CN114477231A - Preparation process of high-purity sodium nitroprusside bulk drug - Google Patents
Preparation process of high-purity sodium nitroprusside bulk drug Download PDFInfo
- Publication number
- CN114477231A CN114477231A CN202210009167.9A CN202210009167A CN114477231A CN 114477231 A CN114477231 A CN 114477231A CN 202210009167 A CN202210009167 A CN 202210009167A CN 114477231 A CN114477231 A CN 114477231A
- Authority
- CN
- China
- Prior art keywords
- product
- nitroprusside
- reaction
- stirring
- heating
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229940083618 sodium nitroprusside Drugs 0.000 title claims abstract description 71
- 239000003814 drug Substances 0.000 title claims abstract description 35
- 229940079593 drug Drugs 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- XEYBHCRIKKKOSS-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide Chemical compound [Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N XEYBHCRIKKKOSS-UHFFFAOYSA-N 0.000 title claims abstract 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 88
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 49
- YEESUBCSWGVPCE-UHFFFAOYSA-N azanylidyneoxidanium iron(2+) pentacyanide Chemical compound [Fe++].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.N#[O+] YEESUBCSWGVPCE-UHFFFAOYSA-N 0.000 claims abstract description 44
- 229960002460 nitroprusside Drugs 0.000 claims abstract description 44
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims abstract description 30
- 235000017557 sodium bicarbonate Nutrition 0.000 claims abstract description 30
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 29
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims abstract description 27
- 229910000365 copper sulfate Inorganic materials 0.000 claims abstract description 25
- 239000000276 potassium ferrocyanide Substances 0.000 claims abstract description 17
- XOGGUFAVLNCTRS-UHFFFAOYSA-N tetrapotassium;iron(2+);hexacyanide Chemical compound [K+].[K+].[K+].[K+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] XOGGUFAVLNCTRS-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229960000583 acetic acid Drugs 0.000 claims abstract description 15
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 15
- 239000013078 crystal Substances 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 239000000047 product Substances 0.000 claims description 68
- 238000003756 stirring Methods 0.000 claims description 62
- 238000010438 heat treatment Methods 0.000 claims description 59
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 59
- 239000007787 solid Substances 0.000 claims description 45
- 239000000706 filtrate Substances 0.000 claims description 38
- 238000005406 washing Methods 0.000 claims description 32
- 238000001816 cooling Methods 0.000 claims description 31
- 239000012065 filter cake Substances 0.000 claims description 31
- 239000000243 solution Substances 0.000 claims description 27
- 239000002244 precipitate Substances 0.000 claims description 25
- 239000008213 purified water Substances 0.000 claims description 21
- 239000007788 liquid Substances 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 15
- 239000010949 copper Substances 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 13
- 235000019441 ethanol Nutrition 0.000 claims description 11
- 239000011790 ferrous sulphate Substances 0.000 claims description 11
- 235000003891 ferrous sulphate Nutrition 0.000 claims description 11
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 11
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- 239000012085 test solution Substances 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 238000005070 sampling Methods 0.000 claims description 7
- 239000006228 supernatant Substances 0.000 claims description 7
- 238000001291 vacuum drying Methods 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 5
- PECOKVKJVPMJBN-UHFFFAOYSA-N disodium;iron(4+);nitroxyl anion;pentacyanide Chemical compound [Na+].[Na+].[Fe+4].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].O=[N-] PECOKVKJVPMJBN-UHFFFAOYSA-N 0.000 claims description 5
- OVFCVRIJCCDFNQ-UHFFFAOYSA-N carbonic acid;copper Chemical compound [Cu].OC(O)=O OVFCVRIJCCDFNQ-UHFFFAOYSA-N 0.000 claims description 4
- 229910000009 copper(II) carbonate Inorganic materials 0.000 claims description 4
- 239000011646 cupric carbonate Substances 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 17
- 230000008569 process Effects 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000001514 detection method Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 238000013341 scale-up Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract 1
- SPBWMYPZWNFWES-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide;dihydrate Chemical compound O.O.[Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N SPBWMYPZWNFWES-UHFFFAOYSA-N 0.000 description 54
- 239000012535 impurity Substances 0.000 description 11
- 229910052802 copper Inorganic materials 0.000 description 8
- 238000002390 rotary evaporation Methods 0.000 description 8
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 7
- -1 Sodium nitroferricyanide dihydrate Chemical compound 0.000 description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 5
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 5
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 5
- 229910002651 NO3 Inorganic materials 0.000 description 4
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- UTYXJYFJPBYDKY-UHFFFAOYSA-N tetrapotassium;iron(2+);hexacyanide;trihydrate Chemical compound O.O.O.[K+].[K+].[K+].[K+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] UTYXJYFJPBYDKY-UHFFFAOYSA-N 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 238000007034 nitrosation reaction Methods 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 230000002861 ventricular Effects 0.000 description 2
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 description 1
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 1
- 206010063083 Chronic left ventricular failure Diseases 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010078321 Guanylate Cyclase Proteins 0.000 description 1
- 102000014469 Guanylate cyclase Human genes 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- OKUKPTPBWZBYSX-UHFFFAOYSA-N dipotassium;azanylidyneoxidanium;iron(2+);pentacyanide Chemical compound [K+].[K+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N OKUKPTPBWZBYSX-UHFFFAOYSA-N 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01C—AMMONIA; CYANOGEN; COMPOUNDS THEREOF
- C01C3/00—Cyanogen; Compounds thereof
- C01C3/08—Simple or complex cyanides of metals
- C01C3/12—Simple or complex iron cyanides
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2006/00—Physical properties of inorganic compounds
- C01P2006/80—Compositional purity
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Toxicology (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of chemical drug synthesis, and particularly discloses a preparation process of a high-purity sodium nitroprusside bulk drug, which comprises the following steps: s1, reacting potassium ferrocyanide with concentrated nitric acid to generate a product 1 nitroprusside; s2, reacting the product 1 nitroprusside with copper sulfate to generate a product 2; s3, reacting the product 2 with sodium bicarbonate; after sodium bicarbonate is added in the step S3 for reaction, glacial acetic acid is added to adjust the pH value to 5-7, and then absolute ethyl alcohol is added for further purification to precipitate red sodium nitroprusside crystals; the obtained product has purity of 99.6% (calculated on dry product) by detection, meets the requirements related to pharmacopeia, and can be used as raw material medicine. The method has the advantages of simple process, high product yield, good purity, mild and controllable reaction process, economic and easily-purchased raw materials and suitability for process scale-up production.
Description
Technical Field
The invention belongs to the field of chemical drug synthesis, and particularly discloses a preparation process of a high-purity sodium nitroprusside bulk drug.
Background
Sodium nitroprusside, formula C5H4FeN6Na2O3(ii) a Molecular weight: 297.95, the structural formula is as follows:
sodium nitroprusside (Sodium nitroprusside dihydrate), chemically known as Sodium nitroferricyanide dihydrate, is a potent dilator acting directly on the arteriovenous vascular bed. The composition has direct dilating effect on resistance and volume blood vessel, and has effect on afterload greater than nitroglycerin, so as to reduce left ventricular filling pressure and increase cardiac output. Sodium nitroprusside is more rapidly and strongly efficacious than furosemide in acute decompensation of chronic left ventricular failure patients. The action mechanism is the same as that of nitrate, and the nitrate can enable vascular endothelial cells to release NO and activate guanylate cyclase, increase the intracellular cGMP level and dilate blood vessels. The specific type of hemodynamic changes and the underlying pathological basis may help in the selection of drugs. The short-term intravenous drip of sodium nitroprusside is preferably selected for patients with obviously abnormal pump function, increased left ventricular filling pressure and obviously increased peripheral vascular resistance, reduced cardiac output and normal or increased arterial pressure. The half-life of sodium nitroprusside is extremely short. The action is maintained for only 5-15 min, so the curative effect should be maintained by intravenous drip. It is first converted by erythrocytes to cyanide and then by the enzyme rhodanese in the liver to the end metabolite thiocyanate. The thiocyanic acid is discharged from the kidney, and the half-life period of the patient with normal renal function is 4-7 days. Patients with renal failure have an accumulation property. If the dosage is too large, the metabolite thiocyanate in the blood is too high, and poisoning easily occurs.
In order to ensure the safety of clinical medication, the content of sodium nitroprusside is limited in the pharmacopoeia, which is stipulated in the Chinese pharmacopoeia (2020 th edition), and contains Na calculated as a dry product2Fe(CN)5NO should not be less than 99.0%. However, the purity of sodium nitroprusside prepared by the methods of the prior published documents is not high, so that a preparation method of high-purity sodium nitroprusside needs to be provided to solve the problem that the sodium nitroprusside prepared by the prior art is not high in purity.
The patent application with publication number CN110615448A discloses a synthesis process of sodium nitroprusside (sodium nitrosoferricyanide), which comprises performing nitrosation reaction on potassium ferrocyanide and nitric acid to obtain nitroprusside, and adding sodium carbonate to react to obtain sodium nitroprusside. The reaction formula is as follows:
K4[Fe(CN)6]+6HNO3→H2[Fe(CN)5(NO)]+CO2+NH4NO3+4KNO3
H2[Fe(CN)5(NO)]+Na2CO3→Na2[Fe(CN)5(NO)]+CO2+H2O
the method has the advantages of short reaction steps, but a large amount of inorganic salt impurities such as potassium nitrate, ammonium nitrate, sodium nitrate and the like are generated in the reaction process, are difficult to remove, and are complicated to operate.
The patent application with publication number CN103159233A discloses a synthesis process of sodium nitroprusside (sodium nitrosoferricyanide), which takes potassium nitrosoferricyanide and copper sulfate pentahydrate as reaction raw materials to react under proper conditions to generate copper nitrosoferricyanide, which then reacts with sodium bicarbonate to generate sodium nitroprusside. The reaction formula is as follows:
K2[Fe(CN)5(NO)]+CuSO4→Cu[Fe(CN)5(NO)]+K2SO4
Cu[Fe(CN)5(NO)]+2NaHCO3→Na2[Fe(CN)5(NO)]+CuCO3+CO2+H2O
the potassium nitroprusside used as the raw material in the method is expensive and not easy to purchase, and is not suitable for industrial production, and the purity of the prepared sodium nitroprusside is only 96 percent and can not meet the requirements of Chinese pharmacopoeia (not less than 99.0 percent).
The patent application with publication number CN110342541A discloses a synthesis process of sodium nitroprusside (sodium nitrosoferricyanide), wherein potassium ferrocyanide and nitric acid are subjected to nitrosation reaction to obtain nitroprusside, the nitroprusside is reacted with copper sulfate pentahydrate to obtain nitroprusside, and the nitroprusside is reacted with sodium bicarbonate to obtain the sodium nitroprusside. The reaction formula is as follows:
K4[Fe(CN)6]+6HNO3→H2[Fe(CN)5(NO)]+CO2+NH4NO3+4KNO3
H2[Fe(CN)5(NO)]+CuSO4→Cu[Fe(CN)5(NO)]+H2SO4
Cu[Fe(CN)5(NO)]+2NaHCO3→Na2[Fe(CN)5(NO)]+CuCO3+CO2+H2O
the method has simple reaction, the copper nitroprusside precipitate generated in the second step can effectively remove inorganic salt impurities generated in the first step, but the finally obtained sodium nitroprusside contains unreacted sodium bicarbonate which is difficult to remove, so that the content of the sodium nitroprusside is lower than the content requirement in Chinese pharmacopoeia (not lower than 99.0%). Aiming at the problems in the prior art, the invention discloses a preparation process of a high-purity sodium nitroprusside bulk drug, which has the advantages of less impurities and high yield in the preparation process, improves the product purity, is higher than the content requirement in Chinese pharmacopoeia, reduces the production cost and has wide application market prospect.
Disclosure of Invention
Aiming at the defects, the invention discloses a preparation process of a high-purity sodium nitroprusside bulk drug, which has the advantages of high product yield, good purity, mild and controllable reaction process, economic and easily-purchased raw materials and suitability for process amplification production.
The technical scheme of the invention is as follows:
a preparation process of a high-purity sodium nitroprusside bulk drug comprises the following steps:
s1, reacting potassium ferrocyanide with concentrated nitric acid to generate a product 1 nitroprusside;
s2, reacting the product 1 nitroprusside with copper sulfate to generate a product 2 nitroprusside;
s3, reacting the product 2 with sodium bicarbonate to generate sodium nitroprusside;
the reaction scheme is shown as the following formula:
①K4[Fe(CN)6]+6HNO3＝H2[Fe(CN)5(NO)]+4KNO3+NH4NO3+CO2
②H2[Fe(CN)5(NO)]+CusO4＝Cu[Fe(CN)5(NO)]+H2SO4
③Cu[Fe(CN)5(NO)]+2NaHCO3＝Na2[Fe(CN)5(NO)]+CuCO3+CO2+H2O
and (3) after sodium bicarbonate is added in the step S3 for reaction, glacial acetic acid is added to adjust the pH value to 5-7, and then absolute ethyl alcohol is added to further purify and precipitate red sodium nitroprusside crystals.
Further, in the preparation process of the high-purity sodium nitroprusside bulk drug, the step S1 specifically includes:
1) adding purified water into potassium ferrocyanide, heating and stirring to dissolve;
2) slowly dropwise adding concentrated nitric acid while stirring, and heating to 65-75 ℃ for reaction after dropwise adding of the concentrated nitric acid is finished;
3) stirring at 65-75 ℃ for reaction, sampling every 1-3 hours, and dripping into a freshly prepared ferrous sulfate test solution, wherein the reaction is complete when a gray-green precipitate is generated and a blue precipitate is not generated; the reaction progress is detected in real time, the full reaction is ensured, and the yield is improved.
Further, in the preparation process of the high-purity sodium nitroprusside bulk drug, the step S1 further includes:
4) cooling to room temperature, adding anhydrous sodium carbonate in batches until no bubbles are generated, and stirring for 0.5-1.5 h; and redundant nitric acid is neutralized, so that the influence on the next reaction is prevented, and the generation of impurities is reduced.
Further, in the preparation process of the high-purity sodium nitroprusside bulk drug, the step S2 specifically includes:
1) heating purified water to 45-55 ℃, adding copper sulfate solid, stirring to dissolve, heating the product 1 nitroprusside obtained in the step S1 to about 45-55 ℃, and then dropwise adding a copper sulfate solution while the solution is hot;
2) after the dropwise addition is finished, heating to 65-75 ℃ for reaction;
3) standing overnight, layering, discarding supernatant, centrifuging lower solid-liquid mixture, washing filter cake with pure water for several times until the washing liquid is colorless and has pH of 5-7;
4) and drying the filter cake at the temperature of 45-55 ℃ to constant weight to obtain a product 2 nitro-p-copper crude product, wherein the yield of the step is over 92%.
Further, in the preparation process of the high-purity sodium nitroprusside bulk drug, the step S3 specifically includes:
1) adding the product 2 and purified water into a reaction kettle, heating to 45-55 ℃, stirring to uniformly disperse the product, and adding sodium bicarbonate solid in batches;
2) after the sodium bicarbonate is added, heating to 65-75 ℃ for reaction, and gradually changing the solution into brown;
3) after the reaction is finished, cooling to room temperature, centrifuging, adding pure water into the filter cake to wash, and combining the filtrate and the washing liquor, wherein the filter cake is brown and the filtrate is red;
4) distilling the obtained filtrate at 65-75 deg.C under reduced pressure to remove part of water, adding glacial acetic acid dropwise under stirring to adjust pH to 5-7, concentrating until near saturation, and filtering if solid appears; the glacial acetic acid is used for neutralizing the redundant sodium bicarbonate, the generated sodium acetate is easier to remove than the sodium bicarbonate, and the product purity is improved.
5) Slightly cooling, adding anhydrous ethanol, separating out solids, filtering, discarding filter residues, distilling under reduced pressure to recover ethanol, further concentrating until solids are separated out, cooling for crystallization, centrifuging to obtain red sodium nitroprusside solid, and vacuum drying to obtain the product. Concentrating to be nearly saturated, adding anhydrous ethanol with the volume twice, separating out impurities firstly, filtering to remove the impurities after the impurities are separated out, performing rotary evaporation on the obtained filtrate to recover the ethanol, concentrating until solids are separated out, cooling and crystallizing, wherein the separated out sodium nitroprusside is reddish brown.
Further, the preparation process of the high-purity sodium nitroprusside raw material medicine comprises the following steps:
s1, reacting potassium ferrocyanide with concentrated nitric acid to generate 1 nitroprusside, which specifically comprises the following steps:
1) adding purified water into potassium ferrocyanide, heating and stirring to dissolve;
2) slowly dropwise adding concentrated nitric acid while stirring, and heating to 65-75 ℃ for reaction after dropwise adding of the concentrated nitric acid is finished;
3) stirring at 65-75 ℃ for reaction, sampling every 1-3 hours, and dripping into a freshly prepared ferrous sulfate test solution, wherein the reaction is complete when a gray-green precipitate is generated and a blue precipitate is not generated;
4) cooling to room temperature, adding anhydrous sodium carbonate in batches until no bubbles are generated, and stirring for 0.5-1.5 h;
s2, reacting the product 1 nitroprusside with copper sulfate to generate a product 2, which specifically comprises:
1) heating purified water to 45-55 ℃, adding copper sulfate solid, stirring to dissolve, heating the product 1 nitroprusside obtained in the step S1 to about 45-55 ℃, and then dropwise adding a copper sulfate solution while the solution is hot;
2) after the dropwise addition is finished, heating to 65-75 ℃ for reaction;
3) standing overnight, layering, discarding supernatant, centrifuging lower solid-liquid mixture, washing filter cake with pure water for several times until the washing liquid is colorless and has pH of 5-7;
4) drying the filter cake at 45-55 ℃ to constant weight to obtain a product 2 nitroprusside crude product;
s3, reacting the product 2 with sodium bicarbonate to generate sodium nitroprusside, which specifically comprises the following steps:
1) adding the product 2 and purified water into a reaction kettle, heating to 45-55 ℃, stirring to uniformly disperse the product, and adding sodium bicarbonate solid in batches;
2) after the sodium bicarbonate is added, heating to 65-75 ℃ for reaction, and gradually changing the solution into brown;
3) after the reaction is finished, cooling to room temperature, centrifuging, adding pure water into the filter cake to wash, and combining the filtrate and the washing liquor, wherein the filter cake is brown and the filtrate is red;
4) distilling the obtained filtrate at 65-75 deg.C under reduced pressure to remove part of water, adding glacial acetic acid under stirring to adjust pH to 5-7, concentrating until it is nearly saturated, and filtering if solid appears;
5) slightly cooling, adding anhydrous ethanol, separating out solids, filtering, discarding filter residues, distilling under reduced pressure to recover ethanol, further concentrating until solids are separated out, cooling for crystallization, centrifuging to obtain red sodium nitroprusside solid, and vacuum drying to obtain the product.
Further, according to the preparation process of the high-purity sodium nitroprusside bulk drug, the total yield of the preparation process is more than 83%.
Furthermore, the high-purity sodium nitroprusside bulk drug prepared by the preparation process of the high-purity sodium nitroprusside bulk drug is obtained.
Furthermore, the purity of the high-purity sodium nitroprusside bulk drug is more than or equal to 99.6%.
According to the technical scheme, the preparation process of the high-purity sodium nitroprusside bulk drug disclosed by the invention has the following beneficial effects:
1. in the step (3) of the step S1, the solution is added dropwise to a freshly prepared ferrous sulfate solution, and the reaction is completed when a grayish green precipitate is generated and a blue precipitate is not generated; the reaction progress can be detected in real time, the reaction is ensured to be sufficient, and the yield is improved.
2. In the step (4) of the step S1, cooling to room temperature, adding anhydrous sodium carbonate in batches until no bubbles are generated, and stirring for 0.5-1.5 h; and redundant nitric acid is neutralized, so that the influence on the next reaction is prevented, and the generation of impurities is reduced.
3. In step S3 (4), the excess sodium bicarbonate is neutralized with glacial acetic acid, and the generated sodium acetate is easier to remove than sodium bicarbonate, thereby improving the product purity.
4. In the step (5) of the step S3, after the solution is concentrated to be nearly saturated, anhydrous ethanol with twice volume is added, at the moment, impurities are separated out firstly, after the impurities are separated out, the impurities are removed by filtering, the obtained filtrate is subjected to rotary evaporation to recover the anhydrous ethanol, the solution is continuously concentrated until solids are separated out, and at the moment, the separated solid is a reddish brown sodium nitroprusside crystal. The yield of the step is more than 90 percent, and the total yield is more than 83 percent.
The purity of the obtained product can reach 99.6 percent (calculated by dry products) through detection, meets the related requirements of pharmacopeia, and can be used as a raw material medicine. The method has the advantages of simple process, high product yield, good purity, mild and controllable reaction process, economic and easily-purchased raw materials and suitability for process scale-up production.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all 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 reagents or instruments used in the examples of the present invention are not indicated by manufacturers, and are all conventional reagent products commercially available.
Example 1
A preparation process of a high-purity sodium nitroprusside bulk drug comprises the following steps:
s1, reacting potassium ferrocyanide with concentrated nitric acid to generate 1 nitroprusside, which specifically comprises the following steps:
1) adding purified water into potassium ferrocyanide, heating and stirring to dissolve;
2) slowly dropwise adding concentrated nitric acid while stirring, and heating to 65 ℃ for reaction after dropwise adding of the concentrated nitric acid is finished;
3) stirring at 65 ℃ for reaction, sampling every 3 hours, and dripping into a freshly prepared ferrous sulfate test solution, wherein the reaction is complete when a grayish green precipitate is generated and a blue precipitate is not generated;
4) cooling to room temperature, adding anhydrous sodium carbonate in batches until no bubbles are generated, and stirring for 0.5 h;
s2, reacting the product 1 nitroprusside with copper sulfate to generate a product 2, which specifically comprises the following steps:
1) heating purified water to 45 ℃, adding copper sulfate solid, stirring to dissolve the copper sulfate solid, heating the product 1 nitroprusside obtained in the step S1 to about 45 ℃, and then dropwise adding a copper sulfate solution while the solution is hot;
2) after the dropwise addition, heating to 65 ℃ for reaction;
3) standing overnight, layering, removing supernatant, centrifuging lower layer solid-liquid mixture, washing filter cake with pure water for several times until the washing liquid is colorless and has pH of 5;
4) drying the filter cake at 45 ℃ to constant weight to obtain a product 2, namely a crude nitroprusside product;
s3, reacting the product 2 with sodium bicarbonate to generate sodium nitroprusside, which specifically comprises the following steps:
1) adding the product 2 and purified water into a reaction kettle, heating to 45 ℃, stirring to uniformly disperse the product, and adding sodium bicarbonate solid in batches;
2) after the sodium bicarbonate is added, heating to 65 ℃ for reaction, and gradually changing the solution into brown;
3) after the reaction is finished, cooling to room temperature, centrifuging, adding pure water into the filter cake for washing, and combining the filtrate and the washing liquid, wherein the filter cake is brown, and the filtrate is red;
4) distilling the obtained filtrate at 65 deg.C under reduced pressure to remove part of water, adding glacial acetic acid under stirring to adjust pH to 5-7, concentrating until it is nearly saturated, and filtering if solid appears;
5) slightly cooling, adding anhydrous ethanol, separating out solid, filtering, discarding residue, distilling under reduced pressure to recover ethanol, centrifuging to obtain red sodium nitroprusside solid, and vacuum drying to obtain the final product.
The total yield is 83.4% by calculation, and the purity is 99.61% by detection according to a pharmacopoeia method.
Example 2
A preparation process of a high-purity sodium nitroprusside bulk drug comprises the following steps:
s1, reacting potassium ferrocyanide with concentrated nitric acid to generate 1 nitroprusside, which specifically comprises the following steps:
1) adding purified water into potassium ferrocyanide, heating and stirring to dissolve;
2) slowly dropwise adding concentrated nitric acid while stirring, and heating to 70 ℃ for reaction after dropwise adding of the concentrated nitric acid is finished;
3) stirring at 70 ℃ for reaction, sampling every 2 hours, and dripping into a freshly prepared ferrous sulfate test solution, wherein the reaction is complete when a grayish green precipitate is generated and a blue precipitate is not generated;
4) cooling to room temperature, adding anhydrous sodium carbonate in batches until no bubbles are generated, and stirring for 1 h;
s2, reacting the product 1 nitroprusside with copper sulfate to generate a product 2, which specifically comprises the following steps:
1) heating purified water to 50 ℃, adding copper sulfate solid, stirring to dissolve the copper sulfate solid, heating the product 1 nitroprusside obtained in the step S1 to about 50 ℃, and then dropwise adding a copper sulfate solution while the solution is hot;
2) after the dropwise addition, heating to 70 ℃ for reaction;
3) standing overnight, layering, removing supernatant, centrifuging lower layer solid-liquid mixture, washing filter cake with pure water for several times until the washing liquid is colorless and has pH of 6;
4) drying the filter cake at 50 ℃ to constant weight to obtain a product 2, namely a nitroprusside crude product;
s3, reacting the product 2 with sodium bicarbonate to generate sodium nitroprusside, which specifically comprises the following steps:
1) adding the product 2 and purified water into a reaction kettle, heating to 50 ℃, stirring to uniformly disperse the product, and adding sodium bicarbonate solid in batches;
2) after the sodium bicarbonate is added, heating to 70 ℃ for reaction, and gradually changing the solution into brown;
3) after the reaction is finished, cooling to room temperature, centrifuging, adding pure water into the filter cake to wash, and combining the filtrate and the washing liquor, wherein the filter cake is brown and the filtrate is red;
4) distilling the obtained filtrate at 70 deg.C under reduced pressure to remove part of water, adding glacial acetic acid under stirring to adjust pH to 6, concentrating until it is nearly saturated, and filtering if solid appears;
5) slightly cooling, adding absolute ethyl alcohol, separating out solid, filtering, discarding filter residue, distilling under reduced pressure to recover ethanol, centrifuging to obtain red sodium nitroprusside solid, and vacuum drying to obtain the product.
The total yield is 83.6% by calculation, and the purity is 99.65% by detection according to a pharmacopoeia method.
Example 3
A preparation process of a high-purity sodium nitroprusside bulk drug comprises the following steps:
s1, reacting potassium ferrocyanide with concentrated nitric acid to generate 1 nitroprusside, which specifically comprises the following steps:
1) adding purified water into potassium ferrocyanide, heating and stirring to dissolve;
2) slowly dropwise adding concentrated nitric acid while stirring, and heating to 75 ℃ for reaction after dropwise adding of the concentrated nitric acid is finished;
3) stirring for reaction at 75 ℃, sampling every 1 hour, and dripping into a freshly prepared ferrous sulfate test solution, wherein the reaction is complete when a grayish green precipitate is generated and a blue precipitate is not generated;
4) cooling to room temperature, adding anhydrous sodium carbonate in batches until no bubbles are generated, and stirring for 1.5 h;
s2, reacting the product 1 nitroprusside with copper sulfate to generate a product 2, which specifically comprises the following steps:
1) heating purified water to 55 ℃, adding copper sulfate solid, stirring to dissolve the copper sulfate solid, heating the product 1 nitroprusside obtained in the step S1 to about 55 ℃, and then dropwise adding a copper sulfate solution while the solution is hot;
2) after the dropwise addition, heating to 75 ℃ for reaction;
3) standing overnight, layering, removing supernatant, centrifuging lower layer solid-liquid mixture, washing filter cake with pure water for several times until the washing liquid is colorless and has pH of 7;
4) drying the filter cake at 55 ℃ to constant weight to obtain a product 2, namely a crude nitroprusside product;
s3, reacting the product 2 with sodium bicarbonate to generate sodium nitroprusside, which specifically comprises the following steps:
1) adding the product 2 and purified water into a reaction kettle, heating to 55 ℃, stirring to uniformly disperse the product, and adding sodium bicarbonate solid in batches;
2) after the sodium bicarbonate is added, heating to 75 ℃ for reaction, and gradually changing the solution into brown;
3) after the reaction is finished, cooling to room temperature, centrifuging, adding pure water into the filter cake for washing, and combining the filtrate and the washing liquid, wherein the filter cake is brown, and the filtrate is red;
4) distilling the obtained filtrate at 75 deg.C under reduced pressure to remove part of water, adding glacial acetic acid under stirring to adjust pH to 7, concentrating until it is nearly saturated, and filtering if solid appears;
5) slightly cooling, adding anhydrous ethanol, separating out solid, filtering, discarding residue, distilling under reduced pressure to recover ethanol, centrifuging to obtain red sodium nitroprusside solid, and vacuum drying to obtain the final product.
The total yield is 83.4% by calculation, and the purity is 99.63% by detection according to a pharmacopoeia method.
Example 4
(1) Adding 1000g (2.367mol) of potassium ferrocyanide trihydrate and 2000g of distilled water into a 110L glass reaction kettle, heating to dissolve the mixture, slowly dropwise adding 1336g (14.205mol) of nitric acid under stirring at 40 ℃, heating to 70 ℃ after dropwise adding, reacting, and monitoring the reaction process by using a ferrous sulfate test solution (when a grayish green precipitate is generated and a blue precipitate is not generated, the reaction is complete). After the reaction is finished, cooling to room temperature, adding 300g of anhydrous sodium carbonate, continuing stirring for 1h, and directly carrying out the step 2 on the reaction liquid.
(2) Step 2
600g (2.4mol) of blue vitriol is dissolved in pure water, and is dripped into the reaction kettle in the last step at room temperature, and the temperature is raised to 70 ℃ for reaction for 3 hours. Centrifuging while hot, washing filter cake with water, and drying to obtain 714g of nitroprusside (the nitroprusside contains three crystal waters), with the yield of 90.3%.
(3) Step 3
Heating the copper nitroprusside and 1428g of pure water to 40 ℃, stirring for 1h, adding 359g of sodium bicarbonate, heating to 70 ℃, and reacting for 1 h. And centrifuging while the mixture is hot, collecting the mixed filtrate and washing liquor, and dropwise adding glacial acetic acid while stirring until the pH value is approximately equal to 6. And (2) carrying out rotary evaporation and concentration on the filtrate until the filtrate is nearly saturated, adding absolute ethyl alcohol, slowly stirring for 3min, centrifuging, carrying out rotary evaporation on the filtrate to recover the ethyl alcohol, continuously concentrating until the filtrate is supersaturated, cooling to 5 ℃ for crystallization for 2h, centrifuging to obtain red crystals, washing with the absolute ethyl alcohol, and drying at the temperature of 20-30 ℃ in vacuum to obtain 573g of sodium nitroprusside with the yield of 90%, wherein the content is 99.6% and the total yield is 81.2% when all items are qualified according to the test of Chinese pharmacopoeia (2020).
Example 5
(1) Adding 1000g (2.367mol) of potassium ferrocyanide trihydrate and 2000g of distilled water into a 110L glass reaction kettle, heating to dissolve the mixture, slowly dropwise adding 1336g (14.205mol) of nitric acid under stirring at 45 ℃, heating to 70 ℃ after dropwise adding, reacting, and monitoring the reaction process by using a ferrous sulfate test solution (when a grayish green precipitate is generated and a blue precipitate is not generated, the reaction is complete). After the reaction, the mixture was cooled to room temperature, 300g of anhydrous sodium carbonate was added, the mixture was stirred for 1 hour, and the reaction mixture was directly subjected to the next step.
(2) Step 2
600g (2.4mol) of blue vitriol is dissolved in pure water, and is dripped into the reaction kettle in the last step at the temperature of 45 ℃, and the temperature is raised to 70 ℃ for reaction for 3 hours. Centrifuging while hot, washing filter cake with water, and drying to obtain 731g of copper nitroprusside (the copper nitroprusside contains three crystal waters), with a yield of 92.5%.
(3) Step 3
Heating 1462g of copper nitroprusside and pure water to 45 ℃, stirring for 1h, adding 368g of sodium bicarbonate, heating to 70 ℃, and reacting for 1 h. Centrifuging while hot, collecting the mixed filtrate and washing liquid, stirring and dropwise adding glacial acetic acid until the pH value is approximately equal to 6. And (2) carrying out rotary evaporation and concentration on the filtrate until the filtrate is nearly saturated, adding absolute ethyl alcohol, slowly stirring for 3min, centrifuging, carrying out rotary evaporation on the filtrate to recover the ethyl alcohol, continuously concentrating until the filtrate is supersaturated, cooling to 5 ℃ for crystallization for 2h, centrifuging to obtain red crystals, washing with the absolute ethyl alcohol, and drying at the temperature of 20-30 ℃ in vacuum to obtain 591g of sodium nitroprusside, wherein the yield is 90.7%, the content is 99.7% and the total yield is 83.9% according to the detection items of Chinese pharmacopoeia (2020 edition).
Example 6
(1) Adding 1000g (2.367mol) of potassium ferrocyanide trihydrate and 2000g of distilled water into a 110L glass reaction kettle, heating to dissolve the mixture, slowly dropwise adding 1336g (14.205mol) of nitric acid under stirring at 50 ℃, heating to 70 ℃ after dropwise adding, reacting, and monitoring the reaction process by using a ferrous sulfate test solution (when a grayish green precipitate is generated and a blue precipitate is not generated, the reaction is complete). After the reaction, the mixture was cooled to room temperature, 300g of anhydrous sodium carbonate was added, the mixture was stirred for 1 hour, and the reaction mixture was directly subjected to the next step.
(2) Step 2
600g (2.4mol) of blue vitriol is dissolved in pure water, and is dripped into the reaction kettle in the last step at the temperature of 45 ℃, and the temperature is raised to 70 ℃ for reaction for 3 hours. Centrifuging while hot, washing filter cakes with water, and drying to obtain 720g of copper nitroprusside (the copper nitroprusside contains three crystal waters), wherein the yield is 91.0%.
(3) Step 3
1440g of nitroprusside and pure water were heated to 45 ℃ and stirred for 1 hour, 453g of sodium bicarbonate was added, and the temperature was raised to 70 ℃ to react for 1 hour. And centrifuging while the mixture is hot, collecting the mixed filtrate and washing liquor, and dropwise adding glacial acetic acid while stirring until the pH value is approximately equal to 6. And (2) carrying out rotary evaporation and concentration on the filtrate until the filtrate is nearly saturated, adding absolute ethyl alcohol, slowly stirring for 3min, centrifuging, carrying out rotary evaporation on the filtrate to recover the ethyl alcohol, continuously concentrating until the filtrate is supersaturated, cooling to 5 ℃ for crystallization for 2h, centrifuging to obtain red crystals, washing with the absolute ethyl alcohol, and drying at the temperature of 20-30 ℃ in vacuum to obtain 574g of sodium nitroprusside, wherein the yield is 89.3%, the sodium nitroprusside is qualified according to various items detected in Chinese pharmacopoeia (2020 edition), the content is 99.2%, and the total yield is 81.3%.
The above examples only show 1 embodiment of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.
Claims (9)
1. A preparation process of a high-purity sodium nitroprusside bulk drug is characterized by comprising the following steps:
s1, reacting potassium ferrocyanide with concentrated nitric acid to generate a product 1 nitroprusside;
s2, reacting the product 1 nitroprusside with copper sulfate to generate a product 2;
s3, reacting the product 2 with sodium bicarbonate to generate sodium nitroprusside;
the reaction scheme is shown as the following formula:
①K4[Fe(CN)6]+6HNO3＝H2[Fe(CN)5(NO)]+4KNO3+NH4NO3+CO2
②H2[Fe(CN)5(NO)]+CusO4＝Cu[Fe(CN)5(NO)]+H2SO4
③Cu[Fe(CN)5(NO)]+2NaHCO3＝Na2[Fe(CN)5(NO)]+CuCO3+CO2+H2O
after sodium bicarbonate is added in the step S3 for reaction, glacial acetic acid is added to adjust the pH value to 5-7, and then absolute ethyl alcohol is added to further purify and precipitate red sodium nitroprusside crystals.
2. The preparation process of a high-purity sodium nitroprusside bulk drug according to claim 1, wherein the step S1 specifically comprises:
1) adding purified water into potassium ferrocyanide, heating and stirring to dissolve;
2) slowly dropwise adding concentrated nitric acid while stirring, and heating to 65-75 ℃ for reaction after dropwise adding of the concentrated nitric acid is finished;
3) stirring at 65-75 deg.C for reaction, sampling every 1-3 hr, and dripping into freshly prepared ferrous sulfate solution to obtain completely reacted product when the grayish green precipitate is formed and the blue precipitate is not formed.
3. The preparation process of a high-purity sodium nitroprusside bulk drug according to claim 2, wherein the step S1 further comprises:
4) cooling to room temperature, adding anhydrous sodium carbonate in batches until no bubbles are generated, and stirring for 0.5-1.5 h.
4. The preparation process of a high-purity sodium nitroprusside bulk drug according to claim 1, wherein the step S2 specifically comprises:
1) heating purified water to 45-55 ℃, adding copper sulfate solid, stirring to dissolve, heating the product 1 nitroprusside obtained in the step S1 to about 45-55 ℃, and then dropwise adding a copper sulfate solution while the solution is hot;
2) after the dropwise addition is finished, heating to 65-75 ℃ for reaction;
3) standing overnight, layering, discarding supernatant, centrifuging lower solid-liquid mixture, washing filter cake with pure water for several times until the washing liquid is colorless and has pH of 5-7;
4) and drying the filter cake at the temperature of 45-55 ℃ to constant weight to obtain a product, namely a 2-nitro-pricopper crude product.
5. The preparation process of a high-purity sodium nitroprusside bulk drug according to claim 1, wherein the step S3 specifically comprises:
1) adding the product 2 and purified water into a reaction kettle, heating to 45-55 ℃, stirring to uniformly disperse the product, and adding sodium bicarbonate solid in batches;
2) after the sodium bicarbonate is added, heating to 65-75 ℃ for reaction, and gradually changing the solution into brown;
3) after the reaction is finished, cooling to room temperature, centrifuging, adding pure water into the filter cake to wash, and combining the filtrate and the washing liquor, wherein the filter cake is brown and the filtrate is red;
4) distilling the obtained filtrate at 65-75 deg.C under reduced pressure to remove part of water, adding glacial acetic acid dropwise while stirring to adjust pH to 5-7, concentrating until near saturation, and filtering if solid appears;
5) slightly cooling, adding anhydrous ethanol, separating out solids, filtering, discarding filter residues, distilling under reduced pressure to recover ethanol, further concentrating until solids are separated out, cooling for crystallization, centrifuging to obtain red sodium nitroprusside solid, and vacuum drying to obtain the product.
6. The preparation process of the high-purity sodium nitroprusside bulk drug according to claim 1, characterized by comprising the following steps:
s1, reacting potassium ferrocyanide with concentrated nitric acid to generate 1 nitroprusside, which specifically comprises the following steps:
1) adding purified water into potassium ferrocyanide, heating and stirring to dissolve;
2) slowly dropwise adding concentrated nitric acid while stirring, and heating to 65-75 ℃ for reaction after dropwise adding of the concentrated nitric acid is finished;
3) stirring at 65-75 ℃ for reaction, sampling every 1-3 hours, and dripping into a freshly prepared ferrous sulfate test solution, wherein the reaction is complete when a gray-green precipitate is generated and a blue precipitate is not generated;
4) cooling to room temperature, adding anhydrous sodium carbonate in batches until no bubbles are generated, and stirring for 0.5-1.5 h;
s2, reacting the product 1 nitroprusside with copper sulfate to generate a product 2, which specifically comprises the following steps:
1) heating purified water to 45-55 ℃, adding copper sulfate solid, stirring to dissolve, heating the product 1 nitroprusside obtained in the step S1 to about 45-55 ℃, and then dropwise adding a copper sulfate solution while the solution is hot;
2) after the dropwise addition is finished, heating to 65-75 ℃ for reaction;
3) standing overnight, layering, discarding supernatant, centrifuging lower solid-liquid mixture, washing filter cake with pure water for several times until the washing liquid is colorless and has pH of 5-7;
4) drying the filter cake at 45-55 ℃ to constant weight to obtain a product 2 nitroprusside crude product;
s3, reacting the product 2 with sodium bicarbonate to generate sodium nitroprusside, which specifically comprises the following steps:
1) adding the product 2 and purified water into a reaction kettle, heating to 45-55 ℃, stirring to uniformly disperse the product, and adding sodium bicarbonate solid in batches;
2) after the sodium bicarbonate is added, heating to 65-75 ℃ for reaction, and gradually changing the solution into brown;
3) after the reaction is finished, cooling to room temperature, centrifuging, adding pure water into the filter cake to wash, and combining the filtrate and the washing liquor, wherein the filter cake is brown and the filtrate is red;
4) distilling the obtained filtrate at 65-75 deg.C under reduced pressure to remove part of water, adding glacial acetic acid under stirring to adjust pH to 5-7, concentrating until it is nearly saturated, and filtering if solid appears;
5) slightly cooling, adding absolute ethyl alcohol, separating out solids, filtering, discarding filter residues, distilling under reduced pressure to recover ethanol, further concentrating until solids are separated out, cooling for crystallization, centrifuging to obtain red sodium nitroprusside solid, and vacuum drying to obtain the product.
7. The process for preparing a high-purity sodium nitroprusside bulk pharmaceutical drug according to any of claims 1 to 6, wherein the total yield of the preparation process is more than 83%.
8. The high-purity sodium nitroprusside bulk drug prepared by the preparation process of the high-purity sodium nitroprusside bulk drug as claimed in any one of claims 1 to 6.
9. The high-purity sodium nitroprusside bulk drug according to claim 8, wherein the purity is greater than or equal to 99.6%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210009167.9A CN114477231A (en) | 2022-01-05 | 2022-01-05 | Preparation process of high-purity sodium nitroprusside bulk drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210009167.9A CN114477231A (en) | 2022-01-05 | 2022-01-05 | Preparation process of high-purity sodium nitroprusside bulk drug |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114477231A true CN114477231A (en) | 2022-05-13 |
Family
ID=81510429
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210009167.9A Pending CN114477231A (en) | 2022-01-05 | 2022-01-05 | Preparation process of high-purity sodium nitroprusside bulk drug |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114477231A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115893447A (en) * | 2022-09-26 | 2023-04-04 | 安徽普利药业有限公司 | Preparation method of high-purity sodium nitroprusside bulk drug |
| CN116354363A (en) * | 2023-03-31 | 2023-06-30 | 重庆晨沃力化工技术有限公司 | A kind of preparation method and production system of sodium nitroprusside |
| WO2025066723A1 (en) * | 2023-09-27 | 2025-04-03 | 海南紫程众投生物科技有限公司 | Improved method for preparing high-purity sodium nitroprusside dihydrate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159233A (en) * | 2011-12-09 | 2013-06-19 | 康普药业股份有限公司 | Sodium nitroprusside synthesis process |
| CN110342541A (en) * | 2019-07-01 | 2019-10-18 | 嘉实（湖南）医药科技有限公司 | A kind of method that the general hydrogen of nitre prepares sodium nitroprussiate |
| CN110615448A (en) * | 2018-06-20 | 2019-12-27 | 四川科瑞德凯华制药有限公司 | Method for preparing sodium nitroprusside |
| US20210301408A1 (en) * | 2018-08-03 | 2021-09-30 | The Board Of Trustees Of The Leland Stanford Junior University | A Method for the Electrochemical Synthesis of Ammonia from Nitrates and Water |
-
2022
- 2022-01-05 CN CN202210009167.9A patent/CN114477231A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159233A (en) * | 2011-12-09 | 2013-06-19 | 康普药业股份有限公司 | Sodium nitroprusside synthesis process |
| CN110615448A (en) * | 2018-06-20 | 2019-12-27 | 四川科瑞德凯华制药有限公司 | Method for preparing sodium nitroprusside |
| US20210301408A1 (en) * | 2018-08-03 | 2021-09-30 | The Board Of Trustees Of The Leland Stanford Junior University | A Method for the Electrochemical Synthesis of Ammonia from Nitrates and Water |
| CN110342541A (en) * | 2019-07-01 | 2019-10-18 | 嘉实（湖南）医药科技有限公司 | A kind of method that the general hydrogen of nitre prepares sodium nitroprussiate |
Non-Patent Citations (2)
| Title |
|---|
| 卡里亚金等: "《纯化学物质的制备》", vol. 1, 山西科学教育出版社, pages: 220 - 221 * |
| 陈伯銮: "硝普钠在麻醉中的应用(文献综述)", 国际外科学杂志, no. 02 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115893447A (en) * | 2022-09-26 | 2023-04-04 | 安徽普利药业有限公司 | Preparation method of high-purity sodium nitroprusside bulk drug |
| CN116354363A (en) * | 2023-03-31 | 2023-06-30 | 重庆晨沃力化工技术有限公司 | A kind of preparation method and production system of sodium nitroprusside |
| WO2025066723A1 (en) * | 2023-09-27 | 2025-04-03 | 海南紫程众投生物科技有限公司 | Improved method for preparing high-purity sodium nitroprusside dihydrate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114477231A (en) | Preparation process of high-purity sodium nitroprusside bulk drug | |
| CN110615448B (en) | Method for preparing sodium nitroprusside | |
| CN101317850B (en) | Sucrose absorption inhibitor | |
| CN110342541A (en) | A kind of method that the general hydrogen of nitre prepares sodium nitroprussiate | |
| CN102491918A (en) | Alanyl glutamine compound and preparation method thereof | |
| CN112979603A (en) | Continuous flow micro-channel synthesis process of flavonoid compound | |
| US5206265A (en) | Iron citrate complex, process for its production, and its pharmaceutical | |
| CN106632548A (en) | High-purity troxerutin and preparation method thereof | |
| CN110627792A (en) | Pentoxifylline compound | |
| WO2021212535A1 (en) | Method for refining benzhexol hydrochloride | |
| EP0532173B1 (en) | Crystalline lactulose trihydrate and a method for its manufacture | |
| CN113800537B (en) | Preparation method of sodium nitroprusside | |
| CN107573385B (en) | Oxaliplatin impurity C and preparation method and application thereof | |
| CN1112418A (en) | Preparing method of calcium ascorbate | |
| CN113173953B (en) | Purification method of high-purity lobaplatin trihydrate for preparing antitumor drugs | |
| JPS6155901B2 (en) | ||
| SU504705A1 (en) | The method of obtaining crystalline silver nitrate | |
| CN111004230A (en) | Thiamine hydrochloride, its synthesis method and medicine | |
| CN111100180A (en) | A kind of synthetic method of octadecyl glycyrrhetinate | |
| CN114368762B (en) | A kind of synthesis method of exogenous 15NO donor sodium nitroprusside-(15NO) | |
| CN115385809A (en) | Preparation method of sarcosine magnesium chelate | |
| CN114369020A (en) | A kind of preparation method of calcium gluconate anhydrous | |
| CN116135832A (en) | Preparation method of ferrous gluconate | |
| CN116395762B (en) | A method for preparing trichlorohexammineruthenium suitable for industrial production | |
| CN115368477B (en) | Preparation method of ferric carboxymaltose with high yield and high iron content |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20220513 |
|
| RJ01 | Rejection of invention patent application after publication |