects 0.000 description 2
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 241001529453 unidentified herpesvirus Species 0.000 description 2
- 101150059573 AGTR1 gene Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- KWTSZCJMWHGPOS-UHFFFAOYSA-M chloro(trimethyl)stannane Chemical compound C[Sn](C)(C)Cl KWTSZCJMWHGPOS-UHFFFAOYSA-M 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000007674 genetic toxicity Effects 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000004104 valsartan derivatives Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- 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
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 a method for controlling valsartan impurities, which relates to the technical field of organic chemical heterocyclic compounds and comprises triphenylnickel chloride, a tetrahydrofuran solvent, o-chlorobenzonitrile, nitrogen, ethyl acetate, a hydrochloric acid solution, sodium hydroxide concentration, saturated saline water, anhydrous sodium sulfate, isopropanol, N-hexane, N-bromosuccinimide, dibenzoyl peroxide, carbon tetrachloride, anhydrous methanol, thionyl chloride, anhydrous ether, diisopropylethylamine, dimethylformamide and chloromethyl; according to the valsartan impurity, in the step of synthesizing the valsartan, the synthesis reaction time, the temperature and the proportion of the raw materials are gradually controlled in the formula for synthesizing the valsartan, so that the generation of the impurity types and the content of the valsartan is controlled, the problem of leaving toxic impurities when the valsartan is synthesized on the raw materials is solved, and the function of reducing repeated procedures of purifying and removing impurities of the valsartan mixed with the impurities is realized.
Description
Technical Field
The invention relates to the technical field of organic chemical heterocyclic compounds, in particular to a method for controlling valsartan impurities.
Background
With the continuous development of the social and economic levels, more and more old people have high risk of hypertension due to unhealthy long-term life styles, such as drinking, smoking and body obesity, and the working pressure of middle-aged people in order to keep up with fast-paced life, and the national drug administration adopts ACEI medicines and ARB medicines in treating hypertension, wherein valsartan belongs to ARB medicines, and is used for hypertension patients to reduce blood pressure and protect the functions of heart and kidney.
Valsartan is an antihypertensive drug of angiotensin II receptor antagonist, and plays a role in promoting type I AT of angiotensin II 1 Receptor blockade, elevated angiotensin II plasma levels, stimulation of unblocked AT 2 The receptor simultaneously counteracts the effect of AT1 receptor, thereby achieving the effect of dilating blood vessels and lowering blood pressure, but before the preparation of the valsartan medicament, operations such as purification, filtration, drying, detection and the like of valsartan impurities are required to reduce the content of the impurities and take out toxic and harmful impurities.
The existing valsartan impurity causes genetic toxicity impurity when raw materials are chemically reacted to synthesize valsartan, the content of the valsartan impurity is measured by adopting a high performance liquid chromatography, the production content of the valsartan impurity is controlled from the source of production and preparation, the existing valsartan impurity is purified again after production, the impurity is separated, the preparation and extraction work is complex, the detection data is inaccurate, the problem that the content of the valsartan impurity is not accurately controlled, toxic impurity is contained in a valsartan finished product, and potential hidden danger and poisoning risk exist in human body use.
Disclosure of Invention
Technical problem to be solved
Aiming at the defects of the prior art, the invention provides a method for controlling valsartan impurities, which solves the problems that the traditional method for controlling valsartan impurities is not safe enough in raw materials, scientific in material proportion, incapable of meeting edible standards and not ideal in treatment effect on skin diseases.
(II) technical scheme
In order to achieve the purpose, the invention provides the following technical scheme: a method for controlling valsartan impurity comprises the following raw materials of triphenyl nickel chloride, tetrahydrofuran solvent, o-chlorobenzonitrile, nitrogen, ethyl acetate, hydrochloric acid solution, sodium hydroxide concentration, saturated saline, anhydrous sodium sulfate, isopropanol, N-hexane, N-bromosuccinimide, dibenzoyl peroxide, carbon tetrachloride, anhydrous methanol, thionyl chloride, anhydrous ether, diisopropylethylamine, dimethylformamide, chloromethyl, anhydrous ethanol, dichloromethane, valeryl chloride, sodium azide, chlorotrifluoromethyltin, xylene, and acetonitrile solution:
the valsartan impurity is controlled from the beginning of synthesis of valsartan by the following steps:
s1, firstly, placing triphenylnickel chloride, o-chlorobenzonitrile and nitrogen in a molar ratio of 1
S2, taking another reaction vessel, putting 2' -cyano-4-methyl biphenyl, N-bromosuccinimide, dibenzoyl peroxide and carbon tetrachloride in a molar ratio of 10
S3, then adding L-valine and anhydrous methanol in a molar ratio of 1One tenth of the amount, dropping into the reaction kettle, reacting, keeping the temperature for 20-24h, concentrating, evaporating methanol and acidic gas, adding anhydrous ether into the residual solution, separating out solid compound, cooling in a refrigerating chamber to 5 deg.C, and filtering to obtain L-valine methyl ester hydrochloride with structural formula
S4, then placing 2 'cyano-4-methyl biphenyl, L-valine methyl ester hydrochloride, diisopropylethylamine and dimethylformamide into a reactor beaker, heating to 80 ℃, continuously stirring to ensure that the reaction time ranges from 2 to 4 hours, cooling to room temperature, adding purified water, stirring, extracting and combining with chloromethyl to obtain a dichloromethyl base layer, concentrating to dryness, adding absolute ethyl alcohol to dissolve, slowly dropwise adding ethanol to ensure that the pH value of the solution tends to PH =2, separating out solids, and performing suction filtration to obtain the N- [2' cyano-4- (biphenyl-4-yl) methyl]-L-valine methyl ester hydrochloride having the structural formula
S5, then reacting the N- [2' -monocyanomono (biphenyl-4-yl) monomethyl radical thus obtained]Adding sodium carbonate, dichloromethane and valeryl chloride into L-valine methyl ester hydrochloride, heating to 40 deg.C, reacting at constant temperature for 10-12h, washing the solution with water and hydrochloric acid, neutralizing with water, drying with anhydrous sodium sulfate in dichloromethane layer for 10-12h, evaporating to remove solvent to obtain N- [ (2' -cyano-biphenyl-4-yl) methyl]-N-valeryl-L-valine methyl ester with the structural formula
S6, and then reacting N- [ (2' -cyanobiphenyl-4-yl) monomethyl]-N-valeryl-L-valine methyl ester, sodium azide, chlorotrifluortin and xylene in a molar ratio range of 1Yl-biphenyl-4-yl) methyl]Stirring sodium hydroxide solution with the same mass as N-valeryl-L-valine methyl ester for 10-12h, standing for layering, separating lower layer liquid, slowly adding hydrochloric acid until the solution is acidified to PH =2, separating out solid, extracting the solid with ethyl acetate for layering, drying an ethyl acetate dissolved layer with anhydrous sodium sulfate for 10-12h, evaporating the ethyl acetate by a reduced pressure evaporation method, and separating out to obtain the valsartan mixed with impurities, wherein the structural formula of the valsartan is shown in the specification
S7, taking out the valsartan mixed with impurities, adding an ethyl acetate solution, heating to 65 ℃, stirring for 30-40min, filtering while hot, putting the filtrate into a refrigerating chamber, cooling to 5 ℃ to separate out solids, and performing suction filtration to obtain the valsartan and trace valsartan impurities;
and S8, finally, taking out the valsartan and a trace amount of valsartan impurities, putting the valsartan and a trace amount of valsartan impurities into a beaker, adding an acetonitrile solution, diluting and uniformly stirring for 5-10min, wherein the concentration range of the diluted solution is 0.05-0.1 microgram/ml, measuring the content of the valsartan impurities in the solution by adopting a high performance liquid chromatography, and controlling the content of the valsartan impurities by adjusting the concentration, the quality and the reaction time of the preparation raw materials and the method adopted by adding the solvent.
Preferably, the purity of the triphenylnickel chloride is 99.9% and the density of the tetrahydrofuran solvent is 0.89g/cm at room temperature of 25 ℃ 3 The density of the o-chlorobenzonitrile is 1.18g/cm 3 The density of nitrogen was 1.25g/L and the density of ethyl acetate was 0.902g/cm 3 The concentration of the hydrochloric acid solution is 20 percent, the concentration of the sodium hydroxide solution is 52 percent, the concentration of the saturated saline is 26.4 percent, the molar mass of the anhydrous sodium sulfate is 142g/mol, the concentration is 0.2mol/L, the purity of the isopropanol is 99 percent, and the concentration of the normal hexane is 180mg/cm 3 The density of the N-bromosuccinimide is 2.097g/cm 3 Density of dibenzoyl peroxide 1.16g/cm 3 At a concentration of 0.1mg/cm 3 The concentration of carbon tetrachloride is 0.063mg/L, the purity of anhydrous methanol is 99.9%, and the density of thionyl chloride is 1.638g/cm 3 0.21mg/L concentration, anhydrousThe purity of the diethyl ether was 99.5%, and the density of diisopropylethylamine was 0.776g/cm 3 Purity of 99.9%, purity of dimethylformamide of 99.9%, density of chloromethyl group of 0.916g/cm 3 The concentration is 280mg/cm 3 The concentration of absolute ethyl alcohol is 98 percent, and the density of dichloromethane is 1.325g/cm 3 The purity is 99.5 percent, and the density of the valeryl chloride is 1.016g/cm 3 Purity of 98% and density of sodium azide of 1.846g/cm 3 The concentration is 0.02 percent, and the density of the chlorotrifluoromethyltin is 1.2g/cm 3 The purity is 99 percent, the concentration of the dimethylbenzene is 278mg/L, and the density of the acetonitrile solution is 0.776g/cm 3 The concentration was 70mg/L.
Preferably, the 2' -monocyano4-methylbiphenyl is a white crystalline powder having a density of 1.17g/cm 3 For the synthesis of novel sartan antihypertensive agents; the 4' monobromomethyl-2-cyanobiphenyl is a valsartan genotoxin impurity with the density of 1.43g/cm 3 The purity is 99 percent, and the valsartan is used as a medical intermediate for preparing valsartan; the L-valine methyl ester hydrochloride is an organic compound of white crystalline powder at room temperature, has the purity of 98 percent, is used for synthesizing a prodrug of valsartan medicaments, and is characterized by an orally active acyclic nucleoside antiviral substance with inhibitory activity on a plurality of herpes viruses.
Preferably, the N- [2' -monocyanomono (biphenyl-4-yl) monomethyl group]The L-valine methyl ester hydrochloride is also called valsartan secondary amine methyl ester, is an ash white crystal at normal temperature, has stable property and the concentration of 99.9 percent, and is used as a medical intermediate for preparing valsartan; the N- [ (2' -cyanobiphenyl-4-yl) monomethyl group]-N-valeryl-L-valine methyl ester, also known as valsartan acylate, is a condensate of valsartan with a density of 1.1g/cm 3 The valsartan is also named as N-valeryl-N- [ [2'- (1H-tetrazole-5-yl) [1,1' -biphenyl ] as intermediate for preparing sartan medicaments]-4-yl]Methyl radical]L-valine as a white crystalline powder having a density of 1.212g/cm 3 It can be used for treating hypertension, and protecting heart and renal functions.
Preferably, the HPLC is measured by HPLC (high performance liquid chromatography) which meets the national drug administration accuracy, and the HPLC consists of a liquid storage device, a pump, a sample injector, a chromatographic column, a detector and a recorder and is used for detecting and analyzing organic compounds with high boiling points, difficult volatilization, unstable heating and large molecular weight.
Preferably, the substance chromatographic conditions for detecting the valsartan and trace valsartan impurities by the high performance liquid chromatography specifically adopting the molecular exclusion chromatography are as follows;
high performance liquid chromatography instrument: HPLC
A chromatographic column: 100 mm. Times.3.0 mm. Times.1.8. Mu.g
Detection wavelength: 250nm
Flow rate: 1.0ml/min
Column temperature: 60 ℃ C
Detecting the sample introduction amount: 2.5. Mu.l
Operating time: 15-20min.
(III) advantageous effects
The invention provides a method for controlling valsartan impurities, which has the following beneficial effects:
(1) This valsartan impurity is through in the step of preparing synthetic valsartan, control synthetic reaction time one by one in the formulation of synthetic preparation valsartan, the temperature, raw materials account for the proportion, the generation of this control valsartan impurity type and content, when valsartan is synthesized on raw materials, solved the problem of leaving behind toxin impurity, the realization has reduced the function of the repeated process of the impurity removal of valsartan purification of the valsartan mixing with impurity, reached and synthesized all detection impurity content of step each time of valsartan, from the effect of preparing the source control valsartan impurity content, reduce the harm that valsartan caused to the human body.
Detailed Description
All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1:
the invention provides a technical scheme that: a method for controlling valsartan impurities, wherein the valsartan impurities comprise the following components: triphenylnickel chloride, tetrahydrofuran solvent, o-chlorobenzonitrile, nitrogen, ethyl acetate, hydrochloric acid solution, sodium hydroxide concentration, saturated saline, anhydrous sodium sulfate, isopropanol, N-hexane, N-bromosuccinimide, dibenzoyl peroxide, carbon tetrachloride, anhydrous methanol, thionyl chloride, anhydrous diethyl ether, diisopropylethylamine, dimethylformamide, chloromethyl, anhydrous ethanol, dichloromethane, valeryl chloride, sodium azide, chlorotrifluoromethyltin, xylene, and acetonitrile solution.
The hydrolysis reaction is to add ethyl acetate and hydrochloric acid solution, and the raw materials comprise, by weight, 9 parts of ethyl acetate and 10 parts of hydrochloric acid solution.
The organic layer was washed by adding sodium hydroxide and saturated brine, 9 parts sodium hydroxide, and 10 parts saturated brine.
The 4 '-bromomethyl-2-cyanobiphenyl is composed of 10 parts of 2' -cyano-4-methylbiphenyl, 9 parts of N-bromosuccinimide, 1 part of dibenzoyl peroxide and 70 parts of carbon tetrachloride.
The valsartan impurity comprises N- [ (2 '-cyano-biphenyl-4-yl) methyl ] -N-valeryl-L-valine methyl ester, sodium azide, chlorotrifluoromethane and xylene, 1 part of N- [ (2' -cyano-biphenyl-4-yl) methyl ] -N-valeryl-L-valine methyl ester, 1 part of sodium azide, 1 part of chlorotrifluoromethane and 1 part of xylene.
The method for controlling the valsartan impurity comprises the following steps:
s1, firstly, placing triphenylnickel chloride, o-chlorobenzonitrile and nitrogen in a molar ratio of 1;
s2, taking another reaction vessel, adding 2 '-cyano-4-methyl biphenyl, N-bromosuccinimide, dibenzoyl peroxide and carbon tetrachloride in a molar ratio of 10 to 1, stirring for 3 hours, cooling to room temperature of 25 ℃, filtering, and concentrating and crystallizing the filtrate to obtain 4' -bromomethyl-2-cyano biphenyl;
s3, adding L-valine and anhydrous methanol with a molar ratio of 1 to 5, dropwise adding a dehydrating agent thionyl chloride for 6 hours, wherein the content of the thionyl chloride is one tenth of the input amount of the anhydrous methanol, keeping the temperature for 20 hours after the full reaction, concentrating and evaporating the methanol and the acidic gas, adding anhydrous ether into the residual solution, separating out a solid compound, putting the solid compound into a refrigerating chamber, cooling to 5 ℃, and filtering to prepare L-valine methyl ester hydrochloride;
s4, then placing 2 'cyano-4-methyl biphenyl, L-valine methyl ester hydrochloride, diisopropylethylamine and dimethylformamide into a reactor beaker, heating to 80 ℃, continuously stirring to allow the reaction time to be 2 hours, cooling to room temperature, adding purified water, stirring, extracting and combining with chloromethyl to obtain a dichloromethyl base layer, concentrating to dryness, adding absolute ethyl alcohol to dissolve, slowly dropwise adding ethanol to allow the pH value of the solution to tend to PH =2, precipitating a solid, and performing suction filtration to obtain N- [2' cyano-4- (biphenyl-4-yl) monomethyl ] -L-valine methyl ester hydrochloride;
s5, adding sodium carbonate, dichloromethane and valeryl chloride into the prepared N- [2 'cyano-biphenyl-4-yl) methyl ] -L-valine methyl ester hydrochloride, heating to 40 ℃, fully reacting for 10-12h at a constant temperature, washing the solution with water and hydrochloric acid respectively after the reaction, washing the solution with water to be neutral, drying the dichloromethane layer with anhydrous sodium sulfate for 10h, and evaporating the solvent by an evaporation method to obtain N- [ (2' cyano-biphenyl-4-yl) methyl ] -N-valeryl-L-valine methyl ester;
s6, adding N- [ (2' monocyanobiphenyl-4-yl) monomethyl ] -N-valeryl-L-valine methyl ester, sodium azide, chlorotrimethyltin and xylene into a reaction kettle according to a molar ratio range of 1;
s7, taking out the valsartan mixed with impurities, adding an ethyl acetate solution, heating to 65 ℃, stirring for 30min, filtering while hot, putting the filtrate into a refrigerating chamber, cooling to 5 ℃, separating out solids, and performing suction filtration to obtain the valsartan and trace valsartan impurities;
and S8, finally, taking out the valsartan and a trace amount of valsartan impurities, putting the valsartan and the trace amount of valsartan impurities into a beaker, adding an acetonitrile solution, diluting and uniformly stirring for 5min, wherein the concentration of the diluted solution is 0.05 mu g/ml, measuring the content of the valsartan impurities in the solution by adopting a high performance liquid chromatography, and controlling the content of the valsartan impurities by adjusting the concentration, the quality and the reaction time of the preparation raw materials and a method for adding a solvent.
Wherein, at room temperature of 25 deg.C, the purity of triphenyl nickel chloride is 99.9%, and the density of tetrahydrofuran solvent is 0.89g/cm 3 The density of o-chlorobenzonitrile is 1.18g/cm 3 The density of nitrogen was 1.25g/L and the density of ethyl acetate was 0.902g/cm 3 The concentration of the hydrochloric acid solution is 20 percent, the concentration of the sodium hydroxide solution is 52 percent, the concentration of the saturated saline is 26.4 percent, the molar mass of the anhydrous sodium sulfate is 142g/mol, the concentration is 0.2mol/L, the purity of the isopropanol is 99 percent, and the concentration of normal hexane is 180mg/cm 3 The density of the N-bromosuccinimide is 2.097g/cm 3 Density of dibenzoyl peroxide 1.16g/cm 3 At a concentration of 0.1mg/cm 3 The concentration of carbon tetrachloride is 0.063mg/L, purity of anhydrous methanol 99.9%, density of thionyl chloride 1.638g/cm 3 The concentration is 0.21mg/L, the purity of the anhydrous ether is 99.5 percent, and the density of the diisopropylethylamine is 0.776g/cm 3 Purity of 99.9%, purity of dimethylformamide of 99.9%, density of chloromethyl group of 0.916g/cm 3 The concentration is 280mg/cm 3 The concentration of absolute ethyl alcohol is 98 percent, and the density of dichloromethane is 1.325g/cm 3 The purity is 99.5 percent, and the density of the valeryl chloride is 1.016g/cm 3 Purity of 98% and density of sodium azide of 1.846g/cm 3 The concentration is 0.02%, and the density of the chlorotrifluoromethyltin is 1.2g/cm 3 The purity is 99 percent, the concentration of the dimethylbenzene is 278mg/L, and the density of the acetonitrile solution is 0.776g/cm 3 The concentration is 70mg/L.
Wherein the 2' -monocyano4-methylbiphenyl is a white crystalline powder having a density of 1.17g/cm 3 For the synthesis of novel sartan antihypertensive agents; the 4' monobromomethyl-2-cyanobiphenyl is a valsartan genotoxin impurity with the density of 1.43g/cm 3 The purity is 99 percent, and the valsartan is used as a medical intermediate for preparing valsartan; the L-valine methyl ester hydrochloride is an organic compound of white crystalline powder at room temperature, has the purity of 98 percent, is used for synthesizing a prodrug of valsartan medicaments, and is characterized by an orally active acyclic nucleoside antiviral substance with inhibitory activity on a plurality of herpes viruses.
Wherein said N- [2' -cyanomono (biphenyl-4-yl) monomethyl]The L-valine methyl ester hydrochloride is also called valsartan secondary amine methyl ester, is an ash white crystal at normal temperature, has stable property and the concentration of 99.9 percent, and is used as a medical intermediate for preparing valsartan; the N- [ (2' -cyanobiphenyl-4-yl) monomethyl group]-N-valeryl-L-valine methyl ester, also known as valsartan acylate, is a condensate of valsartan with a density of 1.1g/cm 3 The valsartan is also called N-valeryl-N- [ [2'- (1H-tetrazole-5-yl) [1,1' -biphenyl ] as intermediate for preparing sartan medicaments]-4-yl]Methyl radical]L-valine as a white crystalline powder having a density of 1.212g/cm 3 It can be used for treating hypertension, and protecting heart and renal functions.
The high performance liquid chromatography adopts a High Performance Liquid Chromatography (HPLC) instrument which accords with the accuracy of the national drug administration to measure, and the HPLC instrument consists of a liquid storage device, a pump, a sample injector, a chromatographic column, a detector and a recorder and is used for detecting and analyzing organic compounds with high boiling points, difficult volatilization, unstable heating and large molecular weight.
The high performance liquid chromatography specifically adopts a molecular exclusion chromatography to detect the substance chromatographic conditions of the valsartan and trace valsartan impurities as follows;
high performance liquid chromatography instrument: HPLC
A chromatographic column: 100 mm. Times.3.0 mm. Times.1.8. Mu.g
Detection wavelength: 250nm
Flow rate: 1.0ml/min
Column temperature: 60 deg.C
Detecting the sample injection amount: 2.5. Mu.l
Operating time: 15-20min.
Example 2:
the invention provides a technical scheme that: a method for controlling valsartan impurities, wherein the valsartan impurities comprise the following components: triphenylnickel chloride, tetrahydrofuran solvent, o-chlorobenzonitrile, nitrogen, ethyl acetate, hydrochloric acid solution, sodium hydroxide concentration, saturated saline, anhydrous sodium sulfate, isopropanol, N-hexane, N-bromosuccinimide, dibenzoyl peroxide, carbon tetrachloride, anhydrous methanol, thionyl chloride, anhydrous diethyl ether, diisopropylethylamine, dimethylformamide, chloromethyl, anhydrous ethanol, dichloromethane, valeryl chloride, sodium azide, chlorotrifluoromethyltin, xylene, and acetonitrile solution.
The hydrolysis reaction is to add ethyl acetate and hydrochloric acid solution, and the raw materials comprise, by weight, 10 parts of ethyl acetate and 10 parts of hydrochloric acid solution.
The organic layer was washed by adding sodium hydroxide and saturated brine, 10 parts sodium hydroxide, and 10 parts saturated brine.
The 4 '-bromomethyl-2-cyanobiphenyl is composed of 10 parts of 2' -cyano-4-methylbiphenyl, 9 parts of N-bromosuccinimide, 1 part of dibenzoyl peroxide and 70 parts of carbon tetrachloride.
The valsartan impurity comprises N- [ (2 '-cyano-biphenyl-4-yl) methyl ] -N-valeryl-L-valine methyl ester, sodium azide, chlorotrifluoromethane and xylene, 1 part of N- [ (2' -cyano-biphenyl-4-yl) methyl ] -N-valeryl-L-valine methyl ester, 1 part of sodium azide, 1 part of chlorotrifluoromethane and 1 part of xylene.
The method for controlling the valsartan impurity comprises the following steps:
s1, firstly, placing triphenylnickel chloride, o-chlorobenzonitrile and nitrogen in a molar ratio of 1;
s2, taking another reaction vessel, putting 2' -cyano-4-methyl biphenyl, N-bromosuccinimide, dibenzoyl peroxide and carbon tetrachloride in a molar ratio of 10;
s3, adding L-valine and anhydrous methanol in a molar ratio of 1;
s4, then placing 2 'cyano-4-methyl biphenyl, L-valine methyl ester hydrochloride, diisopropylethylamine and dimethylformamide into a reactor beaker, heating to 80 ℃, continuously stirring to ensure that the reaction time ranges from 2 to 4 hours, cooling to room temperature, adding purified water, stirring, extracting and combining with chloromethyl to obtain a dichloromethyl base layer, concentrating to dryness, adding absolute ethyl alcohol to dissolve, slowly dropwise adding ethanol to ensure that the pH value of the solution tends to PH =2, separating out solids, and performing suction filtration to obtain N- [2' cyano-4- (biphenyl-4-yl) monomethyl ] -L-valine methyl ester hydrochloride;
s5, adding sodium carbonate, dichloromethane and valeryl chloride into the prepared N- [2 'cyano-biphenyl-4-yl) methyl ] -L-valine methyl ester hydrochloride, heating to 40 ℃, fully reacting for 12 hours at a constant temperature, washing the solution with water and hydrochloric acid respectively after the reaction, washing the solution with water again to be neutral, drying the dichloromethane layer with anhydrous sodium sulfate for 12 hours, and evaporating the solvent by an evaporation method to obtain N- [ (2' cyano-biphenyl-4-yl) methyl ] -N-valeryl-L-valine methyl ester;
s6, adding N- [ (2' monocyanobiphenyl-4-yl) monomethyl ] -N-valeryl-L-valine methyl ester, sodium azide, chlorotrifluortin and xylene into a reaction kettle according to a molar ratio range of 1;
s7, taking out the valsartan mixed with impurities, adding an ethyl acetate solution, heating to 65 ℃, stirring for 40min, filtering while hot, putting the filtrate into a refrigerating chamber, cooling to 5 ℃, separating out solids, and performing suction filtration to obtain the valsartan and trace valsartan impurities;
and S8, finally, taking out the valsartan and a trace amount of valsartan impurities, putting the valsartan and the trace amount of valsartan impurities into a beaker, adding an acetonitrile solution, diluting and uniformly stirring, wherein the stirring time is 8min, the concentration range of the diluted solution is 0.07 mu g/ml, measuring the content of the valsartan impurities in the solution by adopting a high performance liquid chromatography, and controlling the content of the valsartan impurities by adjusting the concentration, the quality and the reaction time of the preparation raw materials and a method for adding a solvent.
Example 3:
the invention provides a technical scheme that: a method for controlling valsartan impurities, wherein the valsartan impurities comprise the following components: triphenylnickel chloride, tetrahydrofuran solvent, o-chlorobenzonitrile, nitrogen, ethyl acetate, hydrochloric acid solution, sodium hydroxide concentration, saturated saline, anhydrous sodium sulfate, isopropanol, N-hexane, N-bromosuccinimide, dibenzoyl peroxide, carbon tetrachloride, anhydrous methanol, thionyl chloride, anhydrous diethyl ether, diisopropylethylamine, dimethylformamide, chloromethyl, anhydrous ethanol, dichloromethane, valeryl chloride, sodium azide, chlorotrifluoromethyltin, xylene, and acetonitrile solution.
The hydrolysis reaction is to add ethyl acetate and hydrochloric acid solution, and the raw materials comprise, by weight, 11 parts of ethyl acetate and 10 parts of hydrochloric acid solution.
The organic layer was washed by adding sodium hydroxide and saturated brine, 11 parts of sodium hydroxide, and 10 parts of saturated brine.
The 4 '-bromomethyl-2-cyanobiphenyl is composed of 11 parts of 2' -cyano-4-methylbiphenyl, 8 parts of N-bromosuccinimide, 1 part of dibenzoyl peroxide and 68 parts of carbon tetrachloride.
The valsartan impurity comprises N- [ (2 '-cyano-biphenyl-4-yl) methyl ] -N-valeryl-L-valine methyl ester, sodium azide, chlorotrifluoromethane and xylene, 4 parts of N- [ (2' -cyano-biphenyl-4-yl) methyl ] -N-valeryl-L-valine methyl ester, 2 parts of sodium azide, 2 parts of chlorotrifluoromethane tin and 3 parts of xylene.
The method for controlling the valsartan impurity comprises the following steps:
s1, firstly, placing triphenylnickel chloride, o-chlorobenzonitrile and nitrogen in a molar ratio of 1;
s2, taking another reaction vessel, putting 2' -cyano-4-methylbiphenyl, N-bromosuccinimide, dibenzoyl peroxide and carbon tetrachloride in a molar ratio of 11;
s3, adding L-valine and anhydrous methanol in a molar ratio of 1;
s4, then placing 2 'cyano-4-methyl biphenyl, L-valine methyl ester hydrochloride, diisopropylethylamine and dimethylformamide into a reactor beaker, heating to 80 ℃, continuously stirring to ensure that the reaction time is 4 hours, cooling to room temperature, adding purified water, stirring, extracting and combining with chloromethyl to obtain a dichloromethyl base layer, concentrating to dryness, adding absolute ethyl alcohol to dissolve, slowly dropwise adding ethanol to ensure that the pH value of the solution tends to PH =2, separating out a solid, and performing suction filtration to obtain N- [2' cyano-4- (biphenyl-4-yl) monomethyl ] -L-valine methyl ester hydrochloride;
s5, adding sodium carbonate, dichloromethane and valeryl chloride into the prepared N- [2 '-cyano-mono (biphenyl-4-yl) methyl ] -L-valine methyl ester hydrochloride, heating to 40 ℃, fully reacting for 12 hours at constant temperature, washing the solution with water and hydrochloric acid respectively after reaction, washing the solution with water to be neutral, drying the dichloromethane layer with anhydrous sodium sulfate for 10-12 hours, and evaporating the solvent by an evaporation method to obtain N- [ (2' -cyano-biphenyl-4-yl) methyl ] -N-valeryl-L-valine methyl ester;
s6, adding N- [ (2' monocyanobiphenyl-4-yl) monomethyl ] -N-valeryl-L-valine methyl ester, sodium azide, chlorotrifluortin and xylene into a reaction kettle according to a molar ratio of 4;
s7, taking out the valsartan mixed with impurities, adding an ethyl acetate solution, heating to 65 ℃, stirring for 40min, filtering while hot, putting the filtrate into a refrigerating chamber, cooling to 5 ℃, separating out solids, and performing suction filtration to obtain the valsartan and trace valsartan impurities;
and S8, finally, taking out the valsartan and a trace amount of valsartan impurities, putting the valsartan and the trace amount of valsartan impurities into a beaker, adding an acetonitrile solution, diluting and uniformly stirring, wherein the stirring time is 10min, the concentration range of the diluted solution is 0.1 mu g/ml, measuring the content of the valsartan impurities in the solution by adopting a high performance liquid chromatography, and controlling the content of the valsartan impurities by adjusting the concentration, the quality and the reaction time of the preparation raw materials and a method for adding a solvent.
Examples of the experiments
Detection examples 1-3 content of valsartan impurity in a diluted solution was determined by HPLC using a HPLC apparatus, with different concentrations of the diluted solution and different stirring times. The following table is obtained:
| stirring time min | Dilution concentration of μ g/ml | Content of impurities% | |
| Example 1 | 5 | 0.05 | Not detected out |
| Example 2 | 8 | 0.07 | 0.08％ |
| Example 3 | 10 | 0.1 | 0.17％ |
In summary, in the method for controlling valsartan impurities, the synthesis reaction time, temperature and proportion of raw materials are sequentially controlled in the formula for synthesizing and preparing valsartan in the step of preparing and synthesizing the valsartan, so that the generation of the impurity types and contents of the valsartan is controlled, and the problem of residual toxin impurities in the valsartan during synthesis on the raw materials is solved.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (7)
1. A method for controlling valsartan impurities is characterized in that the steps of controlling the valsartan impurities from the synthesis of the valsartan are as follows:
s1, firstly putting triphenylnickel chloride, o-chlorobenzonitrile and nitrogen in a molar ratio of 1
S2, taking another reaction vessel, putting 2' -cyano-4-methyl biphenyl, N-bromosuccinimide, dibenzoyl peroxide and carbon tetrachloride in a molar ratio of 10Crystallizing to obtain 4' -bromomethyl-2-cyanobiphenyl with the structural formula
S3, adding L-valine and anhydrous methanol with a molar ratio of 1 to 5, dropwise adding a dehydrating agent thionyl chloride, wherein the dropping time is 6-7 hours, the content of the thionyl chloride is one tenth of the adding amount of the anhydrous methanol, keeping the temperature for 20-24 hours after the full reaction of the thionyl chloride, concentrating and evaporating the methanol and the acid gas, adding anhydrous ether into the residual solution, separating out a solid compound, putting the solid compound into a refrigerating chamber, cooling to 5 ℃, and filtering to prepare L-valine methyl ester hydrochloride, wherein the structural formula of the L-valine methyl ester hydrochloride is as follows
S4, then placing 2 '-cyano-4-methyl biphenyl, L-valine methyl ester hydrochloride, diisopropylethylamine and dimethylformamide into a reactor beaker, heating to 80 ℃, continuously stirring for 2-4 hours of reaction time, cooling to room temperature, adding purified water, stirring, extracting and combining with chloromethyl to obtain dichloromethyl base, concentrating to dryness, adding absolute ethyl alcohol for dissolving, slowly dropwise adding ethanol to ensure that the pH value of the solution tends to PH =2, precipitating solids, and performing suction filtration to obtain N- [2' -cyano-4- (biphenyl-4-yl) methyl]-L-valine methyl ester hydrochloride having the structural formula
S5, then reacting the N- [2' -monocyanomono (biphenyl-4-yl) monomethyl radical thus obtained]Adding sodium carbonate, dichloromethane and valeryl chloride into L-valine methyl ester hydrochloride, heating to 40 ℃, fully reacting for 10-12h at constant temperature, washing the solution with water and hydrochloric acid respectively after the reaction, washing the solution with water to be neutral, drying the dichloromethane layer with anhydrous sodium sulfate for 10-12h, evaporating the solvent by an evaporation method to obtain N- [ (2' -cyano-biphenyl-4-yl) monomethyl]-N-valeryl-L-valine methyl ester with the structural formula
S6, and then reacting N- [ (2' -monocyanobiphenyl-4-yl) methyl]-N-valeryl-L-valine methyl ester, sodium azide, tributyltin chloride and xylene in a molar ratio range of 1]Stirring sodium hydroxide solution with the same mass as N-valeryl-L-valine methyl ester for 10-12h, standing for layering, separating lower layer liquid, slowly adding hydrochloric acid until the solution is acidified to PH =2, separating out solid, extracting the solid with ethyl acetate for layering, drying an ethyl acetate dissolved layer with anhydrous sodium sulfate for 10-12h, evaporating the ethyl acetate by a reduced pressure evaporation method, and separating out to obtain the valsartan mixed with impurities, wherein the structural formula of the valsartan is shown in the specification
S7, taking out the valsartan mixed with impurities, adding an ethyl acetate solution, heating to 65 ℃, stirring for 30-40min, filtering while hot, putting the filtrate into a refrigerating chamber, cooling to 5 ℃ to separate out solids, and performing suction filtration to obtain the valsartan and trace valsartan impurities;
and S8, finally, taking out the valsartan and a trace amount of valsartan impurities, putting the valsartan and a trace amount of valsartan impurities into a beaker, adding an acetonitrile solution, diluting and uniformly stirring for 5-10min, wherein the concentration range of the diluted solution is 0.05-0.1 microgram/ml, measuring the content of the valsartan impurities in the solution by adopting a high performance liquid chromatography, and controlling the content of the valsartan impurities by adjusting the concentration, the quality and the reaction time of the preparation raw materials and the method adopted by adding the solvent.
2. The method for controlling valsartan impurity according to claim 1, characterized in that: valsartan and valsartan impurity preparation raw materials comprise triphenylnickel chloride, tetrahydrofuran solvent, o-chlorobenzonitrile, nitrogen, ethyl acetate, hydrochloric acid solution, sodium hydroxide concentration, saturated saline water, anhydrous sodium sulfate, isopropanol, N-hexane, N-bromosuccinimide, dibenzoyl peroxide, carbon tetrachloride, anhydrous methanol, thionyl chloride, anhydrous ether, diisopropylethylamine, dimethylformamide, chloromethyl, anhydrous ethanol, dichloromethane, valeryl chloride, sodium azide, tributyltin chloride, xylene and acetonitrile solution.
3. The method of controlling the valsartan impurity of claim 1, wherein: at room temperature of 25 deg.C, the purity of triphenylnickel chloride is 99.9%, and the density of tetrahydrofuran solvent is 0.89g/cm 3 The density of o-chlorobenzonitrile is 1.18g/cm 3 The density of nitrogen was 1.25g/L and the density of ethyl acetate was 0.902g/cm 3 The concentration of the hydrochloric acid solution is 20 percent, the concentration of the sodium hydroxide solution is 52 percent, the concentration of the saturated saline is 26.4 percent, the molar mass of the anhydrous sodium sulfate is 142g/mol, the concentration is 0.2mol/L, the purity of the isopropanol is 99 percent, and the concentration of normal hexane is 180mg/cm 3 The density of the N-bromosuccinimide is 2.097g/cm 3 Density of dibenzoyl peroxide 1.16g/cm 3 At a concentration of 0.1mg/cm 3 The concentration of carbon tetrachloride is 0.063mg/L, the purity of anhydrous methanol is 99.9%, and the density of thionyl chloride is 1.638g/cm 3 The concentration is 0.21mg/L, the purity of the anhydrous ether is 99.5 percent, and the density of the diisopropylethylamine is 0.776g/cm 3 Purity of 99.9%, purity of dimethylformamide of 99.9%, density of chloromethyl group of 0.916g/cm 3 The concentration is 280mg/cm 3 The concentration of absolute ethyl alcohol is 98 percent, and the density of dichloromethane is 1.325g/cm 3 Purity of 99.5%, density of valeryl chloride of 1.016g/cm 3 Purity of 98% and density of sodium azide of 1.846g/cm 3 The concentration is 0.02 percent, and the density of the chlorotrifluoromethyltin is 1.2g/cm 3 The purity is 99 percent, the concentration of the dimethylbenzene is 278mg/L, and the density of the acetonitrile solution is 0.776g/cm 3 The concentration was 70mg/L.
4. The method for controlling valsartan impurity according to claim 1, characterized in that:the 2' -monocyano4-methylbiphenyl was a white crystalline powder having a density of 1.17g/cm 3 (ii) a The 4' monobromomethyl-2-cyanobiphenyl is a valsartan genotoxin impurity with the density of 1.43g/cm 3 The purity is 99 percent; the L-valine methyl ester hydrochloride is an organic compound which is white crystalline powder at room temperature and has the purity of 98%.
5. The method for controlling valsartan impurity according to claim 1, characterized in that: the N- [2' -cyanomono (biphenyl-4-yl) monomethyl group]The L-valine methyl ester hydrochloride is also called valsartan secondary amine methyl ester, is an ash white crystal at normal temperature, has stable property and has the concentration of 99.9 percent; the N- [ (2' -cyanobiphenyl-4-yl) monomethyl group]-N-valeryl-L-valine methyl ester, also known as valsartan acylate, is a condensate of valsartan with a density of 1.1g/cm 3 The valsartan is also named as N-valeryl-N- [ [2'- (1H-tetrazole-5-yl) [1,1' -biphenyl]-4-yl]Methyl radical]L-valine as a white crystalline powder having a density of 1.212g/cm 3 。
6. The method of controlling the valsartan impurity of claim 1, wherein: the high performance liquid chromatography adopts a high performance liquid chromatography instrument HPLC which accords with the accuracy of the national drug administration to measure, and the high performance liquid chromatography instrument consists of a liquid storage device, a pump, a sample injector, a chromatographic column, a detector and a recorder.
7. The method for controlling valsartan impurity according to claim 1, wherein the substance chromatographic conditions for detecting valsartan and trace valsartan impurity by high performance liquid chromatography specifically using size exclusion chromatography are as follows;
high performance liquid chromatography instrument: HPLC
And (3) chromatographic column: 100 mm. Times.3.0 mm. Times.1.8. Mu.g
Detection wavelength: 250nm of
Flow rate: 1.0ml/min
Column temperature: 60 deg.C
Detecting the sample introduction amount: 2.5. Mu.l
Operating time: 15-20min.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101585784A (en) * | 2009-07-13 | 2009-11-25 | 北京赛科药业有限责任公司 | A kind of method of purification of losartan side chain compound |
| CN108623497A (en) * | 2018-07-13 | 2018-10-09 | 上海新埠医药科技有限公司 | A kind of preparation method of 2- Cyano-4 '-methylbiphenyls |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101585784A (en) * | 2009-07-13 | 2009-11-25 | 北京赛科药业有限责任公司 | A kind of method of purification of losartan side chain compound |
| CN108623497A (en) * | 2018-07-13 | 2018-10-09 | 上海新埠医药科技有限公司 | A kind of preparation method of 2- Cyano-4 '-methylbiphenyls |
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| AVELINO CORMA: "Polyethyleneglycol as scaffold and solvent for reusable C–C coupling homogeneous Pd catalysts", 《JOURNAL OF CATALYSIS》 * |
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