CN101849930B - Chemical medicine for treating cardiac and cerebral diseases and its prepn - Google Patents
Chemical medicine for treating cardiac and cerebral diseases and its prepn Download PDFInfo
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- CN101849930B CN101849930B CN2009101332821A CN200910133282A CN101849930B CN 101849930 B CN101849930 B CN 101849930B CN 2009101332821 A CN2009101332821 A CN 2009101332821A CN 200910133282 A CN200910133282 A CN 200910133282A CN 101849930 B CN101849930 B CN 101849930B
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Abstract
The invention discloses a sterile powder sodium hydroxybenzene sulfonate for treating cardio-cerebral diseases and a preparation method thereof, which is characterized in that: according to the weight ratio of 1-3 g: 1.2-6.0 g: 0.5-1.5 g: 0.3-0.9 g, the following raw materials of benzenediol, concentrated sulfuric acid, ethanol, calcium chloride and sodium carbonate are prepared into sterile powder sodium hydroxybenzenesulfonate, and the preparation steps are as follows: carrying out sulfonation reaction on benzenediol and concentrated sulfuric acid; (2) adding an ethanol water solution; (3) adding calcium chloride for precipitation reaction; (4) adding sodium carbonate to perform precipitation reaction; (5) mixing ethanol and water, dissolving and crystallizing; (6) drying the refined crystal; (7) and (3) adding the sodium hydroxybenzenesulfonate into water for injection in a ten-thousand-level batching room, heating and cooling to obtain a sodium hydroxybenzenesulfonate product, and packaging, inspecting and warehousing the sodium hydroxybenzenesulfonate product. The preparation method has the advantages of simple operation and low preparation cost, and has the function of obviously improving microcirculation.
Description
Technical field
The invention belongs to medical technical field, specifically, relate to a kind of chemicals of treating cardiac and cerebral diseases of phenolsulfonic acid sodium raw materials and preparation method thereof.
Background technology
Phenolsulfonic acid sodium (Sodium dobesilate) is still unlisted one type of cardio-cerebrovascular disorder treatment new drug microcirculation improving agent.Chemical name: 2,5-dihydroxy benzenes sulfonic acid sodium, molecular formula: C
6H
5NaO
5S, molecular weight: 212.15,
Structural formula:
Early stage, pharmacological evaluation proved: these article are the novel vascular protective agent, and main effect is: wall of micrangium is had its permeability of reduction, the effect of building up one's resistance to disease; Lymph circulation is had the backflow of improvement reduce the edema effect; Can reduce the blood plasma viscosity to blood flow; Correct albumen/globulin ratio, reduce hematoblastic high slurry collection property; Thereby prevent that thrombosis from improving erythrocytic pliability; Simultaneously these article also can suppress the high-permeability effect that vaso-active substance histamine, 5-hydroxy tryptamine, Kallidin I, prostaglandin cause blood capillary, reduce the biology generation that the tunica intima damage improves basement membrane collagen.These article adopt modern galenic pharmacy technology to process phenolsulfonic acid sodium and injection phenolsulfonic acid sodium; Has the disease that prevention and treatment cardio-cerebrovascular disorder cause; Like myocardial infarction, thrombus sequela; Blood viscosity lowering, numb limbs and tense tendons, trick are ice-cold, cerebral thrombosis, cerebral vasospasm, acute and chronic brain insufficiency (alzheimer disease, apoplexy sequela, hypomnesis, absent minded), thrombotic disease prevention and treatment.
The objective of the invention is to develop a kind of new chemicals phenolsulfonic acid sodium, show similar clinically listing kind calcium dobesilate both at home and abroad, only can be used for the tablet of oral administration; This medicine not only is increased in curative effect clinically and increases the indication of medicine; And reach peak concentration in vivo fast, and improve stability of drug, improve drug quality; So that more effectively be used for the cardio-cerebrovascular disorder that microcirculation causes safely; These article have tangible microcirculation improvement effect, and have the toxicity features of smaller for cardio-cerebrovascular disorder treatment new drug.
Summary of the invention
The objective of the invention is to develop a kind of new chemicals phenolsulfonic acid sodium, show similar clinically listing kind calcium dobesilate both at home and abroad, only can be used for the tablet of oral administration; This medicine not only is increased in curative effect clinically and increases the indication of medicine, and reaches peak concentration in vivo fast, improves stability of drug, improves drug quality, so that safely, more effectively be used for the cardio-cerebrovascular disorder that microcirculation causes.
A kind of chemicals of treating cardiac and cerebral diseases and preparation method thereof, it is processed by following raw materials according, Benzodiazepines, concentrated sulphuric acid, ethanol, calcium chloride, sodium carbonate; The ratio of their prescription weight is: 1-3g: 1.2～6.0g0.5-1.5g: 0.5～1.5g: 0.3～0.9g; More than prescription is processed aseptic powder phenolsulfonic acid sodium, and the ratio of parts by weight is: phenolsulfonic acid sodium 1000g, process 1000 bottles; Phenolsulfonic acid sodium 500g processes 1000 bottles; Phenolsulfonic acid sodium 250g processes 1000 bottles.
Described a kind of chemicals of treating cardiac and cerebral diseases and preparation method thereof, preparation process:
(1) carries out sulfonating reaction with Benzodiazepines and concentrated sulphuric acid, get white dope;
(2) add ethanol water;
(3) add calcium chloride and carry out precipitation, calcium chloride saturated aqueous solution addition no longer produces with filtrating and is precipitated as index (promptly showing sulfate in the filtrating) and crosses and filter filtrating;
(4) add sodium carbonate and carry out precipitation and add 200～600ml sodium carbonate saturated aqueous solution, addition no longer produces with filtrating and is precipitated as index (promptly showing calcium salt in the filtrating), filters, and must filtrate, concentrate, cool off crystallization;
(5) the second alcohol and water mix or single carry out with a kind of solvent wherein dissolving crystallized, reconcentration, cool off crystallization;
(6) purified crystal carries out drying;
(7) ten thousand gradating materials are indoor; Phenolsulfonic acid sodium is added in the water for injection; Through slowly heat up 40 ℃～60 ℃, add water 1000～3000mL dissolving, stir 5～10 minutes ,-10 ℃～50 ℃ coolings 2～15 hours phenolsulfonic acid sodium aseptic powder dry product, packing, check, warehouse-in.
The invention has the beneficial effects as follows: method for preparing of the present invention is simple to operate; Cost of manufacture is low; This medicine injection phenolsulfonic acid sodium has obvious microcirculation improvement effect; Be used to clinically prevent and treat the disease that cardio-cerebrovascular disorder causes, specifically comprise: cardiovascular disease: myocardial infarction, thrombus sequela, numb limbs and tense tendons, trick are ice-cold, pain, varicosis syndrome, and blood viscosity raises; Cerebrovascular disease: cerebral thrombosis, cerebral vasospasm, acute and chronic brain insufficiency (alzheimer disease, apoplexy sequela, hypomnesis, absent minded), thrombotic disease etc.
Description of drawings:
Fig. 1 is the embodiment of the invention 4 injection phenolsulfonic acid sodium freeze-drying curve figure.
Wherein the abscissa of curve chart 1 is represented: the time, vertical coordinate is represented: temperature.
The specific embodiment
Below in conjunction with embodiment the present invention is described.
A kind of chemicals of treating cardiac and cerebral diseases and preparation method thereof, it is processed by following raw materials according, Benzodiazepines, concentrated sulphuric acid, ethanol, calcium chloride, sodium carbonate; The ratio of their prescription weight is: 1-3g: 1.2～6.0g 0.5-1.5g: 0.5～1.5g: 0.3～0.9g; More than prescription is processed aseptic powder phenolsulfonic acid sodium, and the ratio of parts by weight is: phenolsulfonic acid sodium 1000g, process 1000 bottles; Phenolsulfonic acid sodium 500g processes 1000 bottles; Phenolsulfonic acid sodium 250g processes 1000 bottles.
Described a kind of chemicals of treating cardiac and cerebral diseases and preparation method thereof, phenolsulfonic acid sodium preparation process:
(1) carries out sulfonating reaction with Benzodiazepines and concentrated sulphuric acid, get white dope;
(2) add ethanol water;
(3) add calcium chloride and carry out precipitation, calcium chloride saturated aqueous solution addition no longer produces with filtrating and is precipitated as index (promptly showing sulfate in the filtrating) and crosses and filter filtrating;
(4) add sodium carbonate and carry out precipitation and add 200～600ml sodium carbonate saturated aqueous solution, addition no longer produces with filtrating and is precipitated as index (promptly showing calcium salt in the filtrating), filters, and must filtrate, concentrate, cool off crystallization;
(5) the second alcohol and water mix or single carry out with a kind of solvent wherein dissolving crystallized, reconcentration, cool off crystallization;
(6) purified crystal carries out drying;
(7) ten thousand gradating materials are indoor; Phenolsulfonic acid sodium is added in the water for injection; Through slowly heat up 40 ℃～60 ℃, add water 1000～3000mL dissolving, stir 5～10 minutes ,-10 ℃～50 ℃ coolings 2～15 hours phenolsulfonic acid sodium aseptic powder dry product, packing, check, warehouse-in.
Phenolsulfonic acid sodium preparation process: first method:
A kind of chemicals of treating cardiac and cerebral diseases and preparation method thereof, phenolsulfonic acid sodium preparation process:
(1) sulfonating reaction is got 1200g to 6000g concentrated sulphuric acid, under constantly stirring, slowly adds 1000g to 3000g hydroquinone, continues to stir at 50～100 ℃, gets white dope.
(2) sucking filtration filters above-mentioned solution through sintered filter funnel, washes with small amount of ethanol (10ml to 500ml).
(3) neutralization neutralizes with sodium hydroxide solution (concentration be 2 to 0.1mol/L), and pH value is 5 to 9.
(4) concentrated, crystallization.Add sodium carbonate and carry out precipitation and add 200～600ml sodium carbonate saturated aqueous solution, filter, must filtrate 50～100 ℃ of following water-baths, concentrate, cool off crystallization.
(5) refiningly mix (1: 1) or singly carry out dissolving crystallizedly with a kind of solvent wherein with the second alcohol and water, reconcentration cools off crystallization.
(6) dry 50～120 ℃ are carried out constant pressure and dry or drying under reduced pressure.
(7) pulverize the elaboration that drying is got and pulverize, carry out drying again.
(8) packing is sieved the Aluminum Drum intermediate package of packing into through 18 orders.
Phenolsulfonic acid sodium preparation process: second method:
A kind of chemicals of treating cardiac and cerebral diseases and preparation method thereof, phenolsulfonic acid sodium preparation process:
(1) sulfonating reaction is got 1200g to 6000g concentrated sulphuric acid, under constantly stirring, slowly adds 1000g to 3000g hydroquinone, continues to stir at 50～100 ℃, gets white dope.
(2) precipitation adds 500～1000ml ethanol in above-mentioned dope, and stirring and dissolving adds 500～1000ml calcium chloride saturated aqueous solution under constantly stirring; Calcium chloride saturated aqueous solution addition no longer produces with filtrating and is precipitated as index (promptly not showing sulfate in the filtrating); Filter, get filtrating
(3) above-mentioned filtrating is got in salt-forming reaction, under constantly stirring, adds 200～600ml sodium carbonate saturated aqueous solution, and addition no longer produces with filtrating and is precipitated as index (promptly not showing calcium salt in the filtrating), filters, and gets filtrating.
(4) concentrate and to get above-mentioned filtrating, water-bath concentrates, and heat filters, cooling, crystallization.
(5) refiningly mix (1: 1) or singly carry out dissolving crystallizedly with a kind of solvent wherein with the second alcohol and water, reconcentration cools off crystallization.
(6) dry 50～120 ℃ are carried out constant pressure and dry or drying under reduced pressure.
(7) pulverize the elaboration that drying is got and pulverize, carry out drying again.
(8) packing is sieved the Aluminum Drum intermediate package of packing into through 18 orders.
Embodiment 1
A kind of chemicals of treating cardiac and cerebral diseases and preparation method thereof, phenolsulfonic acid sodium preparation process:
(1) sulfonating reaction is got the 1200g concentrated sulphuric acid, under constantly stirring, slowly adds the 1000g hydroquinone, continues to stir at 50～100 ℃, gets white dope.
(2) sucking filtration filters above-mentioned solution through sintered filter funnel, washes with small amount of ethanol (10ml to 500ml).
(3) neutralization neutralizes with sodium hydroxide solution (concentration be 2 to 0.1mol/L), and pH value is 5 to 9.
(4) concentrated, crystallization.Add sodium carbonate and carry out precipitation and add 200～600ml sodium carbonate saturated aqueous solution, filter, must filtrate 50～100 ℃ of following water-baths, concentrate, cool off crystallization.
(5) refiningly mix (1: 1) or singly carry out dissolving crystallizedly with a kind of solvent wherein with the second alcohol and water, reconcentration cools off crystallization.
(6) dry 50～120 ℃ are carried out constant pressure and dry or drying under reduced pressure.
(7) pulverize the elaboration that drying is got and pulverize, carry out drying again.
(8) packing is sieved the Aluminum Drum intermediate package of packing into through 18 orders.
Embodiment 2
A kind of chemicals of treating cardiac and cerebral diseases and preparation method thereof, phenolsulfonic acid sodium preparation process:
(1) sulfonating reaction is got the 1200g concentrated sulphuric acid, under constantly stirring, slowly adds the 1000g hydroquinone, continues to stir at 60 ℃, gets white dope.
(2) precipitation adds 700ml ethanol in above-mentioned dope, and stirring and dissolving adds 700ml calcium chloride saturated aqueous solution under constantly stirring; Drip 72ml calcium chloride saturated aqueous solution again, filtrating no longer produces deposition (promptly not showing sulfate in the filtrating), filters; Get filtrating
(3) above-mentioned filtrating is got in salt-forming reaction, is constantly stirring down, adds 200ml sodium carbonate saturated aqueous solution, be added dropwise to 26ml after, its filtrating no longer produces deposition (promptly showing calcium salt in the filtrating), filtrating is got in filtration.
(4) concentrate and to get above-mentioned filtrating, water-bath concentrates, and heat filters, cooling, crystallization.
(5) refining with second alcohol and water mixing (1: 1) dissolving crystallized about 800ml, reconcentration, cooling, crystallization.
(6) dry 105 ℃ are carried out constant pressure and dry.
(7) pulverize the elaboration that drying is got and pulverize, carry out drying again.
(8) packing is sieved the Aluminum Drum intermediate package of packing into through 18 orders.
Embodiment 3
A kind of chemicals of treating cardiac and cerebral diseases and preparation method thereof, phenolsulfonic acid sodium preparation process:
(1) sulfonating reaction is got the 6000g concentrated sulphuric acid, under constantly stirring, slowly adds the 3000g hydroquinone, continues to stir at 50～100 ℃, gets white dope.
(2) sucking filtration filters above-mentioned solution through sintered filter funnel, washes with small amount of ethanol (10ml to 500ml).
(3) neutralization neutralizes with sodium hydroxide solution (concentration be 2 to 0.1mol/L), and pH value is 5 to 9.
(4) concentrated, crystallization.Add sodium carbonate and carry out precipitation and add 200～600ml sodium carbonate saturated aqueous solution, filter, must filtrate 50～100 ℃ of following water-baths, concentrate, cool off crystallization.
(5) refiningly mix (1: 1) or singly carry out dissolving crystallizedly with a kind of solvent wherein with the second alcohol and water, reconcentration cools off crystallization.
(6) dry 50～120 ℃ are carried out constant pressure and dry or drying under reduced pressure.
(7) pulverize the elaboration that drying is got and pulverize, carry out drying again.
(8) packing is sieved the Aluminum Drum intermediate package of packing into through 18 orders.
Embodiment 4
A kind of chemicals of treating cardiac and cerebral diseases and preparation method thereof, phenolsulfonic acid sodium preparation process:
(1) sulfonating reaction is got the 6000g concentrated sulphuric acid, under constantly stirring, slowly adds the 3000g hydroquinone, continues to stir at 60 ℃, gets white dope.
(2) precipitation adds 700ml ethanol in above-mentioned dope, and stirring and dissolving adds 700ml calcium chloride saturated aqueous solution under constantly stirring; Drip 72ml calcium chloride saturated aqueous solution again, filtrating no longer produces deposition (promptly not showing sulfate in the filtrating), filters; Get filtrating
(3) above-mentioned filtrating is got in salt-forming reaction, is constantly stirring down, adds 200ml sodium carbonate saturated aqueous solution, be added dropwise to 26ml after, its filtrating no longer produces deposition (promptly showing calcium salt in the filtrating), filtrating is got in filtration.
(4) concentrate and to get above-mentioned filtrating, water-bath concentrates, and heat filters, cooling, crystallization.
(5) refining with second alcohol and water mixing (1: 1) dissolving crystallized about 800ml, reconcentration, cooling, crystallization.
(6) dry 105 ℃ are carried out constant pressure and dry.
(7) pulverize the elaboration that drying is got and pulverize, carry out drying again.
(8) packing is sieved the Aluminum Drum intermediate package of packing into through 18 orders.
Embodiment 5
A kind of chemicals of treating cardiac and cerebral diseases and preparation method thereof, injection phenolsulfonic acid sodium preparation process:
(1) indoor at ten thousand gradating materials, the prescription of according to the form below is measured phenolsulfonic acid sodium, mannitol.Add water 2000ml, slowly be warmed up to 60 ℃, stir and make dissolving.
Prescription 1
Prescription 2
Prescription 3
(2) pin that adds is used charcoal, makes the dosing amount contain pin with charcoal 0.5%～1.0% (g/ml), and 60 ℃ were stirred 15 minutes.
(3) filter under hundred grades of laminar flows under ten thousand grades of controls, decarbonization filtering is filtrated through 0.45 μ m filter membrane coarse filtration while hot, again through 0.22 μ m microporous filter membrane fine straining.Add the injection water again to 5000ml.
(4) intermediate assay (consistent with phenolsulfonic acid sodium theoretical value in the corresponding prescription), pH value are measured (pH value should 5.0～7.5).
(5) packing is carried out packing by every bottle of 5ml
(6) the lyophilizing sample was-10 ℃ to-50 ℃ pre-freezes 2～5 hours, and reuse was warming up to 10～60 ℃ in 5～50 hours, 10～60 ℃ dry 3～10 hours down.
The eutectic point of these article is-28 ℃.
Embodiment 6
A kind of chemicals of treating cardiac and cerebral diseases and preparation method thereof, injection phenolsulfonic acid sodium (specification is 1g) preparation process
(1) indoor at ten thousand gradating materials, get phenolsulfonic acid sodium 1000g, mannitol 1000g.Add water 2000ml, slowly be warmed up to 60 ℃, stir and make dissolving.
The active carbon 10g of the injection that (2) adds makes the dosing amount contain pin with charcoal 1.0% (g/ml), and 60 ℃ were stirred 15 minutes.
(3) filter under hundred grades of laminar flows under ten thousand grades of controls, decarbonization filtering is filtrated through 0.45 μ m filter membrane coarse filtration while hot, again through 0.22 μ m microporous filter membrane fine straining.Add the injection water again to 5000ml.
(4) intermediate assay (intermediate contains phenolsulfonic acid sodium 0.2g/ml), pH value is measured (pH value is 6.0).
(5) packing is carried out packing by every bottle of 5ml
(6) the lyophilizing sample was-35 ℃ of pre-freezes 5 hours, and reuse was warming up to 35 ℃ in 40 hours, 35 ℃ dry 10 hours down.
The present invention carries out the pharmacological toxicology test, and anxious poison research shows the LD of mouse mainline administration
50Value is 2101.8mg/kg, the LD of rat intravenous injection administration
50Value is 1975.8mg/lg, the LD of Beagle dog
50Value＞2500mg/kg.The pharmacodynamic study result shows that the injection phenolsulfonic acid can suppress vaso-active substance and cause capillary permeability increase effect; Significantly reduce platelet aggregation rate and platelet adhesion rate; Obviously improve blood plasma and serum adhesiveness; Obviously improve the blood capillary microcirculation, arteriole and thin vein external caliber are increased and increase blood capillary opening amount.
Claims (2)
1. method for preparing of treating the aseptic powder phenolsulfonic acid sodium of cardiac and cerebral diseases; It is characterized in that: press 1-3g: 1.2～6.0g: 0.5～1.5g: 0.5～1.5g: the weight proportion of 0.3～0.9g; Take off row benzene feedstock diphenol, concentrated sulphuric acid, ethanol, calcium chloride, sodium carbonate and process aseptic powder phenolsulfonic acid sodium, preparation process is:
1) carries out sulfonating reaction with Benzodiazepines and concentrated sulphuric acid, get white dope;
2) add ethanol water;
3) add calcium chloride and carry out precipitation
Calcium chloride saturated aqueous solution addition no longer produces with filtrating and is precipitated as index, crosses and filters filtrating;
4) add sodium carbonate and carry out precipitation
Add 200～600ml sodium carbonate saturated aqueous solution, addition no longer produces with filtrating and is precipitated as index, filters, and must filtrate, concentrate, cool off crystallization;
5) the second alcohol and water mix or single carry out with a kind of solvent wherein dissolving crystallized, reconcentration, cool off crystallization;
6) purified crystal carries out drying;
7) indoor at ten thousand gradating materials; The above-mentioned phenolsulfonic acid sodium that makes is added in the water for injection; Through slowly heat up 40～60 ℃, add water 1000～3000ml dissolving, stir 5～10 minutes ,-10～50 ℃ of coolings 2～15 hours, phenolsulfonic acid sodium aseptic powder dry product, packing, check, warehouse-in.
2. the aseptic powder phenolsulfonic acid sodium that obtains according to the said method for preparing of claim 1 is characterized in that: phenolsulfonic acid sodium 1000g, process 1000 bottles, and perhaps phenolsulfonic acid sodium 500g processes 1000 bottles, and perhaps phenolsulfonic acid sodium 250g processes 1000 bottles.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101332821A CN101849930B (en) | 2009-03-31 | 2009-03-31 | Chemical medicine for treating cardiac and cerebral diseases and its prepn |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101332821A CN101849930B (en) | 2009-03-31 | 2009-03-31 | Chemical medicine for treating cardiac and cerebral diseases and its prepn |
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| Publication Number | Publication Date |
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| CN101849930A CN101849930A (en) | 2010-10-06 |
| CN101849930B true CN101849930B (en) | 2012-04-04 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1359897A (en) * | 2001-12-11 | 2002-07-24 | 西安利君制药股份有限公司 | Process for synthesizing hydrate of calcium phenolsulfonate |
| CN101062011A (en) * | 2006-04-30 | 2007-10-31 | 沈阳市兴齐制药有限责任公司 | Calcium dobesilate injection |
-
2009
- 2009-03-31 CN CN2009101332821A patent/CN101849930B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1359897A (en) * | 2001-12-11 | 2002-07-24 | 西安利君制药股份有限公司 | Process for synthesizing hydrate of calcium phenolsulfonate |
| CN101062011A (en) * | 2006-04-30 | 2007-10-31 | 沈阳市兴齐制药有限责任公司 | Calcium dobesilate injection |
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| CN101849930A (en) | 2010-10-06 |
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