CN103408586A - Phosphoric citrate and synthesis method thereof - Google Patents
Phosphoric citrate and synthesis method thereof Download PDFInfo
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Abstract
The invention relates to a method for synthesizing phosphoric citrate. According to the method, triethyl citrate and methoxyl phosphorus dichloride serve as starting raw materials, the method comprises five-step reactions, raw materials which are cheap and easy to get are adopted in each step, the reaction conditions are mild, and a white powdery phosphoric citrate product is obtained finally and is good in quality. The method is applicable to a kilogram-level mass synthesis scale. The method has the advantages that the cost can be reduced greatly, and the obtained product is high in yield and good in quality. The phosphoric citrate has an effect equivalent to that of the original arthritis resisting drugs, and has more considerable social and economic benefits.
Description
Technical field
The present invention relates to a kind of synthetic method of phosphocitrate, relate in particular to pharmaceutical salts and combination of compounds thereof.
Background technology
Developing society rapidly, osteoarthritis and rheumatoid arthritis have become a kind of common disease, and present and increase progressively trend.The phosphocitrate of this paper synthesized is exactly specially for this illness.
This kind phosphocitrate is a kind of natural biomolecules, nontoxic.It can suppress the appearance of crystal, thereby stops Ca
2+Comprise crystal deposition in cartilage.U.S. periodical J.Org.Chem.2007, in 72,1470-1471, introduces the similar structures compou nd synthesis is arranged, but synthesis step is loaded down with trivial details, and energy consumption is large, is unsuitable for a large amount of production.The phosphocitrate that this paper synthesizes can be used for fractured bones sacroiliitis and prevents involutional osteoporosis.
The synthetic method of similar structures such as U.S. periodical J.Org.Chem.2007, shown in 72,1470-1471:
Ion exchange resin is used in the method final step reaction, and the relative silica gel of price is high, and expects that from former target product has nine steps, and technique is more loaded down with trivial details, is not suitable for a large amount of synthetic.
Summary of the invention
The problem to be solved in the present invention is, the synthetic method of a kind of phosphocitrate of design, and phosphoric acid Chinese holly edge hydrochlorate and original arthritis medicine have suitable effect, and synthetic method is easier, and energy consumption is low, has more considerable society and economic benefit.Develop synthesis technique.Products obtained therefrom Functionality, quality and appealing design, applicable feather weight be synthetic scale in a large number.
Technical scheme of the present invention is as follows:
A kind of synthetic method of phosphocitrate is characterized in that step is as follows:
1) triethyl citrate and anhydrous triethylamine are dissolved in ether, the mass ratio of triethyl citrate and anhydrous triethylamine and ether is 1:(0.3～0.7): (6～12); The methoxyl group phosphorus dichloride is slowly joined in mixture, and the mass ratio of triethyl citrate and methoxyl group phosphorus dichloride is 1:(0.5～1), stirring at room makes to react completely simultaneously; Under nitrogen protection, filter and obtain;
2) the first step reactor product is dissolved in ether, be cooled to-5～0 ℃, the ether mixing solutions of anhydrous methanol and anhydrous triethylamine is joined to reaction system under nitrogen protection in, the stirring at room reaction, be cooled to-5～0 ℃, the first step reaction product and methyl alcohol, triethylamine, the mass ratio of ether is 1:(0.05～0.1): (0.1～0.5): (2～7), in system, slowly add SULPHURYL CHLORIDE, the mass ratio of the first step target product and SULPHURYL CHLORIDE is 1:0.2～0.7, the stirring at room reaction, except dereaction forms the ether in precipitation and filtrate, by silica gel column chromatography purification of crude product, obtain colorless oil,
3) the second step reaction product is dissolved in water, adds sodium bicarbonate, stirring at room, pressure reducing and steaming solvent; The mass ratio of second step reaction product and water, sodium bicarbonate is 1:(3～8): (0.1～0.5); In resistates, add trichloromethane, the mass ratio of second step reaction product and trichloromethane is 1:35～45, carries out drying with sodium sulfate, and underpressure distillation obtains colorless oil;
4) the three-step reaction product is dissolved in acetonitrile, sodium bicarbonate and bromotrimethylsilane are joined in mixture, the stirring at room reaction, the mass ratio of three-step reaction product and acetonitrile, sodium bicarbonate, bromotrimethylsilane is 1:(10～15): (0.1～0.5): (0.5～1); Filter the solid that reaction forms, the filtrate decompression distillation, resistates dissolve with methanol, the mass ratio of three-step reaction product and anhydrous methanol are 1:4.0～4.5, stirring at room, underpressure distillation obtains thick product orange; Thick product is dissolved in water, and sodium bicarbonate is joined in mixture, and the mass ratio of thick product and sodium bicarbonate is 1:0.1～0.5, washing, PH ≈ 1 is adjusted in acid, mixture ethyl acetate extraction three times, organic phase is washed, drying, underpressure distillation obtains colorless oil;
5) the four-step reaction product is dissolved in water, be cooled to 4 ℃, the sodium hydroxide solution that slowly adds massfraction 32.8%, be cooled to again 4 ℃, the mass ratio of four-step reaction product and water, aqueous sodium hydroxide solution is 1:(5～8): (0.1～0.5), reaction stirring at room 24 hours, the hydrochloric acid soln that slowly adds massfraction 37%, four-step reaction product and hydrochloric acid soln mass ratio are 1:0.1～0.3, stirring at room 0.5 hour, vacuum-drying, filtering salt wherein, obtain the colorless oil product;
6) products obtained therefrom is dissolved in water, is cooled to 4 ℃, slowly adds sodium bicarbonate, stirring at room, and vacuum-drying, the mass ratio of product and water, sodium bicarbonate is 1:(5～8): (0.5～1) obtains white powder phosphoric acid Chinese holly edge hydrochlorate product.
Synthetic route:
Technical scheme of the present invention is as follows:
The first step reaction:
Triethyl citrate and anhydrous triethylamine are dissolved in ether, the mass ratio of triethyl citrate and anhydrous triethylamine is 1:0.3～0.7, the mass ratio of triethyl citrate and ether is 1:6～12, slowly join the methoxyl group phosphorus dichloride in mixture, the mass ratio of triethyl citrate and methoxyl group phosphorus dichloride is 1:0.5～1, because reaction is more responsive to water and air, need under nitrogen protection, carry out, stirring at room is 24 hours simultaneously, tlc (sherwood oil: ethyl acetate=2:1, radio frequency=0.3) detection reaction is complete, under nitrogen protection, filter and obtain thick product.Need not continue purifying, be directly used in next step reaction.
The second step reaction:
The first step reaction product is dissolved in ether, the mass ratio of the first step target product and ether is 1:2～7, temperature is cooled to-5～0 ℃, the ether mixture solution of anhydrous methanol and anhydrous triethylamine joins reaction mixture under the condition that passes into nitrogen and stirring in, stirring at room reaction 3 hours, the mass ratio of the first step target product and methyl alcohol is 1:0.05～0.1, with the mass ratio of triethylamine be 1:0.1～0.5, with nitrogen, blow away solvent, volume reduces, and it is cooled to-5～0 ℃, in system, slowly add SULPHURYL CHLORIDE, the mass ratio of the first step target product and SULPHURYL CHLORIDE is 1:0.2～0.7, mixture is stirring reaction 1 hour at room temperature, filter and remove the formed precipitation of reaction, the ether in filtrate is removed in evaporation, (silicon-dioxide needs 120 ℃ of oven dryings by silica gel column chromatography purification of crude product as eluent by ethyl acetate/petroleum ether (1:5), ethyl acetate need be used dried over mgso before use), obtaining product is colorless oil.Need not continue purifying, directly use with next step and react.
Three-step reaction:
The second step reaction product is dissolved in water, and the mass ratio of PC-A-3 and water is 1:3～8, adds sodium bicarbonate, and the mass ratio of second step target product and sodium bicarbonate is 1:0.1～0.5, stirring at room 1 hour, pressure reducing and steaming solvent.In residue, add trichloromethane, the mass ratio of second step target product and trichloromethane is 1:35～45, carries out drying with sodium sulfate, and underpressure distillation obtains colorless oil.Need not continue purifying, be directly used in next step reaction.
Four-step reaction:
The three-step reaction product is dissolved in acetonitrile, the mass ratio of three-step reaction product and acetonitrile is 1:10～15, sodium bicarbonate and bromotrimethylsilane join in mixture, the mass ratio of three-step reaction product and sodium bicarbonate is 1:0.1～0.5, with the mass ratio of bromotrimethylsilane be 1:0.5～1, and this reaction mixture was at room temperature stirred 2 hours.Filter out the formed solid of reaction, and by filtrate decompression distillation, resistates dissolve with methanol, the mass ratio of three-step reaction product and anhydrous methanol are 1:4.0～4.5, at room temperature stir 1 hour, then carry out underpressure distillation and obtain the thick product of orange.
Thick product is dissolved in water, sodium bicarbonate joins in mixture in batches, the mass ratio of thick product and sodium bicarbonate is 1:0.1～0.5, with ethyl acetate washing three times, add hydrochloric acid to regulate PH ≈ 1, mixture ethyl acetate extraction three times, the organic phase obtained is water successively, salt solution washs, subsequent drying, and underpressure distillation obtains colorless oil.Need not continue purifying, be directly used in next step reaction.
The 5th step reaction:
The four-step reaction product is dissolved in water, the mass ratio of four-step reaction product and water is 1:5～8, gained solution is cooled to 4 ℃, the aqueous sodium hydroxide solution of massfraction 32.8% slowly adds wherein, the mass ratio of four-step reaction product and aqueous sodium hydroxide solution is 1:0.1～0.5, reaction mixture at room temperature stirred 24 hours, again gained solution is cooled to 4 ℃, the aqueous hydrochloric acid of massfraction 37% slowly adds wherein, four-step reaction product and aqueous hydrochloric acid mass ratio are 1:0.1～0.3, gained solution at room temperature stirred 0.5 hour, in the situation of 60 ℃, vacuum-drying, salt wherein is by removing by filter, obtain the colorless oil product.
Products obtained therefrom is dissolved in water, the mass ratio of product and water is that 1:5～8 are cooled to 4 ℃ by gained solution, slowly add sodium bicarbonate, the mass ratio of product and sodium bicarbonate is 1:0.5～1, reaction mixture at room temperature stirred 0.5 hour, lower than 60 ℃ of lower vacuum-dryings, obtain white powder phosphoric acid Chinese holly edge hydrochlorate product.
The present invention designs and develops a kind of synthetic method of phosphoric acid Chinese holly edge hydrochlorate.With the U.S. periodical J.Org.Chem.2007 of existing similar structures compou nd synthesis method, 72,1470-1471 compares, and in the present invention, the synthetic method treatment process is simple, greatly reduces synthetic cost, and quality product is excellent, is applicable to a large amount of production.
The present invention relates to a kind of synthetic method of phosphocitrate, take triethyl citrate, methoxyl group phosphorus dichloride is starting raw material, through five step reactions, every step all adopts the raw material cheaply be easy to get, the reaction conditions gentleness, finally obtain white powder phosphoric acid Chinese holly edge hydrochlorate product, the products obtained therefrom Functionality, quality and appealing design, applicable feather weight is synthetic scale in a large number.This method not only can reduce costs greatly, and products obtained therefrom output is high, Functionality, quality and appealing design.Applicable feather weight is synthetic scale in a large number.With original arthritis medicine, have suitable effect, have more considerable society and economic benefit.
Embodiment
Synthetic route the following is:
Embodiment 1:
The first step reaction:
200g triethyl citrate and 83ml triethylamine are dissolved in the 1.7L ether; the mass ratio of triethyl citrate and triethylamine is 1:0.3; with the mass ratio of ether be 1:6; slowly join 100g methoxyl group phosphorus dichloride in mixture again; the mass ratio of triethyl citrate and methoxyl group phosphorus dichloride is 1:0.5; stirring at room is 24 hours under nitrogen atmosphere; with tlc (sherwood oil: EA=2:1; radio frequency=0.3) detection reaction is complete; under nitrogen protection, filter and obtain thick product 248g, productive rate is 91.9%.Need not continue purifying, be directly used in next step reaction.
The second step reaction:
The first step reaction product 100g is dissolved in the 280ml ether, the mass ratio of the first step reaction product and ether is 1:2, temperature is cooled to-5～0 ℃, 6.5ml the ether mixture solution of anhydrous methanol and 14ml anhydrous triethylamine joins reaction mixture under the condition that passes into nitrogen and stirring in, stirring at room reaction 3 hours, the mass ratio of the first step reaction product and anhydrous methanol is 1:0.05, with the mass ratio of anhydrous triethylamine be 1:0.1, with nitrogen, blow away solvent, be cooled to-5～0 ℃, in system, slowly add the 20g SULPHURYL CHLORIDE, the mass ratio of the first step reaction product and SULPHURYL CHLORIDE is 1:0.2, mixture is stirring reaction 1 hour at room temperature, remove by filter the formed precipitation of reaction, the ether in filtrate is removed in evaporation, (silicon-dioxide needs 120 ℃ of oven dryings by the silica gel column chromatography purifying crude product as eluent by ethyl acetate/petroleum ether (1:5), ethyl acetate need be used dried over mgso before use), obtaining the 32g product is colorless oil, productive rate is 30.7%.Need not continue purifying, be directly used in next step reaction.
Three-step reaction:
Second step reaction product 16g is dissolved in 48ml water, and the mass ratio of second step reaction product and water is 1:3, adds the 1.6g sodium bicarbonate, and the mass ratio of second step reaction product and sodium bicarbonate is 1:0.1, under room temperature, stirs 1 hour the pressure reducing and steaming solvent.In residue, add the 375ml trichloromethane, the mass ratio of second step reaction product and trichloromethane is 1:35, carries out drying with sodium sulfate, and underpressure distillation obtains colorless oil product 6.0g.Productive rate is 39.3%.Need not continue purifying, be directly used in next step reaction.
Four-step reaction:
Three-step reaction product 10g is dissolved in the 126.6ml acetonitrile, 1g sodium bicarbonate and 5g bromotrimethylsilane join in mixture, the mass ratio of three-step reaction product and acetonitrile is 1:10, with the mass ratio of sodium bicarbonate be 1:0.1, with the mass ratio of bromotrimethylsilane be 1:0.5, under the reaction mixture room temperature, stirred 2 hours.Filter out the formed precipitation of reaction, by the filtrate decompression distillation, resistates dissolves with the 51ml anhydrous methanol, and the mass ratio of three-step reaction product and anhydrous methanol is 1:4, stirring at room 1 hour, and underpressure distillation obtains the thick product 16g of orange.
The thick product of 15g is dissolved in water, 1.5g sodium bicarbonate joins in mixture in batches, the mass ratio of thick product and sodium bicarbonate is 1:0.1, with 30ml ethyl acetate washing three times, adds hydrochloric acid to regulate PH ≈ 1, mixture 30ml ethyl acetate extraction three times, the organic phase obtained is water 50ml successively, and salt solution 50ml washs, drying, it is 5.7g that underpressure distillation obtains colorless oil, productive rate 59%.Need not continue purifying, be directly used in next step reaction.
The 5th step reaction:
The product 5g of four-step reaction is dissolved in 25ml water, the product of four-step reaction and the mass ratio of water are 1:5, and gained solution is cooled to 4 ℃, the aqueous sodium hydroxide solution that slowly adds 0.4ml massfraction 32.8%, the product of four-step reaction and the mass ratio of aqueous sodium hydroxide solution are 1:0.1, reaction mixture stirring at room 24 hours, gained solution is cooled to 4 ℃, the aqueous hydrochloric acid that slowly adds 0.5ml massfraction 37%, the product of four-step reaction and aqueous hydrochloric acid mass ratio are 1:0.1, gained solution stirring at room 0.5 hour, lower than 60 ℃ of vacuum-dryings, remove by filter salt wherein, obtain colorless oil product 5.2g.
Products obtained therefrom is dissolved in 26ml water, the mass ratio of product and water is 1:5, gained solution is cooled to 4 ℃, slowly add the 2.6g sodium bicarbonate, the mass ratio of product and sodium bicarbonate is 1:0.5, under the reaction mixture room temperature, stirred 0.5 hour, lower than 60 ℃ of vacuum-dryings, obtaining white powder phosphoric acid Chinese holly edge hydrochlorate product is 4.7g.Productive rate is 92.0%
Embodiment 2:
The first step reaction:
1kg triethyl citrate and 500g triethylamine are dissolved in the 14L ether; the mass ratio of triethyl citrate and triethylamine is 1:0.5; with the mass ratio of ether be 1:10; slowly join 800g methoxyl group phosphorus dichloride in mixture; the mass ratio of triethyl citrate and methoxyl group phosphorus dichloride is 1:0.8; stirring at room is 24 hours under nitrogen atmosphere; with tlc (sherwood oil: EA=2:1; radio frequency=0.3) detection reaction is complete; under nitrogen protection, filter and obtain thick product 1.27kg, productive rate is 94.3%.Need not continue purifying and be directly used in next step reaction.
The second step reaction:
The first step reaction product 1.2kg is dissolved in the 8.4L ether, the mass ratio of the first step reaction product and ether is 1:5, temperature is cooled to-5～0 ℃, the ether mixture solution of 121ml anhydrous methanol and 500ml anhydrous triethylamine is joined to reaction mixture under passing into nitrogen and agitation condition in, stirring at room reaction 3 hours, the mass ratio of the first step reaction product and anhydrous methanol is 1:0.08, with the mass ratio of anhydrous triethylamine be 1:0.3, with nitrogen, blow away solvent, its temperature is cooled to-5～0 ℃, in system, slowly add the 480g SULPHURYL CHLORIDE, the mass ratio of the first step reaction product and SULPHURYL CHLORIDE is 1:0.4, mixture stirring at room reaction 1 hour, remove by filter the formed precipitation of reaction, the ether in filtrate is removed in evaporation, (silicon-dioxide needs 120 ℃ of oven dryings by the silica gel column chromatography purifying crude product as eluent by ethyl acetate/petroleum ether (1:5), ethyl acetate need be used dried over mgso before use), obtain 452g colorless oil product, productive rate is 36.1%.Need not continue purifying, be directly used in next step reaction.
Three-step reaction:
Second step reaction product 450g is dissolved in 2.25L water, and the mass ratio of second step reaction product and water is 1:5, adds the 135g sodium bicarbonate, and the mass ratio of second step reaction product and sodium bicarbonate is 1:0.3, under room temperature, stirs 1 hour the pressure reducing and steaming solvent.In residue, add the 12L trichloromethane, the mass ratio of second step reaction product and trichloromethane is 1:40, carries out drying with sodium sulfate, and underpressure distillation obtains colorless oil product 193g, and productive rate is 45.0%.Need not continue purifying, be directly used in next step reaction.
Four-step reaction:
Three-step reaction product 190g is dissolved in the 3L acetonitrile, 57g sodium bicarbonate and 152g bromotrimethylsilane join in mixture, the mass ratio of three-step reaction product and acetonitrile is 1:12, with the mass ratio of sodium bicarbonate be 1:0.3, with the mass ratio of bromotrimethylsilane be 1:0.8, under the reaction mixture room temperature, stirred 2 hours.Filter out the formed precipitation of reaction, filtrate decompression distillation, resistates 1L dissolve with methanol, the mass ratio of three-step reaction product and anhydrous methanol is 1:4.3, and under room temperature, stirring is 1 hour, and carrying out underpressure distillation, to obtain orange oily crude product be 220g.
The thick product of 210g is dissolved in water, the 63g sodium bicarbonate joins in mixture in batches, the mass ratio of thick product and sodium bicarbonate is 1:0.3, with 600ml ethyl acetate washing three times, adds hydrochloric acid to regulate PH ≈ 1, mixture 600ml ethyl acetate extraction three times, the organic phase obtained is successively used 800ml water, and 800ml salt solution washs, drying, it is 122.5g that underpressure distillation obtains colorless oil, productive rate 67.0%.Need not continue purifying, directly carry out next step reaction.
The 5th step reaction:
Four-step reaction product 120g is dissolved in 780ml water, the mass ratio of four-step reaction product and water is 1:6.5, gained solution is cooled to 4 ℃, the aqueous sodium hydroxide solution that slowly adds 27ml massfraction 32.8%, the mass ratio of four-step reaction product and aqueous sodium hydroxide solution is 1:0.3, reaction mixture stirring at room 24 hours, again gained solution is cooled to 4 ℃, the aqueous hydrochloric acid that slowly adds 20ml massfraction 37%, four-step reaction product and aqueous hydrochloric acid mass ratio are 1:0.2, gained solution stirring at room 0.5 hour, lower than 60 ℃ of vacuum-dryings, remove by filter salt wherein, obtain colorless oil product 130g.
Products obtained therefrom is dissolved in 845ml water, the mass ratio of product and water is 1:6.5, gained solution is cooled to 4 ℃, slowly add the 104g sodium bicarbonate, the mass ratio of product and sodium bicarbonate is 1:0.8, and reaction mixture stirring at room 0.5 hour, lower than 60 ℃ of vacuum-dryings, obtaining the white powder product is 119.5g, and productive rate is 96.9%.
Embodiment 3:
The first step reaction:
1.5kg triethyl citrate and 1050g triethylamine are dissolved in the 25L ether; the mass ratio of triethyl citrate and triethylamine is 1:0.7; with the mass ratio of ether be 1:12; slowly join 1.5Kg methoxyl group phosphorus dichloride in mixture; the mass ratio of triethyl citrate and methoxyl group phosphorus dichloride is 1:1; stirring at room is 24 hours under nitrogen atmosphere; with tlc (sherwood oil: EA=2:1; radio frequency=0.3) detection reaction is complete; under nitrogen protection, filter and obtain thick product 1.88kg, productive rate is 93.0%.Need not continue purifying, be directly used in next step reaction.
The second step reaction:
The product 1.8kg of the first step reaction is dissolved in the 17.7L ether, the mass ratio of the first step reaction product and ether is 1:7, temperature is cooled to-5～0 ℃, the ether mixture solution of 228ml anhydrous methanol and 1.24L anhydrous triethylamine is joined to reaction mixture under passing into nitrogen and agitation condition in, stirring at room reaction 3 hours, the mass ratio of the first step reaction product and anhydrous methanol is 1:0.1, with the mass ratio of anhydrous triethylamine be 1:0.5, with nitrogen, blow away solvent, its temperature is cooled to-5～0 ℃, in system, slowly add the 1260g SULPHURYL CHLORIDE, the mass ratio of the first step reaction product and SULPHURYL CHLORIDE is 1:0.7, mixture stirring at room reaction 1 hour, remove by filter the formed precipitation of reaction, the ether in filtrate is removed in evaporation, (silicon-dioxide needs 120 ℃ of oven dryings by the silica gel column chromatography purifying crude product as eluent by ethyl acetate/petroleum ether (1:5), ethyl acetate need be used dried over mgso before use), obtain 648g colorless oil product, productive rate is 34.5%.Need not continue purifying, be directly used in next step reaction.
Three-step reaction:
The product 620g of second step reaction is dissolved in 4.96L water, and the mass ratio of second step reaction product and water is 1:8, adds the 310g sodium bicarbonate, and the mass ratio of second step reaction product and sodium bicarbonate is 1:0.5, under room temperature, stirs 1 hour the pressure reducing and steaming solvent.In residue, add the 18.8L trichloromethane, the mass ratio of second step reaction product and trichloromethane is 1:45, carries out drying with sodium sulfate, and underpressure distillation obtains colorless oil product 252g, and productive rate is 42.7%.Need not continue purifying, be directly used in next step reaction.
Four-step reaction:
Three-step reaction product 240g is dissolved in the 4.56L acetonitrile, 120g sodium bicarbonate and 240g bromotrimethylsilane join in mixture, the mass ratio of three-step reaction product and acetonitrile is 1:15, with the mass ratio of sodium bicarbonate be 1:0.5, with the mass ratio of bromotrimethylsilane be 1:1, under the reaction mixture room temperature, stirred 2 hours.Filter out the formed precipitation of reaction, filtrate decompression distillation, resistates 1.37L dissolve with methanol, the mass ratio of three-step reaction product and anhydrous methanol is 1:4.5, and under room temperature, stirring is 1 hour, and carrying out underpressure distillation, to obtain orange oily crude product be 310g.
The thick product of 310g is dissolved in water, the 155g sodium bicarbonate joins in mixture in batches, the mass ratio of thick product and sodium bicarbonate is 1:0.5, with 1L ethyl acetate washing three times, adds hydrochloric acid to regulate PH ≈ 1, mixture 1L ethyl acetate extraction three times, the organic phase obtained is successively used 800ml water, and 800ml salt solution washs, drying, it is 145.7g that underpressure distillation obtains colorless oil, productive rate 63.1%.Need not continue purifying, be directly used in next step reaction.
The 5th step reaction:
Four-step reaction product 140g is dissolved in 1120ml water, the mass ratio of four-step reaction product and water is 1:8, gained solution is cooled to 4 ℃, the aqueous sodium hydroxide solution that slowly adds 52ml massfraction 32.8%, the mass ratio of four-step reaction product and aqueous sodium hydroxide solution is 1:0.5, reaction mixture stirring at room 24 hours, again gained solution is cooled to 4 ℃, the aqueous hydrochloric acid that slowly adds 35.5ml massfraction 37%, four-step reaction product and aqueous hydrochloric acid mass ratio are 1:0.3, gained solution stirring at room 0.5 hour, lower than 60 ℃ of vacuum-dryings, remove by filter salt wherein, obtain colorless oil product 152g.
Products obtained therefrom is dissolved in 1216ml water, the mass ratio of product and water is 1:8, gained solution is cooled to 4 ℃, slowly add the 152g sodium bicarbonate, the mass ratio of product and sodium bicarbonate is 1:1, and reaction mixture stirring at room 0.5 hour, lower than 60 ℃ of vacuum-dryings, obtaining the white powder product is 135.7g, and productive rate is 94.3%.
Claims (1)
1. the synthetic method of a kind of phosphocitrate of claim is characterized in that step is as follows:
1) triethyl citrate and anhydrous triethylamine are dissolved in ether, the mass ratio of triethyl citrate and anhydrous triethylamine and ether is 1:(0.3～0.7): (6～12); The methoxyl group phosphorus dichloride is slowly joined in mixture, and the mass ratio of triethyl citrate and methoxyl group phosphorus dichloride is 1:(0.5～1), stirring at room makes to react completely simultaneously; Under nitrogen protection, filter and obtain;
2) the first step reactor product is dissolved in ether, be cooled to-5～0 ℃, the ether mixing solutions of anhydrous methanol and anhydrous triethylamine is joined to reaction system under nitrogen protection in, the stirring at room reaction, be cooled to-5～0 ℃, the first step reaction product and methyl alcohol, triethylamine, the mass ratio of ether is 1:(0.05～0.1): (0.1～0.5): (2～7), in system, slowly add SULPHURYL CHLORIDE, the mass ratio of the first step target product and SULPHURYL CHLORIDE is 1:(0.2～0.7), the stirring at room reaction, except dereaction forms the ether in precipitation and filtrate, by silica gel column chromatography purification of crude product, obtain colorless oil,
3) the second step reaction product is dissolved in water, adds sodium bicarbonate, stirring at room, pressure reducing and steaming solvent; The mass ratio of second step reaction product and water, sodium bicarbonate is 1:(3～8): (0.1～0.5); In resistates, add trichloromethane, the mass ratio of second step reaction product and trichloromethane is 1:(35～45), with sodium sulfate, carry out drying, underpressure distillation obtains colorless oil;
4) the three-step reaction product is dissolved in acetonitrile, sodium bicarbonate and bromotrimethylsilane are joined in mixture, the stirring at room reaction, the mass ratio of three-step reaction product and acetonitrile, sodium bicarbonate, bromotrimethylsilane is 1:(10～15): (0.1～0.5): (0.5～1); Filter the solid that reaction forms, the filtrate decompression distillation, resistates dissolve with methanol, the mass ratio of three-step reaction product and anhydrous methanol are 1:(4.0～4.5), stirring at room, underpressure distillation obtains thick product orange; Thick product is dissolved in water, and sodium bicarbonate is joined in mixture, and the mass ratio of thick product and sodium bicarbonate is 1:(0.1～0.5), washing, it is 1 that pH is adjusted in acid, mixture ethyl acetate extraction three times, organic phase is washed, drying, underpressure distillation obtains colorless oil;
5) the four-step reaction product is dissolved in water, be cooled to 4 ℃, the sodium hydroxide solution that slowly adds massfraction 32.8%, be cooled to again 4 ℃, the mass ratio of four-step reaction product and water, aqueous sodium hydroxide solution is 1:(5～8): (0.1～0.5), reaction stirring at room 24 hours, the hydrochloric acid soln that slowly adds massfraction 37%, four-step reaction product and hydrochloric acid soln mass ratio are 1:(0.1～0.3), stirring at room is more than 0.5 hour, vacuum-drying, filtering salt wherein, obtain the colorless oil product;
6) products obtained therefrom is dissolved in water, is cooled to 4 ℃, slowly adds sodium bicarbonate, stirring at room, and vacuum-drying, the mass ratio of product and water, sodium bicarbonate is 1:(5～8): (0.5～1) obtains white powder phosphoric acid Chinese holly edge hydrochlorate product.
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Cited By (1)
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| CN109298123A (en) * | 2018-04-23 | 2019-02-01 | 河北丰研翔科技发展限公司 | A kind of novel thin layer chromatogram scanner and the analysis method using the scanner |
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2013
- 2013-08-26 CN CN2013103762229A patent/CN103408586A/en active Pending
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| ANDREW A.PANKOWSKI等: "Synthesis via a Cyclic Dioxatrichloropbospborane of 1,3-Dibenzyl-2-Phosphonooxy Citrate", 《TETRAHEDRON LETTERS》 * |
| JOE MEYER等: "The Synthesis of Citric Acid Phosphate", 《J.AM.SOC.CHEM.》 * |
| PETRI A.TURHANEN等: ""A Novel Strategy for the Preparation of Naturally Occurring Phosphocitrate and Its Partially Esterified Derivatives"", 《J.ORG.CHEM.》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109298123A (en) * | 2018-04-23 | 2019-02-01 | 河北丰研翔科技发展限公司 | A kind of novel thin layer chromatogram scanner and the analysis method using the scanner |
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Application publication date: 20131127 |