CN113354574B - Synthesis method of sodium picosulfate - Google Patents
Synthesis method of sodium picosulfate Download PDFInfo
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- CN113354574B CN113354574B CN202110392738.7A CN202110392738A CN113354574B CN 113354574 B CN113354574 B CN 113354574B CN 202110392738 A CN202110392738 A CN 202110392738A CN 113354574 B CN113354574 B CN 113354574B
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- sodium picosulfate
- picosulfate
- alkaline substance
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- 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 57
- 229960005077 sodium picosulfate Drugs 0.000 title claims abstract description 56
- 238000001308 synthesis method Methods 0.000 title description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 31
- 239000000126 substance Substances 0.000 claims abstract description 20
- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical compound C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229930185605 Bisphenol Natural products 0.000 claims abstract description 13
- -1 2-picolyl Chemical group 0.000 claims abstract description 12
- 238000001914 filtration Methods 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- KHOITXIGCFIULA-UHFFFAOYSA-N Alophen Chemical compound C1=CC(OC(=O)C)=CC=C1C(C=1N=CC=CC=1)C1=CC=C(OC(C)=O)C=C1 KHOITXIGCFIULA-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229960000503 bisacodyl Drugs 0.000 claims abstract description 7
- 238000010791 quenching Methods 0.000 claims abstract description 3
- 230000000171 quenching effect Effects 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 47
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 21
- 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 claims description 20
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 238000006277 sulfonation reaction Methods 0.000 claims description 3
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical compound O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 239000004280 Sodium formate Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 2
- 235000019254 sodium formate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 abstract description 8
- 230000007547 defect Effects 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 41
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
- 239000007787 solid Substances 0.000 description 31
- 229910052757 nitrogen Inorganic materials 0.000 description 19
- 238000010992 reflux Methods 0.000 description 14
- 238000001816 cooling Methods 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 230000001276 controlling effect Effects 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 238000011010 flushing procedure Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 230000001376 precipitating effect Effects 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 230000000630 rising effect Effects 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 238000009776 industrial production Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000012043 crude product Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- ISPYQTSUDJAMAB-UHFFFAOYSA-N 2-chlorophenol Chemical compound OC1=CC=CC=C1Cl ISPYQTSUDJAMAB-UHFFFAOYSA-N 0.000 description 2
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 2
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 210000002429 large intestine Anatomy 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 1
- 229910000838 Al alloy Inorganic materials 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- UEYBBSUJHVLZKR-UHFFFAOYSA-N acetonitrile sulfurochloridic acid Chemical compound C(C)#N.ClS(=O)(=O)O UEYBBSUJHVLZKR-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000013872 defecation Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000008141 laxative Substances 0.000 description 1
- 229940125722 laxative agent Drugs 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a synthetic method of sodium picosulfate, which comprises the following steps: adding bisacodyl into an organic solvent, adding an alkaline substance for reaction, then adjusting the pH value, and filtering to obtain 4,4' - (2-picolyl) bisphenol; adding 4,4' - (2-picolyl) bisphenol into a reaction solvent, adding an alkaline substance, and then adding a sulfonating reagent for reaction; after the reaction is finished, quenching, extracting, concentrating and recrystallizing to obtain a crude sodium picosulfate product; and recrystallizing the crude sodium picosulfate product again to obtain a qualified sodium picosulfate product. The invention has the advantages of simple process route, simpler operation, higher yield and the like from the industrial point of view, and the intermediate produced by the method has high purity, and can easily obtain the sodium picosulfate meeting pharmacopoeia requirements, so as to solve the defects caused by the prior art.
Description
Technical Field
The invention relates to the field of medicine preparation, in particular to a synthetic method of sodium picosulfate.
Background
Sodium picosulfate (Sodium Picosulfate), also called sodium picosulfate, is a clinically common laxative agent, has a unique action mode, generates active ingredient diphenols after being metabolized by enzymes generated by colonic flora, can directly treat large intestine mucosa, promote intestinal peristalsis, inhibit water absorption in intestinal tracts, and shows diarrhea guiding effect;
The sodium picosulfate has mild diarrhea guiding effect, and is suitable for various constipation, postoperative auxiliary defecation, promotion of excretion after administration of contrast agent, preoperative intestinal canal content elimination, preoperative treatment for large intestine examination (endoscope), intestinal canal content elimination and the like;
The chemical name of the sodium picosulfate is 4,4' - (pyridine-2-ylmethylene) diphenyl disulfate sodium salt monohydrate, the medicine is developed by Italian DeAngeli company at first, then introduced and developed by Japanese emperor pharmaceutical company, and the commercial license is obtained by Laxoberon in 1980 and 5 months;
The preparation methods of the sodium picosulfate reported in the current literature mainly comprise the following steps:
method one (patent CN105175317 a):
Taking 2-chlorophenol and 2-pyridylaldehyde as raw materials, performing condensation reaction, then reducing by nickel-aluminum alloy to obtain 4,4' - (2-pyridylmethyl) bisphenol, performing sulfuric acid esterification reaction by chlorosulfonic acid, and adding sodium hydroxide for post-treatment to obtain sodium picosulfate. However, the condensation of 2-chlorophenol with 2-pyridylaldehyde inevitably produces isomeric byproducts of 4,4' - (2-pyridylmethyl) bisphenol, which are difficult to remove, resulting in lower purity of the final product;
method two (patent CN105294544B, CN105884678 a):
Condensing phenol and 2-pyridine formaldehyde, then carrying out sulfuric acid esterification reaction on phenolic hydroxyl by chlorosulfonic acid, and finally adding sodium hydroxide to form salt to obtain sodium picosulfate. In the patent CN105294544B, a heterogeneous reaction of phenol and pyridylaldehyde is performed in a solvent-free environment, and under a low-temperature reaction system, the reactant is relatively viscous, and the stirring is inconvenient, so that the requirement on production equipment is high. While patent CN105884678a uses chloroform as solvent to solve the problem of uneven reaction, the subsequent purification process is complex and the production cost is high;
Method three (patent US 2827465):
taking 4', 4' -dimethoxy diphenyl acetonitrile and 2-bromopyridine as raw materials, performing nucleophilic substitution reaction to obtain 4', 4' -dimethoxy diphenyl- (2-pyridine) -acetonitrile, refluxing with 48% hydrobromic acid to hydrolyze cyano and remove methyl, obtaining 4', 4' -dimethoxy diphenyl- (2-pyridine) -acetamide, heating and refluxing in a potassium carbonate aqueous solution to obtain 4,4' - (2-picolyl) bisphenol, performing sulfuric acid esterification reaction with chlorosulfonic acid, and adding sodium hydroxide for post-treatment to obtain sodium picosulfate. The synthesis method is complex in operation, raw materials are not easy to obtain, and the method is not suitable for industrial production.
Disclosure of Invention
The invention aims to solve the technical problems that the existing synthesis method is complex in operation, raw materials are not easy to obtain and not suitable for industrial production, and the invention provides the synthesis method of the sodium picosulfate.
The invention provides the following technical scheme for solving the technical problems:
a synthetic method of sodium picosulfate, which comprises the following steps:
Step 1: adding bisacodyl into an organic solvent, adding an alkaline substance for reaction, then adjusting the pH value, and filtering to obtain 4,4' - (2-picolyl) bisphenol (a compound with a structural formula P-1);
step 2: adding 4,4' - (2-picolyl) bisphenol (compound with structural formula P-1) into a reaction solvent, adding an alkaline substance, and then adding a sulfonating reagent for reaction; after the reaction is finished, quenching, extracting, concentrating and recrystallizing to obtain a crude sodium picosulfate product;
Step 3: recrystallizing the crude sodium picosulfate product again to obtain a qualified sodium picosulfate product;
The reaction formula of the method is as follows:
The synthetic method of the sodium picosulfate comprises the following steps that in the step 1, the reaction condition after adding the alkaline substance is that the temperature is 20-50 ℃, and the time for dropwise adding the alkaline substance is 1-2 hours;
the alkaline substance is one or more of sodium hydroxide, potassium hydroxide, sodium acetate and sodium formate, preferably sodium hydroxide;
The organic solvent is selected from one or more of methanol, ethanol, isopropanol, acetonitrile and water, preferably ethanol and water.
The acidic substance for regulating the pH value is one or more of sulfuric acid, hydrochloric acid, hydrobromic acid and hydrofluoric acid, preferably hydrochloric acid.
In the above synthetic method of sodium picosulfate, in the step 2, 4' - (2-picolyl) bisphenol is added into a reaction solvent, and an alkaline substance is added;
the sulfonating reagent is one or more of chlorosulfonic acid and sulfur trioxide pyridine. The sulfonation reagent is one or more of chlorosulfonic acid and sulfur trioxide pyridine, and is preferably chlorosulfonic acid solution;
The reaction solvent is selected from one or more of N, N-dimethylformamide, acetonitrile, dichloromethane and tetrahydrofuran, and is preferably acetonitrile;
The alkaline substance is selected from one or more of triethylamine, pyridine and diethylamine, preferably pyridine.
The synthesis method of the sodium picosulfate comprises the following steps of:
Dropwise adding chlorosulfonic acid into the reaction solvent at the temperature of 0-30 ℃ for 10-30min;
the reaction solvent is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile and N, N-dimethylformamide, preferably acetonitrile;
the alkali is one or more selected from pyridine, triethylamine and diethylamine, preferably pyridine, acetonitrile is adopted as a solvent, and pyridine is used as alkali, so that the technical scheme is a major technical breakthrough and is specifically expressed as follows: the acetonitrile is used for diluting chlorosulfonic acid, so that the reaction process is easy to control, the post-treatment is simple and environment-friendly, the use amount of pyridine is reduced, and the material cost is reduced.
The synthesis method of the sodium picosulfate comprises the following steps of dropwise adding chlorosulfonic acid solution in the step 2 for reaction at the temperature of-50 ℃ to 0 ℃ for 1-2 hours;
In the step 2, after adding a sulfonating reagent for reaction, adding alkali to adjust the pH value to 7-8, and then using an organic solvent for extraction and retaining a water layer;
The alkali is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and sodium bicarbonate, preferably sodium carbonate;
the organic solvent is selected from one or more of dichloromethane, ethyl acetate and methyl tertiary butyl ether, preferably dichloromethane.
In the above method for synthesizing sodium picosulfate, the recrystallization solvent in step 2 and step 3 is one or more selected from methanol, ethanol, isopropanol and water, preferably ethanol and water.
In the production process of 4,4' - (2-picolyl) bisphenol (P-1) adopted in the method for synthesizing sodium picosulfate, bisacodyl is taken as a raw material, ethanol and water which are solvent systems for reaction are taken as alkali, sodium hydroxide is taken as alkali, so that the reaction time is shortened, the reaction yield is improved, and the product purity is improved; in the production process of sodium picosulfate (API), the sulfonation reaction condition is changed, acetonitrile is used as a solvent, chlorosulfonic acid is used as a sulfonating agent, the price is low, more impurities can not be generated in the reaction, and the post-reaction treatment is simple.
The technical scheme provided by the synthetic method of the sodium picosulfate provided by the invention has the following technical effects:
the novel method for synthesizing the sodium picosulfate is developed, the total yield of the whole synthesis route is 46.80%, the yield is stable, the reaction process is easy to control, and the industrial production is easy to realize;
the reaction condition is optimized, the operation steps are simplified, particularly the post-treatment of the reaction is simplified, all the steps are considered in priority from the production perspective, and the reaction time is shortened;
the 4,4' - (2-picolyl) bisphenol (P-1) produced by the synthetic method of the sodium picosulfate has the appearance of white solid, the total purity reaches 99.7 percent, the sodium picosulfate (API) produced by the method has the appearance of white solid, the single impurity control is less than 0.10 percent, the total purity of the product reaches 99.8 percent, and the requirements of pharmacopoeia can be completely met;
Therefore, the invention not only can improve the yield and quality of the whole process, save the material cost and optimize the process production process, but also provides a more excellent large-scale production method for the sodium picosulfate, and can be well applied to industrial production;
compared with a method for preparing sodium picosulfate with the patent application number of CN105175317A, the method has the advantages of shorter reaction steps, higher yield and higher purity;
compared with the preparation method of the high-purity sodium picosulfate with the patent application number of CN105294544B, the preparation method has the advantages of shorter reaction steps and higher yield;
Compared with a sodium picosulfate intermediate and a preparation method of sodium picosulfate, which are disclosed by the invention, the preparation method has the advantages that the reaction process is simpler, the operation is more convenient, and solvents with larger harm to human bodies, such as chloroform, are avoided;
Compared with a method for preparing sodium picosulfate with the patent application number of US2827465, the method is simple to operate, easy to obtain raw materials and more suitable for industrial production.
Drawings
FIG. 1 is a High Performance Liquid Chromatography (HPLC) of sodium picosulfate (API) prepared in example 1 of the present invention.
Detailed Description
The following description of the present invention will be made clearly and fully, and it is apparent that the embodiments described are some, but not all, of the embodiments of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The compounds or reagents used in the examples below are all commercial compounds or reagents, unless otherwise specified.
The Chinese paraphrasing of the abbreviations of the present invention: TLC: thin layer chromatography.
Example 1:
The reaction scheme for example 1 is as follows:
Adding bisacodyl (200 g,1.0 eq) into 95% ethanol (1000 mL), dropwise adding 3mol/L sodium hydroxide aqueous solution (830 mL,4.5 eq) under stirring, controlling the temperature to be 30-40 ℃ for about 2 hours, stirring at room temperature for 2 hours after the dropwise adding is finished, TLC detecting reaction, decompressing and distilling half liquid (900 mL) after the reaction is complete, adding water (800 mL,40 v/w) into the rest liquid, adding active carbon (10 g,0.05 w/w), stirring for 30 minutes, and carrying out suction filtration; dropwise adding 3mol/L hydrochloric acid (480 mL) into the filtrate under stirring at normal temperature, leading pH to be=5-6, stirring at normal temperature for 30min, filtering, flushing a filter cake with water (1000 mL,5 v/w), and drying the solid at 50 ℃ in vacuum for 16 hours to obtain white solid P-1 (151.5 g,98.7% yield);
Dropwise adding chlorosulfonic acid (189.07 g,3.0 eq) into acetonitrile (450 mL,3.0 v/w) under the protection of nitrogen, controlling the temperature to be 0-10 ℃ for 30min, adding p-1 (150.0 g,1.0 eq) into acetonitrile (1050 mL,7.0 v/w) under the protection of nitrogen, stirring, controlling the temperature to be-20 ℃, adding anhydrous pyridine (220.14 mL,5.0 eq), dropwise adding an acetonitrile chlorosulfonate solution at 0 ℃ at-30 ℃ to-20 ℃ for 1.5h, keeping the temperature to-20 ℃ for 30min, slowly rising to room temperature, stirring for 18 h at room temperature, pouring the reaction solution into ice water (4500 mL,30 v/w) under the protection of nitrogen, stirring for 20-30min, naturally rising to room temperature, stirring, adding sodium carbonate (about 724 g) in batches to adjust the pH=7.8 (7-8), extracting with Dichloromethane (DCM) (1500 mL,10 v/w) four times, and reserving a water layer; concentrating the water layer under reduced pressure, adding the dried solid into 95% ethanol (4500 mL,30 v/w), stirring and heating, adding active carbon (15 g,0.1 v/w) after reflux, refluxing for 30min, and vacuum filtering while hot; stirring under the protection of nitrogen, cooling filtrate to room temperature, cooling to 0-5 ℃, keeping the temperature for 4 hours, and precipitating a large amount of white solid; suction filtration under nitrogen protection, flushing with 95% ethanol (170 mL,1.0 v/w), drying the solid at 50℃for 16 hours under vacuum to give a white solid (170.17 g,64.7% yield);
adding 95% ethanol (3400 mL,20 v/w) into the crude product (170 g,1.0 eq), stirring and heating, adding active carbon (8.5 g,0.05 v/w) after starting reflux, refluxing for 30min, and filtering while the mixture is hot; stirring under nitrogen protection, cooling filtrate to room temperature, cooling to 0-5deg.C, maintaining temperature for 4 hr, precipitating a large amount of white solid, vacuum filtering under nitrogen protection, washing with 95% ethanol (170 mL,1.0 v/w), and drying the solid at 50deg.C for 16 hr to obtain white solid (129.4 g,73.3% yield) to obtain sodium picosulfate (API), the High Performance Liquid Chromatography (HPLC) of which is shown in figure 1.
Example 2:
The reaction scheme for example 2 is as follows:
Adding bisacodyl (200 g,1.0 eq) into 95% methanol (1000 mL), dropwise adding 3mol/L sodium hydroxide aqueous solution (830 mL,4.5 eq) under stirring, controlling the temperature to 40-50 ℃ for about 1 hour, stirring at room temperature for 1-2 hours after the dropwise adding is finished, performing TLC detection reaction, decompressing and distilling off half of liquid (900 mL) after the reaction is finished, adding water (800 mL,40 v/w) into the rest liquid, adding active carbon (10 g,0.05 w/w), stirring for 30min, and performing suction filtration; 3mol/L sulfuric acid (240 mL) is added dropwise to the filtrate under stirring at normal temperature, pH=5-6, stirring is carried out at normal temperature for 30min, suction filtration is started, filter cakes are washed with water (1000 mL,5 v/w), and the solid is dried in vacuum at 50 ℃ for 16 hours to obtain white solid P-1 (151.7 g,98.8% yield);
Dropwise adding chlorosulfonic acid (252.10 g,4.0 eq) into tetrahydrofuran (450 mL,3.0 v/w) under the protection of nitrogen, controlling the temperature to be 10-20 ℃ for 20min, adding P-1 (150.0 g,1.0 eq) into tetrahydrofuran (1050mL, 7.0 v/w) under the protection of nitrogen, stirring, controlling the temperature to be-20 ℃, adding triethylamine (383.13 g,7.0 eq), dropwise adding chlorosulfonic acid solution at 0 ℃ at-50 ℃ to-30 ℃ for 2h, keeping the temperature to-30 ℃ for 30min, slowly rising to room temperature, stirring for 18 h at room temperature, after the reaction is completed, pouring the reaction solution into ice water (4500 mL,30 v/w), stirring for 20-30min, naturally rising to room temperature, stirring, adding sodium bicarbonate (about 1296 g) in batches, adjusting the pH=7.8 (7-8), extracting with ethyl acetate (1500 mL,10 v/w) four times, evaporating a water layer, and drying under reduced pressure, and preserving the water layer; ethanol (750 mL,5 v/w) is added into the evaporated solid, stirring is carried out for 10min, reduced pressure evaporation is carried out, the evaporated solid is added into 95% ethanol (4500 mL,30 v/w), stirring and heating are carried out, active carbon (15 g,0.1 v/w) is added after reflux is started, and after reflux is carried out for 30min, suction filtration is carried out while the solid is still hot; stirring under the protection of nitrogen, cooling filtrate to room temperature, cooling to 0-5 ℃, keeping the temperature for 4 hours, and precipitating a large amount of white solid; suction filtration under nitrogen protection, flushing with 95% ethanol (150 mL,1.0 v/w), drying the solid at 50℃for 16 hours under vacuum to give a white solid (172.13 g,66.1% yield);
adding 95% ethanol (3400 mL,20 v/w) into the crude product (170 g,1.0 eq), stirring and heating, adding active carbon (8.5 g,0.05 v/w) after starting reflux, refluxing for 30min, and filtering while the mixture is hot; stirring under nitrogen protection, cooling the filtrate to room temperature, cooling to 0-5 ℃ and maintaining the temperature for 4h, precipitating a large amount of white solid, filtering under nitrogen protection, flushing with 95% ethanol (170 ml,1.0 v/w), and drying the solid at 50 ℃ for 16 h under vacuum to obtain white solid (121.3 g,68.71% yield).
Example 3:
The reaction scheme for example 3 is as follows:
Adding bisacodyl (200 g,1.0 eq) into 95% ethanol (1000 mL), dropwise adding 3mol/L potassium hydroxide aqueous solution (830 mL,4.5 eq) under stirring, controlling the temperature to be 20-30 ℃ for about 1 hour, stirring at room temperature for 1-2 hours after the dropwise adding is finished, performing TLC detection reaction, decompressing and distilling half liquid (900 mL) after the reaction is finished, adding water (800 mL,40 v/w) into the rest liquid, adding active carbon (10 g,0.05 w/w), stirring for 30min, and performing suction filtration; dropwise adding 3mol/L hydrochloric acid (480 mL) into the filtrate under stirring at normal temperature to ensure that the pH is=5-6, stirring at normal temperature for 30min, starting suction filtration, flushing a filter cake with water (1000 mL,5 v/w), and drying the solid at 50 ℃ in vacuum for 16 hours to obtain white solid P-1 (151.6 g,98.8% yield);
Dropwise adding chlorosulfonic acid (157.56 g,2.5 eq) into acetonitrile (450 mL,3.0 v/w) under nitrogen protection, controlling the temperature to be 20-30 ℃ for 10min, adding P-1 (150.0 g,1.0 eq) into acetonitrile (1050mL, 7.0 v/w) under nitrogen protection, stirring, controlling the temperature to be 0 ℃, adding triethylamine (217.95 mL,5.0 eq), dropwise adding chlorosulfonic acid solution at 0 ℃ at-20 ℃ to 0 ℃ for 2h, keeping the temperature to be 0 ℃ for 30min, slowly rising to room temperature, stirring for 18h at room temperature, after the TLC detection reaction is completed, pouring the reaction solution into ice water (450 mL,30 v/w), stirring for 20-30min, naturally rising to room temperature, stirring, adding sodium carbonate (about 725 g) in batches to adjust the pH=7.8 (7-8), extracting with methyl tertiary butyl ether (1500 mL,10 v/w) four times, concentrating the water layer under reduced pressure; adding the evaporated solid into 95% ethanol (4500 mL,30 v/w), stirring and heating, adding active carbon (15 g,0.1 v/w) after starting reflux, refluxing for 30min, and filtering while hot; stirring under the protection of nitrogen, cooling filtrate to room temperature, cooling to 0-5 ℃, keeping the temperature for 4 hours, and precipitating a large amount of white solid; suction filtration under nitrogen protection, flushing with 95% ethanol (170 mL,1.0 v/w), drying the solid at 50℃for 16 hours under vacuum to give a white solid (171.33 g,65.8% yield);
adding 95% ethanol (3400 mL,20 v/w) into the crude product (170 g,1.0 eq), stirring and heating, adding active carbon (8.5 g,0.05 v/w) after starting reflux, refluxing for 30min, and filtering while the mixture is hot; stirring under nitrogen protection, cooling the filtrate to room temperature, cooling to 0-5 ℃ and maintaining the temperature for 4h, precipitating a large amount of white solid, filtering under nitrogen protection, flushing with 95% ethanol (170 ml,1.0 v/w), and drying the solid at 50 ℃ for 16 h under vacuum to obtain white solid (122.3 g,69.3% yield).
In conclusion, the synthetic method of the sodium picosulfate has the advantages of simple process route, simpler operation, higher yield and the like from the industrial point of view, and the intermediate produced by the method has high purity and can easily obtain the sodium picosulfate meeting the pharmacopoeia requirements.
The foregoing describes specific embodiments of the invention. It is to be understood that the invention is not limited to the specific embodiments described above, wherein devices and structures not described in detail are to be understood as being implemented in a manner common in the art; numerous variations, changes, or substitutions of light can be made by one skilled in the art without departing from the spirit of the invention and the scope of the claims.
Claims (10)
1. A method for synthesizing sodium picosulfate, which is characterized by comprising the following steps:
step1: adding bisacodyl into an organic solvent, adding an alkaline substance to react at room temperature, then adjusting the pH value, and filtering to obtain 4,4' - (2-picolyl) bisphenol, wherein the organic solvent is methanol or ethanol;
Step2: adding 4,4' - (2-picolyl) bisphenol into a reaction solvent, adding an alkaline substance, and then adding a sulfonating reagent for reaction; after the reaction is finished, quenching, extracting, concentrating and recrystallizing to obtain a crude sodium picosulfate product;
Step 3: recrystallizing the crude sodium picosulfate product again to obtain a qualified sodium picosulfate product;
The reaction formula of the method is as follows:
。
2. The method for synthesizing sodium picosulfate according to claim 1, wherein in step 1, the alkaline substance is added dropwise for 1-2 hours;
The alkaline substance is one or more of sodium hydroxide, potassium hydroxide, sodium acetate and sodium formate;
the acidic substance for regulating the pH value is one or more of sulfuric acid, hydrochloric acid, hydrobromic acid and hydrofluoric acid.
3. The method for synthesizing sodium picosulfate as defined in claim 2, wherein in step 1, the alkaline substance is sodium hydroxide; the acidic substance for regulating the pH value is hydrochloric acid.
4. A method for synthesizing sodium picosulfate as defined in claim 1,2 or 3, wherein in step 2, 4' - (2-picolyl) bisphenol is added to the reaction solvent and a basic material is added;
The reaction solvent is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile and N, N-dimethylformamide;
the alkaline substance is one or more of triethylamine, pyridine and diethylamine;
the sulfonating reagent is one or more of chlorosulfonic acid and sulfur trioxide pyridine.
5. The method for synthesizing sodium picosulfate as defined in claim 4, wherein in step 2, the sulfonation reagent is chlorosulfonic acid solution, and the chlorosulfonic acid solution is prepared by the following steps:
Dropwise adding chlorosulfonic acid into the reaction solvent at the temperature of 0-30 ℃ for 10-30min;
the reaction solvent is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile and N, N-dimethylformamide.
6. The method of synthesizing sodium picosulfate according to claim 4, wherein in step 2, the alkaline substance is pyridine.
7. The method for synthesizing sodium picosulfate according to claim 5, wherein the condition of the reaction by dropwise adding the chlorosulfonic acid solution in the step 2 is a temperature of-50 ℃ to 0 ℃ and the dropwise adding time is 1-2 hours.
8. A process for the synthesis of sodium picosulfate as defined in claim 1, wherein,
In the step 2, after adding a sulfonating reagent for reaction, adding alkali to adjust the pH value to 7-8, and then using an organic solvent for extraction and retaining a water layer;
the alkali is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and sodium bicarbonate;
The organic solvent is one or more of ethyl acetate, dichloromethane and methyl tertiary butyl ether.
9. A method for synthesizing sodium picosulfate as defined in claim 8, wherein,
The alkali is sodium carbonate;
The organic solvent is dichloromethane.
10. The method of synthesizing sodium picosulfate according to claim 1, wherein the recrystallization solvent in step 2 and step 3 is one or more selected from the group consisting of methanol, ethanol, isopropanol, and water.
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