CN114436946A - Impurity in sodium picosulfate intermediate and preparation method thereof - Google Patents
Impurity in sodium picosulfate intermediate and preparation method thereof Download PDFInfo
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- 239000012535 impurity Substances 0.000 title claims abstract description 49
- GOZDTZWAMGHLDY-UHFFFAOYSA-L sodium picosulfate Chemical compound [Na+].[Na+].C1=CC(OS(=O)(=O)[O-])=CC=C1C(C=1N=CC=CC=1)C1=CC=C(OS([O-])(=O)=O)C=C1 GOZDTZWAMGHLDY-UHFFFAOYSA-L 0.000 title claims abstract description 41
- 229960005077 sodium picosulfate Drugs 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 82
- 239000002253 acid Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 27
- 238000002156 mixing Methods 0.000 claims abstract description 27
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 16
- 230000001681 protective effect Effects 0.000 claims abstract description 16
- 230000003472 neutralizing effect Effects 0.000 claims abstract description 12
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 60
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 28
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- 239000007789 gas Substances 0.000 claims description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000003638 chemical reducing agent Substances 0.000 claims description 15
- 229960000583 acetic acid Drugs 0.000 claims description 14
- 239000012362 glacial acetic acid Substances 0.000 claims description 14
- 239000002841 Lewis acid Substances 0.000 claims description 13
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 13
- 150000007517 lewis acids Chemical class 0.000 claims description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 13
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 238000010992 reflux Methods 0.000 claims description 11
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 claims description 10
- 239000007795 chemical reaction product Substances 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 238000006482 condensation reaction Methods 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Substances ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- 239000012279 sodium borohydride Substances 0.000 claims description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 9
- 239000012320 chlorinating reagent Substances 0.000 claims description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 8
- 239000012445 acidic reagent Substances 0.000 claims description 7
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- 229910006124 SOCl2 Inorganic materials 0.000 claims description 5
- 239000011591 potassium Substances 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 229910021576 Iron(III) bromide Inorganic materials 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- 229910019213 POCl3 Inorganic materials 0.000 claims description 3
- VMPVEPPRYRXYNP-UHFFFAOYSA-I antimony(5+);pentachloride Chemical compound Cl[Sb](Cl)(Cl)(Cl)Cl VMPVEPPRYRXYNP-UHFFFAOYSA-I 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 3
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 9
- 238000011160 research Methods 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000004451 qualitative analysis Methods 0.000 abstract description 3
- 238000004445 quantitative analysis Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000003908 quality control method Methods 0.000 abstract description 2
- 238000012827 research and development Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 75
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- 239000000543 intermediate Substances 0.000 description 16
- -1 4, 4' - (pyridin-2-ylmethylene) bis-phenyl bis-sulfate Sodium salt monohydrate Chemical compound 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 229940125904 compound 1 Drugs 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 238000006386 neutralization reaction Methods 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000010009 beating Methods 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- ADNZLHSXIAPURS-UHFFFAOYSA-N (4-hydroxyphenyl)-pyridin-2-ylmethanone Chemical group C1=CC(O)=CC=C1C(=O)C1=CC=CC=N1 ADNZLHSXIAPURS-UHFFFAOYSA-N 0.000 description 2
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010010774 Constipation Diseases 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Substances OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- FJBUQBPKURBOJF-UHFFFAOYSA-N formyl chloride;pyridine Chemical compound ClC=O.C1=CC=NC=C1 FJBUQBPKURBOJF-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940042126 oral powder Drugs 0.000 description 1
- CTYRPMDGLDAWRQ-UHFFFAOYSA-N phenyl hydrogen sulfate Chemical compound OS(=O)(=O)OC1=CC=CC=C1 CTYRPMDGLDAWRQ-UHFFFAOYSA-N 0.000 description 1
- 229940037790 prepopik Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
Abstract
The invention relates to the technical field of medical biology, in particular to an impurity in a sodium picosulfate intermediate and a preparation method thereof, wherein the impurity has a structure shown in a formula I. The method comprises the steps of mixing a compound with a structure shown in a formula II, phenol and a first acid solution under the condition of protective gas, carrying out nucleophilic substitution reaction, neutralizing by using a first alkaline reagent, and purifying to obtain impurities with a structure shown in a formula I. The impurities with the structure shown in the formula I prepared by the invention have high yield and purity. Meanwhile, the preparation method provided by the invention is simple to operate, strong in controllability and mild in condition, can be used for quality standard establishment and quality control links such as sodium picosulfate process research and development and production, and provides technical support for the safety of sodium picosulfate medication. The method can be used for quality research such as qualitative and quantitative analysis of impurities in sodium picosulfate synthesis, thereby being beneficial to improving the quality of the sodium picosulfate and providing important guiding significance for reducing the medication risk of the sodium picosulfate.
Description
Technical Field
The invention relates to the technical field of medical biology, in particular to an impurity in a sodium picosulfate intermediate and a preparation method thereof.
Background
Sodium picosulfate (Sodium picosulfate) chemical name 4, 4' - (pyridin-2-ylmethylene) bis-phenyl bis-sulfate Sodium salt monohydrate, developed by DeAngeli, italy. The drug is licensed on the market under the trade name of Laxoberon in 5 months in 1980, is widely used in Italy, Germany, Japan, Australia and other countries at present, and is approved by FDA in 7 months in 2012 for sodium picosulfate-magnesia-citric acid oral powder (trade name: Prepopik). The medicine has good clinical effect, little side effect and high safety factor, and has great technical advantage compared with the medicine on the market in China in the aspect of treating constipation as a constipation medicine taken for 1 time per day, and the sodium picosulfate has wide market prospect.
The patent for preparing sodium picosulfate is firstly reported to be GB1152199A, and the related patents are US3528986A, ES860452A and the like, and the specific route is mainly as follows:
according to the analysis of reaction mechanism, in the first step of reaction, phenol is used as an initial raw material, and is subjected to condensation reaction with 2-pyridylaldehyde under the action of sulfuric acid to obtain 4, 4 '- (pyridine-2-ylmethylene) biphenol, and then is subjected to sulfation and alkali neutralization with chlorosulfonic acid to obtain 4, 4' - (pyridine-2-ylmethylene) diphenyl disulfate sodium salt (namely sodium picosulfate anhydride).
Disclosure of Invention
In view of this, the technical problem to be solved by the present invention is to provide an impurity in a sodium picosulfate intermediate and a preparation method thereof, wherein the impurity has a structure shown in formula i; the impurities with the structure shown in the formula I prepared by the invention have high yield and purity.
The invention provides impurities in a sodium picosulfate intermediate, which have a structure shown in a formula I:
the invention also provides a preparation method of impurities in the sodium picosulfate intermediate, which comprises the following steps:
under the condition of protective gas, mixing a compound with a structure shown in a formula II, phenol and a first acid solution, carrying out nucleophilic substitution reaction, neutralizing by using a first alkaline reagent, and purifying to obtain an impurity with a structure shown in a formula I;
preferably, the compound having the structure shown in the formula II is prepared according to the following method:
mixing the compound solution with the structure shown in the formula III with a reducing agent, reacting, neutralizing with an acid reagent, and purifying to obtain a compound with the structure shown in the formula II;
preferably, the compound having the structure shown in the formula III is prepared according to the following method:
under the condition of protective gas, mixing a compound with a structure shown in a formula IV, pyridine-2-formaldehyde and a second acid solution, carrying out condensation reaction, neutralizing by adopting a second alkaline reagent, and purifying to obtain a compound with a structure shown in a formula III;
preferably, the compound with the structure shown in the formula IV is prepared according to the following method:
under the condition of protective gas, mixing pyridine-2-formic acid solution with chlorinated reagent, carrying out reflux reaction, reacting the obtained reaction product with phenol, mixing with Lewis acid, carrying out reaction, and purifying to obtain the compound with the structure shown in formula IV.
Preferably, the protective gas is nitrogen;
the solvent in the pyridine-2-carboxylic acid solution comprises at least one of dichloromethane, chloroform, toluene and benzene;
the chlorinating reagent comprises POCl3、PCl5、SOCl2And t-BuOCl;
the temperature of the reflux reaction is 80-90 ℃, and the time is 0.8-1.2 h.
Preferably, the reaction temperature of the reaction product and phenol is 30-35 ℃, and the reaction time is 2-4 h;
the Lewis acid comprises AlCl3、SbCl5、FeCl3、ZnCl2And FeBr3At least one of;
then mixing with Lewis acid, and reacting at 155-165 ℃ for 3.5-4.5 h.
Preferably, the protective gas is nitrogen;
the second acid liquid comprises at least one of concentrated hydrochloric acid, concentrated sulfuric acid, phosphoric acid and glacial acetic acid;
the mol ratio of the compound with the structure shown in the formula IV to the second acid liquid is 1: 9-15;
the second basic agent comprises at least one of sodium hydroxide solution, sodium bicarbonate solution and sodium methoxide solution;
the condensation reaction is carried out at the temperature of 35-40 ℃ for 9-11 h.
Preferably, the solvent in the compound solution having the structure shown in the formula III comprises at least one of methanol, ethanol, acetonitrile and N, N-dimethylformamide;
the reducing agent comprises at least one of trimethyl borate, potassium borohydride, sodium borohydride, calcium chloride, sodium cyanoborohydride and sodium borohydride acetate;
the molar ratio of the compound with the structure shown in the formula III to the reducing agent is 1: 0.25 to 2;
the reaction temperature is 30-35 ℃, and the reaction time is 5-7 h.
Preferably, the protective gas is nitrogen;
the first acid solution comprises at least one of concentrated hydrochloric acid, concentrated sulfuric acid, phosphoric acid and glacial acetic acid;
the mol ratio of the compound with the structure shown in the formula II to the first acid liquid is 1: 12 to 18;
the temperature of the nucleophilic substitution reaction is 90-110 ℃, and the time is 7-9 h;
the first basic solvent includes at least one of a sodium hydroxide solution, a sodium bicarbonate solution, and a sodium methoxide solution.
According to the research of the preparation method of sodium picosulfate in the background technology, the invention discovers that when a sodium picosulfate intermediate is synthesized, the sodium picosulfate intermediate and a starting material pyridine-2-formaldehyde can generate a new impurity (4- ((4-hydroxyphenyl) (pyridine-2-yl) methyl) -2- (pyridine-2-yl methoxyl) phenol), and the structure of the new impurity is confirmed to be shown as a formula I:
thus, the present invention claims novel impurities of the structure shown in formula I.
The invention also provides a preparation method of impurities in the sodium picosulfate intermediate, which comprises the following steps: under the condition of protective gas, mixing the compound with the structure shown in the formula II, phenol and first acid liquor, carrying out nucleophilic substitution reaction, neutralizing by adopting a first alkaline reagent, and purifying to obtain the impurity with the structure shown in the formula I. The impurities with the structure shown in the formula I prepared by the invention have high yield and purity. Meanwhile, the preparation method provided by the invention is simple to operate, strong in controllability and mild in condition, can be used for quality standard establishment and quality control links such as sodium picosulfate process research and development and production, and provides technical support for the safety of sodium picosulfate medication. The method can be used for quality research such as qualitative and quantitative analysis of impurities in sodium picosulfate synthesis, thereby being beneficial to improving the quality of the sodium picosulfate and providing important guiding significance for reducing the medication risk of the sodium picosulfate.
Drawings
FIG. 1 is a mass spectrum of Compound 1 prepared in example 1 of the present invention;
FIG. 2 is a NMR chart of Compound 1 prepared in example 1 of the present invention;
FIG. 3 is a NMR carbon spectrum of Compound 1 prepared in example 1 of the present invention;
FIG. 4 is a high performance liquid chromatogram of Compound 1 prepared in example 1 of the present invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. 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.
The invention provides impurities in a sodium picosulfate intermediate, which have a structure shown in a formula I:
according to the preparation method of the sodium picosulfate, which is disclosed by the background technology, the invention discovers that a new impurity (4- ((4-hydroxyphenyl) (pyridine-2-yl) methyl) -2- (pyridine-2-yl methoxyl) phenol) is generated by the sodium picosulfate intermediate and a starting material pyridine-2-formaldehyde during synthesis of the sodium picosulfate intermediate, and the structure of the new impurity is shown as a formula I after the structure is confirmed. Thus, the present invention claims novel impurities of the structure shown in formula I.
If this impurity remains, it is further esterified with chlorosulfonic acid in a subsequent reaction and neutralized with a base to give sodium 4- (pyridine-2- (3- (pyridine-2-methoxy) -4- (sulfonyloxy) phenyl) methyl) phenyl sulfate, which may remain in the API, and therefore it is important to control this substitution impurity during the preparation of the intermediate 4, 4' - (pyridine-2-ylmethylene) biphenol.
In order to develop the process research and quality research of sodium picosulfate and improve the safety of sodium picosulfate, researchers first need to obtain sufficient impurity control substances for the systematic adaptability and possible impurity addition of the intermediate analysis method. In the course of research, it was found that, when the synthesis method of the above-mentioned document was used, the amount of the substituted impurity was very small (0.5% or less), it was difficult to obtain a sufficient amount of the reference impurity by separating the reaction solution, and the amount of the impurity could not be increased by changing the reaction conditions of the document. Therefore, the impurity prepared can be used for qualitative and quantitative analysis and other quality researches on derivative impurities in sodium picosulfate intermediates or finished products, is beneficial to improving the quality of the sodium picosulfate, and provides important guiding significance for reducing the medication risk of the sodium picosulfate.
The invention also provides a preparation method of impurities in the sodium picosulfate intermediate, which comprises the following steps:
under the condition of protective gas, mixing a compound with a structure shown in a formula II, phenol and a first acid solution, carrying out nucleophilic substitution reaction, neutralizing by using a first alkaline reagent, and purifying to obtain an impurity with a structure shown in a formula I;
the impurity having the structure shown in formula I is 4- ((4-hydroxyphenyl) (pyridin-2-yl) methyl) -2- (pyridin-2-ylmethoxy) phenol.
The compound with the structure shown in the formula II is 4- (hydroxy (pyridine-2-yl) methyl) -2- (pyridine-2-yl methoxyl) phenol.
In certain embodiments of the invention, the compound having the structure shown in formula ii is prepared according to the following method:
mixing the compound solution with the structure shown in the formula III with a reducing agent, reacting, neutralizing with an acid reagent, and purifying to obtain a compound with the structure shown in the formula II;
the compound with the structure shown in the formula III is (4-hydroxy-3- (pyridine-2-yl methoxy) phenyl) (pyridine-2-yl) ketone.
In certain embodiments of the invention, the compound having the structure of formula iii is prepared according to the following method:
under the condition of protective gas, mixing a compound with a structure shown in a formula IV, pyridine-2-formaldehyde and a second acid solution, carrying out condensation reaction, neutralizing by adopting a second alkaline reagent, and purifying to obtain a compound with a structure shown in a formula III;
the compound with the structure shown in the formula IV is (4-hydroxyphenyl) -pyridine-2-yl ketone.
In certain embodiments of the invention, the compound having the structure shown in formula iv is prepared according to the following method:
under the condition of protective gas, mixing pyridine-2-formic acid solution with chlorinated reagent, carrying out reflux reaction, reacting the obtained reaction product with phenol, mixing with Lewis acid, carrying out reaction, and purifying to obtain the compound with the structure shown in formula IV.
In certain embodiments of the invention, the shielding gas is nitrogen.
In the invention, pyridine-2-formic acid has a structure shown in a formula V;
in certain embodiments of the present invention, the solvent in the pyridine-2-carboxylic acid solution comprises at least one of dichloromethane, chloroform, toluene, and benzene; preferably at least one of dichloromethane and benzene; most preferably benzene. The content of pyridine-2-formic acid in the pyridine-2-formic acid solution is 4.5-5.5 g: 15-25 mL. In certain embodiments, the pyridine-2-carboxylic acid solution has a pyridine-2-carboxylic acid content of 4.92 g: 20 mL.
In certain embodiments of the invention, the chlorinating reagent comprises POCl3、PCl5、SOCl2And t-BuOCl; preferably SOCl2And t-BuOCl; most preferably SOCl2. The dosage ratio of the pyridine-2-formic acid to the chlorinated reagent is4.5-5.5 g: 30-42 mL. In certain embodiments, the pyridine-2-carboxylic acid and the chlorinating agent are used in a ratio of 4.92 g: 36 mL.
In certain embodiments of the present invention, prior to mixing the pyridine-2-carboxylic acid solution with the chlorinating agent, further comprising: stirring the pyridine-2-formic acid solution and cooling to below 0 ℃. In certain embodiments, the pyridine-2-carboxylic acid solution is stirred and cooled to-10 ℃. Since the pyridine-2-carboxylic acid solution mixed with the chlorinating agent gives a strong exotherm and affects the safety of the operation, lowering the temperature can avoid the above problems.
In certain embodiments of the invention, mixing the pyridine-2-carboxylic acid solution with a chlorinating agent comprises: the chlorinated reagent was added dropwise to the pyridine-2-carboxylic acid solution.
In some embodiments of the present invention, the temperature of the reflux reaction is 80-90 ℃ and the time is 0.8-1.2 h. In certain embodiments, the reflux reaction is at a temperature of 85 ℃ for 1.0 h.
After the reflux reaction, obtaining a compound (pyridine formyl chloride) with a structure shown in a formula VI;
in some embodiments of the present invention, after the refluxing reaction, the method further comprises:
and cooling the system to 30-35 ℃, concentrating the obtained reaction liquid to be dry, adding tetrahydrofuran and triethylamine into the obtained concentrate, stirring and cooling to below 0 ℃.
In certain embodiments, after the reflux reaction, the system is cooled to 32 ℃.
In certain embodiments of the present invention, concentrating the resulting reaction solution to dryness means: the resulting reaction solution was concentrated to contain only oil.
In the invention, tetrahydrofuran is used as a solvent, and triethylamine is used as an acid-binding agent. In certain embodiments, the volume ratio of tetrahydrofuran to triethylamine is 40: 6.8.
in certain embodiments of the present invention, reacting the resulting reaction product with phenol comprises:
and dropwise adding phenol into the reaction product, and after dropwise adding, adding DMAP for reaction.
In certain embodiments of the present invention, the molar ratio of the phenol to the pyridine-2-carboxylic acid is from 0.5 to 1.5: 0.5 to 1.5. In certain embodiments, the molar ratio of the phenol to the pyridine-2-carboxylic acid is 1: 1.
in some embodiments of the invention, the reaction product and phenol are reacted at a temperature of 30-35 ℃ for 2-4 hours. In certain embodiments, the reaction product is reacted with phenol at a temperature of 32 ℃ for a period of 3 hours.
In the present invention, the DMAP is a catalyst. In certain embodiments of the invention, the molar ratio of pyridine-2-carboxylic acid to DMAP is 1: 0.1 to 0.2. In certain embodiments, the pyridine-2-carboxylic acid is present in a 1: 0.16.
in certain embodiments of the present invention, the reaction product obtained after reacting with phenol further comprises:
and (3) eluting the reaction solution after the reaction by a chromatography method, concentrating the obtained eluent, recrystallizing the obtained concentrate by using normal hexane, filtering and drying.
In certain embodiments of the present invention, the eluent is ethyl acetate.
In some embodiments of the invention, the temperature of recrystallization is 30-35 ℃ and the time is 3-5 h. In certain embodiments, the recrystallization temperature is 30 ℃ and the time is 4 hours.
And after drying, mixing with Lewis acid, reacting, and purifying to obtain the compound with the structure shown in the formula IV.
In certain embodiments of the invention, the lewis acid comprises AlCl3、SbCl5、FeCl3、ZnCl2And FeBr3At least one of; preferably AlCl3And FeBr3At least one of; AlCl is most preferred3. The molar ratio of the pyridine-2-carboxylic acid to the Lewis acid is 1: 2.50 to 3.00. In some casesIn the examples, the molar ratio of the lewis acid to the pyridine-2-carboxylic acid is 1: 2.75.
in some embodiments of the present invention, the reaction is carried out at a temperature of 155 to 165 ℃ for 3.5 to 4.5 hours by mixing with Lewis acid. In certain embodiments, the reaction is at a temperature of 160 ℃ for a period of 4 hours. The reaction is carried out with stirring.
In some embodiments of the present invention, the reaction further comprises, after mixing with the lewis acid: cooling to 0-10 ℃. In certain embodiments, the temperature is reduced to 5 ℃.
In certain embodiments of the invention, the step of purifying comprises:
and extracting the product solution after the reaction by using a mixed solution of hydrochloric acid and dichloromethane, drying by using anhydrous sodium sulfate, eluting by using a chromatography, concentrating the obtained eluent, and drying to obtain the compound with the structure shown in the formula IV.
In certain embodiments of the present invention, the volume ratio of the hydrochloric acid to the dichloromethane is 40 to 60: 120 to 140. In certain embodiments, the volume ratio of hydrochloric acid to dichloromethane is 50: 130. in certain embodiments, the hydrochloric acid has a mass concentration of 36% to 38%.
In some embodiments of the invention, the eluent for the chromatographic elution includes petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 5-100: 1. in certain embodiments, the petroleum ether and ethyl acetate are in a volume ratio of 20: 1.
and after obtaining the compound with the structure shown in the formula IV, mixing the compound with the structure shown in the formula IV, pyridine-2-formaldehyde and a second acid solution under the condition of protective gas, carrying out condensation reaction, neutralizing by adopting a second alkaline reagent, and purifying to obtain the compound with the structure shown in the formula III.
In certain embodiments of the invention, the shielding gas is nitrogen.
In certain embodiments of the present invention, the molar ratio of the compound having the structure of formula iv to pyridine-2-carbaldehyde is 0.8 to 1.2: 1.4 to 1.8. In certain embodiments, the compound having the structure of formula iv and pyridine-2-carbaldehyde are present in a molar ratio of 1: 1.6.
in certain embodiments of the present invention, the second acid solution comprises at least one of concentrated hydrochloric acid, concentrated sulfuric acid, phosphoric acid, and glacial acetic acid; preferably at least one of concentrated hydrochloric acid, glacial acetic acid and concentrated sulfuric acid; most preferably concentrated hydrochloric acid and glacial acetic acid, wherein the molar ratio of the concentrated hydrochloric acid to the glacial acetic acid is 0.2-0.3: 0.02-0.06 or 0.27: 0.04, wherein the mass concentration of the concentrated hydrochloric acid is 36-38%. The mass concentration of the concentrated sulfuric acid is 98%.
In some embodiments of the present invention, the molar ratio of the compound having the structure represented by formula iv to the second acidic solution is 1: 9-15; preferably 1: 9 to 13, most preferably 1: 9 to 12. In certain embodiments, the compound having the structure of formula iv and the second acid solution are present in a molar ratio of 1: 11 or 1: 9.
in some embodiments of the present invention, the condensation reaction is performed at 35-40 ℃ for 9-11 hours. In certain embodiments, the condensation reaction is at a temperature of 38 ℃ for a period of 10 hours.
In certain embodiments of the present invention, after the condensation reaction, further comprising: cooling to 0-10 ℃. In certain embodiments, the temperature is reduced to 5 ℃.
In certain embodiments of the invention, the second basic agent comprises at least one of sodium hydroxide solution, sodium bicarbonate solution, and sodium methoxide solution; preferably at least one of a sodium hydroxide solution and a sodium bicarbonate solution; most preferred is sodium hydroxide solution. In certain embodiments, the sodium hydroxide solution has a mass concentration of 10% and the solvent is water.
In some embodiments of the invention, the pH value of the solution after neutralization with the second alkaline agent is 6-7. In certain embodiments, the pH of the solution after neutralization with the second alkaline agent is 7.
In certain embodiments of the invention, the step of purifying comprises:
and filtering the neutralized reaction solution, pulping the obtained filter cake at 60-70 ℃ by using a mixed solvent comprising ethyl acetate and methanol, filtering, and drying to obtain the compound with the structure shown in the formula III.
In certain embodiments of the invention, the volume ratio of ethyl acetate to methanol is 1: 2.
in certain embodiments of the invention, the beating time is 2.5-3.5 hours. In certain embodiments, the temperature of the beating is 65 ℃ and the time of the beating is 3 hours.
After the compound with the structure shown in the formula III is obtained, the compound solution with the structure shown in the formula III is mixed with a reducing agent for reaction, and then the compound solution is neutralized by an acid reagent and purified to obtain the compound with the structure shown in the formula II.
In certain embodiments of the present invention, the solvent in the solution of the compound having the structure represented by formula iii comprises at least one of methanol, ethanol, acetonitrile, and N, N-dimethylformamide; preferably at least one of methanol and ethanol, most preferably methanol. The content of the compound with the structure shown in the formula III in the compound solution with the structure shown in the formula III is 4-5.5 g: 30-50 mL. In certain embodiments, the compound solution having the structure of formula iii has a compound having the structure of formula iii present in an amount of 4.8 g: 40 mL.
In certain embodiments of the present invention, the reducing agent comprises at least one of trimethyl borate, potassium borohydride, sodium borohydride, calcium chloride, sodium cyanoborohydride, and sodium borohydride acetate; preferably at least one of potassium borohydride, sodium borohydride and sodium borohydride acetate; most preferred are potassium borohydride and sodium borohydride.
In certain embodiments of the invention, the compound having the structure of formula iii is present in a molar ratio of 1: 0.25 to 2; preferably 1: 0.5 to 1.5; most preferably 1: 0.5 to 1. In certain embodiments, the compound having the structure of formula iii is present in a molar ratio to the reducing agent of 1: 1.
in some embodiments of the present invention, the method further comprises, before mixing the solution of the compound having the structure of formula iii with the reducing agent: and stirring the compound solution with the structure shown in the formula III and cooling to below 0 ℃. In certain embodiments, the solution of the compound having the structure of formula iii is stirred and cooled to-5 ℃. After the compound solution with the structure shown in the formula III is mixed with a reducing agent, a violent heat release phenomenon can be generated, the operation safety is influenced, the problem can be avoided by reducing the temperature, and the generation of non-product impurities is reduced.
In certain embodiments of the present invention, mixing a solution of a compound having a structure represented by formula iii with a reducing agent comprises:
and slowly adding a reducing agent into the compound solution with the structure shown in the formula III, wherein the adding time is controlled to be 5-10 min. In certain embodiments, the time of addition is controlled at 8 min.
In some embodiments of the invention, the reaction temperature is 30-35 ℃ and the reaction time is 5-7 h. In certain embodiments, the reaction is at a temperature of 32 ℃ for 6 hours.
In certain embodiments of the invention, the acidic agent is glacial acetic acid.
In certain embodiments of the invention, the compound having the structure of formula iii is present in a molar ratio to the acidic reagent of 1: 90 to 100. In certain embodiments, the compound having the structure of formula iii is present in a 1: 93.
in certain embodiments of the invention, the step of purifying comprises:
and (3) concentrating the solution neutralized by the acidic reagent, recrystallizing by using a mixed solution of pure water and dichloromethane, filtering, and drying to obtain the compound with the structure shown in the formula II.
In the present invention, concentration is used to remove methanol.
In some embodiments of the invention, in the mixed solution of pure water and dichloromethane, the volume ratio of pure water to dichloromethane is 30-50: 140 to 160. In certain embodiments, the volume ratio of pure water to dichloromethane is 40: 150.
after the compound with the structure shown in the formula II is obtained, the compound with the structure shown in the formula II, phenol and a first acid solution are mixed under the condition of protective gas, nucleophilic substitution reaction is carried out, then a first alkaline reagent is adopted for neutralization, and after purification, impurities with the structure shown in the formula I are obtained.
In certain embodiments of the invention, the shielding gas is nitrogen.
In certain embodiments of the present invention, the compound having the structure represented by formula ii and phenol are present in a molar ratio of 1 to 2: 1 to 2. In certain embodiments, the compound having the structure of formula ii and phenol are present in a molar ratio of 1: 1.5.
in certain embodiments of the invention, the first acid solution comprises at least one of concentrated hydrochloric acid, concentrated sulfuric acid, phosphoric acid, and glacial acetic acid; phosphoric acid is preferred. In certain embodiments, the phosphoric acid has a mass concentration of 83% to 87% or 85% and the concentrated sulfuric acid has a mass concentration of 98%.
The mol ratio of the compound with the structure shown in the formula II to the first acid liquid is 1: 12 to 18; preferably 1: 12 to 15. In certain embodiments, the compound having the structure of formula ii and the first acid solution are present in a molar ratio of 1: 14.6.
in some embodiments of the present invention, the temperature of the nucleophilic substitution reaction is 90-110 ℃ and the time is 7-9 h. In certain embodiments, the nucleophilic substitution reaction is at a temperature of 100 ℃ for a time of 8 hours.
In certain embodiments of the present invention, the nucleophilic substitution reaction further comprises: and cooling to 0-10 ℃, and dropwise adding a mixed solution of pure water and ethyl acetate for extraction. In certain embodiments, the temperature is reduced to 5 ℃. The temperature reduction can avoid the phenomenon of violent heat release after the acid solution is mixed with water, and the safety of the operation is influenced, the problems can be avoided by reducing the temperature, and the generation of non-product impurities is reduced. In certain embodiments, the volume ratio of pure water to ethyl acetate is 30-50: 190-210 or 40: 200.
in the invention, the extracted water phase is neutralized by a first alkaline reagent.
In certain embodiments of the present invention, the first basic solvent comprises at least one of sodium hydroxide solution, sodium bicarbonate solution, and sodium methoxide solution; preferably at least one of a sodium hydroxide solution and a sodium bicarbonate solution; most preferred is sodium hydroxide solution. The mass concentration of the sodium hydroxide solution is 10%, and the solvent is water.
In some embodiments of the present invention, the temperature for neutralization with the first alkaline agent is 0-10 ℃. In certain embodiments, the temperature for neutralization with the first alkaline agent is 5 ℃. The alkali neutralization process is exothermic, and excessive temperatures can produce other impurities that affect the purity of the product, and thus, the temperature range defined herein can avoid the above problems.
In some embodiments of the present invention, the pH of the solution after neutralization with the first alkaline agent is 6-7. In certain embodiments, the pH of the solution after neutralization with the first alkaline agent is 7.
In certain embodiments of the invention, the step of purifying comprises:
and filtering the neutralized reaction solution, pulping the obtained filter cake at 40-50 ℃ by using a mixed solvent comprising ethyl acetate and methanol, filtering, and drying to obtain the impurity with the structure shown in the formula I.
In certain embodiments of the invention, the volume ratio of ethyl acetate to methanol is 1: 1.
in certain embodiments of the invention, the beating time is 2-3 hours. In certain embodiments, the time of beating is 2 hours.
The source of the above-mentioned raw materials is not particularly limited, and the raw materials may be generally commercially available.
In order to further illustrate the present invention, the following examples are provided to describe the preparation method of impurities in a sodium picosulfate intermediate of the present invention in detail, but the present invention should not be construed as limiting the scope of the present invention.
The starting materials used in the following examples are all commercially available.
Example 1
Step 1):
under the protection of nitrogen, in a 250mL three-necked bottle, 4.92g (0.04mol) of pyridine-2-formic acid and 20mL of benzene are stirred and cooled to-10 ℃, 36mL of thionyl chloride is dripped, after dripping is finished, the system is heated to 85 ℃, reflux reaction is carried out for 1.0h, the system is cooled to 32 ℃, reaction liquid is concentrated to be dry, 40mL of tetrahydrofuran and 6.8mL of triethylamine are added into the obtained concentrate, the mixture is stirred and cooled to below 0 ℃, 3.8mL (0.04mol) of phenol is dripped, after dripping is finished, 0.8g (0.0065mol) of DMAP is added, the mixture is stirred and heated to 32 ℃, reaction is carried out for 3.0h, the obtained reaction liquid is eluted by chromatography (eluent: ethyl acetate), the obtained eluent is concentrated to be dry, the concentrate is recrystallized for 4.0h at 30 ℃ by 100mL of normal hexane, filtration and drying are carried out, 14.50g (0.11mol) of AlCl is added3Stirring and heating to 160 ℃ for reaction for 4.0h, cooling to 5 ℃, extracting with a mixture of 50mL of hydrochloric acid (the mass concentration of the hydrochloric acid is 37%) and 130mL of dichloromethane, drying with anhydrous sodium sulfate, and eluting by chromatography (the eluent comprises petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate is 20: 1), concentrating the obtained eluent, and drying to obtain 6.24g of compound 4 (formula IV), namely (4-hydroxyphenyl) -pyridin-2-yl ketone (white solid, yield: 87.9%).
Step 2):
under the protection of nitrogen, 6.20g (0.03mol) of compound 4 (formula IV), 5.12g (0.048mol) of pyridine-2-formaldehyde, 22.3mL (0.27mol) of concentrated hydrochloric acid (37% by mass) and 2.5mL (0.04mol) of glacial acetic acid are added into a 250mL three-necked flask, the mixture is condensed at 38 ℃ for 10.0h, the temperature is reduced to 5 ℃, the pH value is adjusted to 7 by NaOH solution (10% by mass), the mixture is filtered, a filter cake is pulped at 65 ℃ for 3.0h by using a mixed solvent of ethyl acetate and methanol (the volume ratio of the ethyl acetate to the methanol is 1: 2), and the mixture is filtered and dried to obtain 4.85g of compound 5 (formula III), namely, (4-hydroxy-3- (pyridine-2-ylmethoxy) phenyl) (pyridine-2-yl) ketone (light yellow solid, the yield is 50.9%).
Step 3):
to a 250mL three-necked flask, 4.80g (0.015mol) of Compound 5 (formula III) and 40mL of methanol were added and dissolved with stirring, and then the mixture was cooled to-5 ℃ to which 0.56g (0.015mol) of NaBH was slowly added4The reaction was carried out for 8min while the addition time was controlled to 8min, the reaction was allowed to warm to 32 ℃ for 6.0h, neutralized with 80mL (1.40mol) of glacial acetic acid, concentrated to remove methanol, and recrystallized from a mixed solution of 40mL of purified water and 150mL of methylene chloride, filtered, and dried to give 3.32g of Compound 6 (formula II), i.e., 4- (hydroxy (pyridin-2-yl) methyl) -2- (pyridin-2-ylmethoxy) phenol (pale yellow solid, yield: 68.7%).
Step 4):
under the protection of nitrogen, 3.00g (0.010mol) of compound 6 (formula II), 1.42g (0.015mol) of phenol, 9.96mL (0.146mol) of phosphoric acid (85% by mass) are added into a 250mL three-necked flask, the mixture is reacted at 100 ℃ for 8.0h, the temperature is reduced to 5 ℃, 40mL of a mixed solution of pure water and 200mL of ethyl acetate is added dropwise for extraction, an aqueous phase is collected, the pH value is adjusted to 7 by NaOH solution (10% by mass) at 5 ℃, the mixture is filtered, a filter cake is beaten for 2h by 80mL of a mixed solvent of ethyl acetate and methanol (the volume ratio of ethyl acetate to methanol is 1: 1) at 45 ℃, and the mixture is filtered and dried to obtain 0.67g of compound 1 (formula I), namely 4- ((4-hydroxyphenyl) (pyridin-2-yl) methyl) -2- (pyridin-2-ylmethoxy) phenol (white-like solid, the yield is 17.7%).
The mass spectrometry analysis of compound 1 prepared in example 1 is shown in fig. 1. FIG. 1 is a mass spectrum of Compound 1 prepared in example 1 of the present invention.
In fig. 1, ms (esi):
m/z calculated for C24H21N2O3[M+H]:385.43,found 385；C24H20N2O3Na[M+Na]:407.43,found 407。
the results of nmr analysis of compound 1 prepared in example 1 are shown in fig. 2 and 3. Fig. 2 is a nuclear magnetic resonance hydrogen spectrum of compound 1 prepared in example 1 of the present invention, and fig. 3 is a nuclear magnetic resonance carbon spectrum of compound 1 prepared in example 1 of the present invention.
In the context of figure 2, it is shown,1H NMR:(500MHz，DMSO)δ(ppm)9.8702(s，1H)，9.2060(s，1H)，8.4582～8.4198(m，2H)，7.7724～7.6412(m，2H)，7.4403～7.4245(d，J＝7.9Hz，1H)，7.2431～7.1118(m，4H)，6.9399～6.8326(m，3H)，6.6862～6.6272(m，3H)，5.8967(s，2H)，5.3781(s，1H)。
in the context of figure 3, it is shown,13C-NMR:(500MHz，DMSO)δ(ppm)163.66，163.63，155.60，152.69，148.97，147.84，147.83，137.22，136.49，133.91，133.78，130.03，129.97，129.88，128.44，128.3，127.72，123.25，122.28，121.30，115.67，114.91，70.39，70.33，59.79，57.13。
example 2
The differences from example 1 are: the chlorinating reagent thionyl chloride in step 1) of example 1 was replaced by phosphorus oxychloride.
Example 3
The differences from example 1 are: the second acid solution (22.3mL (0.27mol) of concentrated hydrochloric acid and 2.5mL (0.04mol) of glacial acetic acid)) in step 2) of example 1 was replaced with 14.70mL (0.27mol) of concentrated sulfuric acid (98% by mass).
Example 4
The differences from example 1 are: the reducing agent NaBH obtained in step 3) of example 14Substituted by KBH4。
Example 5
The differences from example 1 are: the molar ratio of compound 5 to the acidic reagent glacial acetic acid in step 3) of example 1 was replaced by 1: 13.
example 6
The differences from example 1 are: the molar ratio of compound 6 to the first acid phosphoric acid in step 4) of example 1 was replaced by 1: 14.
example 7
The differences from example 1 are: 80mL of the mixed solvent of ethyl acetate and methanol obtained in step 4) of example 1 (volume ratio of ethyl acetate to methanol is 1: 1) the mixed solvent of ethyl acetate and methanol was replaced with 80mL (volume ratio of ethyl acetate to methanol was 2: 1).
Example 8
The differences from example 1 are: the first acid solution phosphoric acid in step 4) of example 1 was replaced with concentrated sulfuric acid (98% by mass).
Example 9
The samples obtained in examples 1 to 6 were examined by liquid chromatography.
The detection conditions are as follows:
a chromatographic column: agilent ZORBAX RX-C8150X 4.6mm, 5 μm; wavelength: 230 nm; mobile phase A: 0.063mol/LKH2PO4(pH adjusted to 5.00 with phosphoric acid): acetonitrile (2250: 250); mobile phase B: 0.063mol/LKH2PO4(pH adjusted to 5.00 with phosphoric acid): acetonitrile (440: 560); flow rate: 1.5 mL/min; column temperature: gradient elution is carried out at 30 ℃.
FIG. 4 is a high performance liquid chromatogram of Compound 1 prepared in example 1 of the present invention.
The results are shown in Table 1.
Table 1 shows the yield and purity of impurities in sodium picosulfate prepared in the examples of the present invention
| Examples | Purity of | Yield of |
| Example 1 | 99.699％ | 17.7％ |
| Example 2 | 99.052％ | 16.2％ |
| Example 3 | 99.238％ | 15.5％ |
| Example 4 | 99.002％ | 16.7％ |
| Example 5 | 99.122％ | 15.2％ |
| Example 6 | 98.947％ | 16.1％ |
| Example 7 | 98.015％ | 18.3％ |
| Example 8 | 99.415％ | 12.5％ |
As can be seen from Table 1, the sodium picosulfate prepared by the method has the highest impurity yield of 18.3 percent and the highest purity of 99.699 percent, has higher sample yield and purity, and can meet the daily detection and impurity control of large-scale preparation and analysis.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. An impurity in a sodium picosulfate intermediate has a structure shown in formula I:
2. a preparation method of impurities in a sodium picosulfate intermediate comprises the following steps:
under the condition of protective gas, mixing a compound with a structure shown in a formula II, phenol and a first acid solution, carrying out nucleophilic substitution reaction, neutralizing by using a first alkaline reagent, and purifying to obtain an impurity with a structure shown in a formula I;
3. the method of claim 1, wherein the compound having the structure of formula ii is prepared by the following method:
mixing the compound solution with the structure shown in the formula III with a reducing agent, reacting, neutralizing with an acid reagent, and purifying to obtain a compound with the structure shown in the formula II;
4. the method according to claim 3, wherein the compound having the structure of formula III is prepared by the following method:
under the condition of protective gas, mixing a compound with a structure shown in a formula IV, pyridine-2-formaldehyde and a second acid solution, carrying out condensation reaction, neutralizing by adopting a second alkaline reagent, and purifying to obtain a compound with a structure shown in a formula III;
5. the method of claim 4, wherein the compound having the structure of formula iv is prepared according to the following method:
under the condition of protective gas, mixing pyridine-2-formic acid solution with chlorinated reagent, carrying out reflux reaction, reacting the obtained reaction product with phenol, mixing with Lewis acid, carrying out reaction, and purifying to obtain the compound with the structure shown in formula IV.
6. The method according to claim 5, wherein the shielding gas is nitrogen;
the solvent in the pyridine-2-carboxylic acid solution comprises at least one of dichloromethane, chloroform, toluene and benzene;
the chlorinating reagent comprises POCl3、PCl5、SOCl2And t-BuOCl;
the temperature of the reflux reaction is 80-90 ℃, and the time is 0.8-1.2 h.
7. The preparation method according to claim 5, wherein the reaction product and phenol are reacted at 30-35 ℃ for 2-4 h;
the Lewis acid comprises AlCl3、SbCl5、FeCl3、ZnCl2And FeBr3At least one of;
then mixing with Lewis acid, and reacting at 155-165 ℃ for 3.5-4.5 h.
8. The method according to claim 4, wherein the shielding gas is nitrogen;
the second acid liquid comprises at least one of concentrated hydrochloric acid, concentrated sulfuric acid, phosphoric acid and glacial acetic acid;
the mol ratio of the compound with the structure shown in the formula IV to the second acid liquid is 1: 9-15;
the second basic agent comprises at least one of sodium hydroxide solution, sodium bicarbonate solution and sodium methoxide solution;
the condensation reaction is carried out at the temperature of 35-40 ℃ for 9-11 h.
9. The method according to claim 3, wherein the solvent in the solution of the compound having the structure represented by formula III comprises at least one of methanol, ethanol, acetonitrile, and N, N-dimethylformamide;
the reducing agent comprises at least one of trimethyl borate, potassium borohydride, sodium borohydride, calcium chloride, sodium cyanoborohydride and sodium borohydride acetate;
the molar ratio of the compound with the structure shown in the formula III to the reducing agent is 1: 0.25 to 2;
the reaction temperature is 30-35 ℃, and the reaction time is 5-7 h.
10. The method of claim 2, wherein the shielding gas is nitrogen;
the first acid solution comprises at least one of concentrated hydrochloric acid, concentrated sulfuric acid, phosphoric acid and glacial acetic acid;
the mol ratio of the compound with the structure shown in the formula II to the first acid liquid is 1: 12 to 18;
the temperature of the nucleophilic substitution reaction is 90-110 ℃, and the time is 7-9 h;
the first basic solvent includes at least one of a sodium hydroxide solution, a sodium bicarbonate solution, and a sodium methoxide solution.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175317A (en) * | 2015-10-23 | 2015-12-23 | 青岛辰达生物科技有限公司 | Method for preparing sodium picosulfate |
| CN105884678A (en) * | 2014-12-26 | 2016-08-24 | 重庆莱美药业股份有限公司 | Sodium picosulfate intermediate and sodium picosulfate preparation method |
| CN109651238A (en) * | 2019-01-29 | 2019-04-19 | 杭州新博思生物医药有限公司 | A kind of new method preparing picosulfate sodium |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105884678A (en) * | 2014-12-26 | 2016-08-24 | 重庆莱美药业股份有限公司 | Sodium picosulfate intermediate and sodium picosulfate preparation method |
| CN105175317A (en) * | 2015-10-23 | 2015-12-23 | 青岛辰达生物科技有限公司 | Method for preparing sodium picosulfate |
| CN109651238A (en) * | 2019-01-29 | 2019-04-19 | 杭州新博思生物医药有限公司 | A kind of new method preparing picosulfate sodium |
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