CN1218477A - Organo phosphorous compounds - Google Patents
Organo phosphorous compounds Download PDFInfo
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- CN1218477A CN1218477A CN97194522A CN97194522A CN1218477A CN 1218477 A CN1218477 A CN 1218477A CN 97194522 A CN97194522 A CN 97194522A CN 97194522 A CN97194522 A CN 97194522A CN 1218477 A CN1218477 A CN 1218477A
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- organic phospho
- phospho acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/386—Polyphosphonic acids containing hydroxy substituents in the hydrocarbon radicals
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/105—Aliphatic or alicyclic compounds
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/179—Colouring agents, e.g. pigmenting or dyeing agents
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K50/00—Feeding-stuffs specially adapted for particular animals
- A23K50/80—Feeding-stuffs specially adapted for particular animals for aquatic animals, e.g. fish, crustaceans or molluscs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
Abstract
Disclosed are organo phosphonic acids having formula (I) where: n = 0 or 1; R1 = H or (a); R2 = (b) or (c); R3 = an alkyl group containing more than 10 carbon atoms; and R4 = H or CH3, that provide improved bio-availability of drugs and nutrients by permiabilising cell membranes. The products are prepared by the method of reacting an acid chloride of long chain aliphatic acid having 10-20 carbon atoms with an alkyl phosphonic acid derivative containing an active amino or hydroxy group in chloroform at temperatures below 5 DEG C. Especially useful are the reaction products of palmitoyl or lauroyl chloride with ethane-1-hydroxy-1,1-diphosphonic acid, 2-amino-ethyl phosphonic acid or 1-amino-ethyl phosphonic acid.
Description
The present invention relates to make the organo phosphorous compounds of medicine and the improvement of nutrient substance bioavailability by saturatingization cytolemma.More particularly described compound can similar lysophospholipid (nanoencapsulation) and the mode of phosphatide seal with the medicine ultra micro that improves nutrient intake, improves the pigment absorption of aquatic products thing and be used for drug release in the donor as animal feedstuff additive." genetically engineered teacher and ergonomist " (the The Genetic Engineer and Biotechnologist) that delivers at David Garnett and Robin Jones, 13 volumes, the 2nd phase, 1993 and International Application No. WO 94/22324 in a kind of mechanism that this bioavailability is improved is proposed.
The compound of the above-mentioned type obtains by natural compounds is purified, and is therefore impure substantially.So when comparing, need high-purity compound (for example can obtain), to improve the thermostability and the antienzyme functionality of compound from chemosynthesis with phosphatide.
Organo phosphorous compounds of the present invention is a phosphatide, and this phosphatide preferably makes by chain alkyl acyl chlorides and the organic phospho acid derivatives reaction that preferably contains activity hydroxy or amino.
One aspect of the present invention provides the compound of the organic phospho acid with following formula:
Wherein,
N=0 or 1
R
3=contain＞alkyl of 10 carbon atoms
R
4=H or CH
3
Preferred R
4It is methyl.
Alkyl acyl chloride has 10 or more carbon atoms, and preferably is no more than the chain length of about 20 carbon atoms, and specially suitable is the acyl chlorides of hexadecanoic acid and dodecylic acid.
Especially suitable phosphonate derivative is ethane-1-hydroxyl-1,1-di 2 ethylhexyl phosphonic acid (Etidronic acid) and 1 and 2 amino-ethyl phosphonic acids.
Therefore, the invention provides and a kind ofly be suitable as animal feedstuff additive, improve aquatic products on the other hand and look for the plain preparation method who absorbs and be used for the organo phosphorous compounds of the present invention of the ultra micro entrapped drug of drug release in the donor, it comprise with the acyl chlorides of longer chain fatty acid and the alkyl phosphonic acid derivative that contains active amino or hydroxyl in non-aqueous media (preferred chloroform) and react under the low temperature, with cold water washing and carry out drying subsequently.
Preferable reaction temperature remains below 5 ℃ and more preferably 3-5 ℃.
Preferred reactant is used by stoichiometric ratio simultaneously.
The present invention also provide above-mentioned as animal feedstuff additive, improve the pigment absorption of aquatic products thing or be used for the organic phosphoric acid that the medicine ultra micro of drug release is sealed in the donor.
Another aspect of the present invention provides can be as animal feedstuff additive and by ethane-1-hydroxyl-1, and the 1-di 2 ethylhexyl phosphonic acid is in non-aqueous media and be lower than the organo phosphorous compounds of the present invention that makes with the reaction of n-Hexadecane acyl chlorides under 5 ℃ the temperature.
Another aspect of the present invention provides the production method of the organic phospho acid derivative of the present invention that a kind of medicine ultra micro that is applicable to that drug disposition discharges seals, this method be with 1 or 2-amino-ethyl phosphonic acids and hexadecyl acyl chlorides be lower than in the non-aqueous media neutralization under 5 ℃ the temperature and react.
The following example illustrates but does not limit the present invention.
Add the solution of 206g Etidonic acid (ethane-1-hydroxyl-1,1-di 2 ethylhexyl phosphonic acid) in the 1L chloroform from a bite of three mouthfuls of glass reaction bottles of 5L that agitator is housed, and make this solution be cooled to 3-5 ℃.When temperature was remained on 3-5 ℃, another mouthful from reaction flask under vigorous stirring added 275g n-Hexadecane acyl chlorides.The hydrochloric acid that reaction is emitted is derived and is made it pass through the sodium hydroxide scrubber through the 3rd mouthful.After all the n-Hexadecane acyl chlorides finishes, continue to stir 60 minutes.With in the content impouring cold water in the reaction flask, separate and remove chloroform and the unreacted n-Hexadecane acyl chlorides that exists with n-Hexadecane carboxylic acid (a kind of wax) form when reaction finishes.Further with of the unreacted Etidonic acid of cold water washing products therefrom with the removal trace.Product is through repetitive scrubbing after-filtration and dry under vacuum.
The yield of product is 90% of a theoretical value.
Product is at about 70 ℃ of following water solubles and to obtain pH be 10.5 solution, and is qualitative by near infrared (NIR) spectrum shown in the accompanying drawing 1 (recording with NIR system series 5000 spectrometers) simultaneously.Can be sure of that product has following structure:
Ethane-1-hexadecanoyl-1, the 1-di 2 ethylhexyl phosphonic acid is described among the embodiment 9 below for the influence of fish pigment picked-up.
Embodiment 2
Substitute Etidonic acid with 125g2-amino-ethyl phosphonic acids and repeat embodiment 1 described method.
Product yield is 90% of a theoretical value.Thereby product is dissolved under 60 ℃ and obtains pH in the water is 3.33 solution.
Product has NIR spectrum as shown in Figure 2 and is had following structure certainly:
Embodiment 3
Replace 2-amino-ethyl phosphonic acids to repeat embodiment 2 with 1-amino-ethyl phosphonic acids.Product yield is 60% and has as shown in Figure 3 NIR spectrum.Product is dissolved under 60 ℃ and obtains pH in the water to be 3.76 solution and to be sure of to have structure as follows:
Embodiment 4
Repeat embodiment 1 with 219g dodecanoyl chloro for the n-Hexadecane acyl chlorides.
Product yield is 23.2% of a theoretical value, and product is dissolved under 60 ℃, and to obtain pH in the water be 10.42 solution.Product is qualitative and be sure of to have structure as follows by NIR spectrum as shown in Figure 4:
Embodiment 5
Repeat embodiment 3 with 219g dodecanoyl chloro for the n-Hexadecane acyl chlorides.Product yield is 20% of a theoretical value.
Be sure of that product has structure as follows:
Replace n-Hexadecane acyl chlorides and Etidronic acid or the reaction of 2-amino-ethyl phosphonic acids not to generate any valuable product with capryl(yl)chloride.
Embodiment 6
The preparation of 1-hexadecanoyl amino-ethyl phosphonic
Preparation divided for three steps carried out.Step 1:
With thiocarbamide (9.89g, 130mmol) add to acetaldehyde (18.57ml, 325mmol) and triphenyl phosphite (68.13ml in acetate 325mmol) (130ml) solution, stirs gained solution, and 80 ℃ down heating obtained orange solution in 1 hour.Add diacetyl oxide (325ml) and, obtain dark brown solution gained solution backflow 2 hours.Refluxed 8 hours then through careful 37% the hydrobromic acid aqueous solution (325ml) of dripping of condenser, and with gained solution, then cooling and rotary evaporation.Dark resistates is dissolved in the ethanol (260ml), and slowly to add methyl oxirane be 6 until pH.Should reinforced the aminophosphonic acid A of following listed reaction product be precipitated out rapidly.Make solid settlement and decantation supernatant liquid.Add new system ethanol (250ml) and with the of short duration backflow of mixture, cool off then and strain except that ethanol.Repeat such washing until sloughing major part is brown.At last that solid is dry under high vacuum, slightly be with look solid aminophosphonic acid A (8.23g, 50.6%), fusing point＜290 ℃ (decomposition).
Step 2:
With phosphoramidic acid A (8.23g, 65.8mmol) and hexamethyldisilazane (55.5ml, mixture 263mmol) heat in 150-160 ℃ oil bath until all solids dissolving (2-5 hour).Steam to remove excessive hexamethyldisilazane and with the resistates distillation, obtain colorless oil and under 15mmHg boiling point be 140 N, O, O-front three silane derivative B (17.50g, 86%), the structure of this product is as shown in following reaction formula:
Step 3:
With hexadecanoic acid (13.18g, 51.4mmol) solution in anhydrous ethyl acetate (80ml) stirs down at-5 ℃, use successively subsequently triethylamine (17.15ml, 5.4mmol) and Vinyl chloroformate (5.57g 51.4mmol) handles, and back one component is dropping.The gained turbid mixture stirred 0.5 hour at-5 ℃, drip the solution of front three silane derivative B in ethyl acetate (35ml) then, and stirred the gained mixture 2 hours at uniform temp, and under not cooling situation, stirred 2 hours then, stirred 3 hours at 80 ℃ at last.From cooling mixture, remove volatile matter by rotary evaporation.Resistates is dissolved in the saturated sodium bicarbonate aqueous solution, with gained solution with 10% hcl acidifying to pH be 2, and leach sedimentary acylamino acid C.To remove remaining hexadecanoic acid, drying under high vacuum obtains white solid 1-hexadecanoyl amino-ethyl phosphonic acids C (16.0g, 86%) to solid crude product then with methanol wash.
The NMR spectrogram of the lysophospholipid of gained as shown in Figure 5.
Embodiment 7
The G-MEM (SigmaG5154) that adds 200mM L-glutaminate (Sigma G7513), 5%TSB (Sigma T8159) and the 10ml/L microbiotic/antimicrobial (Sigma A9909) of 10%FBS (Sigma F2442), 10ml/L with ordinary method and utilization cultivates BHK21 (clone 13) cell.At 37 ℃ and 5%CO
2Under carry out cell cultures.Above-mentioned clone is the European animal cell culture preservation center from using microbe that is positioned at Porton Down and research centre.
Above-mentioned cell is cultivated in 24 hole flat boards (Sigma M9655).All test triplicate.
The hole inner cell is exposed to from the C of 1 μ Ci of 75 μ Ci storing solutions, preparation Hanks balanced salt solution (SigmaH9394)
14Under the inulin.These cells also are exposed under embodiment 1 product of different concns simultaneously.Cultivate and take out medium after 1 hour.With attached cell subsequently with twice of HanksShi solution washing and use trypsinase-EDTA solution (Sigma T5775) pair cell to carry out trysinization again, under 1000rpm and in the Eppendorf that weighs the in advance pipe with cell centrifugation slabbing throw out.Use distilled water lysing cell pellet then.Recentrifuge Eppendorf pipe migrates out equal portions distilled water (100 μ) then, mixes with Sigma fluorine scintillation mixed solution (SigmaFluor Scintillation cocktail) (Sigma S4398) and utilizes the scintillometer reading.After Eppendorfs is weighed once more, the result is scaled DPM/mg cell weight.
The gained result is plotted as the figure shown in the accompanying drawing 6 and knows and demonstrates a kind of two-phase response, wherein, the flux that inulin enters cell under lower concentration reduces very much, but this flux increases significantly under higher dosage, and inulin is a kind of bigger compound and is not very typical being supposed to by the compound of preferential absorption simultaneously.Other big or small molecules also can observe identical effect.
Can draw the conclusion of the emulsion formation characteristic of relevant phosphatide and mixture of phospholipids from the mensuration of lecithin preparations emulsifying capacity.A kind ofly be used to measure that to surpass after 24 hours the empirical method of still stable O/w emulsion percentage amounts as described below:
Get 100ml distilled water and vegetables oil and place beaker.Add Yelkin TTS test sample (being generally 1g).Under 25 ℃, utilize high speed rotating mixing tank homogenizing mixture 1 minute.At once content is all transferred in the recorder jar and and placed 24 hours down at 25 ℃.Calculate the percentage amounts that remains oil-in-water emulsions after 24 hours.
Yelkin TTS compared to measure with 90% Yelkin TTS-10% embodiment, 1 product obtains following result:
Blank (Conto1): 0.0010
Yelkin TTS: 0.1948
The product of 90% Yelkin TTS-10% embodiment 1: 0.222
The above results shows that emulsifying capacity improved 12.3%.
Formed embodiment 2 products that comprise are described among the embodiment 8 below at the improved stability of interior oil-water mixture (Miscelle).Embodiment 8
Prepare liposome by following method:
14, about 30 seconds homogenizing prepares 1% water dispersion of embodiment 2 products under the 000rpm by the Utra-TurrexT25 homogenizer.Preparation two cover liposomes, in preparation, first kind of testing sample is to be formed by pure phosphatidylcholine (Yelkin TTS), and second kind be to make with 10% embodiment 2 products.Utilize Cecil Series2 instrument spectrophotometry liposome concentration under the 500NM wavelength.Liposomal formulation with microscopic examination to carry out spectrophotometric calibration.Oil-water mixture (miscelle) preparation was heated 30 minutes down in 30 heating 10 minutes and 3 hours and at 60 ℃ with water-bath.Analytical results is as follows:
10 minutes 3 hours 60 ℃-30 minutes
Yelkin TTS 1.31 1.288 0.975 Yelkin TTS+10% real 1.34 1.338 1.062
Execute example 2 products
Net added value 0.022% 3.88% 8.92%
The above results shows that oil-water mixture significantly increases in pyritous stability in the presence of the made phosphatide of the present invention.
Embodiment 9 ethane-1-hexadecanoyl-1,1-di 2 ethylhexyl phosphonic acid (Corbinol) is to the influence of salmon pigment picked-up
This test adopt 350 that come by pure Mowi crossability kind, to reach 24 monthly ages and average initial body weight through raising be that the first effluent of 1.2Kg is gone into Atlantic atlantic salmon.
Details are as follows for 5 kinds of used treatment facilities:
Four adjacent 5m proofing boxs of A-
A 12m breeding of B-case (seawater bath blank)
A B diameter 5.0m 12.0m tank wall height 1.2m 1.8m depth of water 0.9m 1.6m capacity 17.6m 180.0m makes up: make the cement box embedding on the ground of plane and undercoat level and smooth.What water-in: A was positioned at the single 100mm in case surface makes advancing of entry direction around tank edge
The mouth of a river.Current are per minute 2000L with butterfly valve control-peak flow.
What B was positioned at case surface single 200mm makes entry direction around tank edge
Water-in.Current are per minute with slide valve control-peak flow
2000L。Water outlet: A is positioned at middle part at the bottom of the case and the 0.6m that links to each other with the long rising pipe of 150mm *
0.6m the horizontal screen of diameter.
B be positioned at middle part at the bottom of the case and with 200mm long go out the 0.5m that bucket links to each other *
0.8m the horizontal screen of diameter.The water source:
A is in order in the autonomous salt solution header tank of a 11kw impeller pump (preparing and carrying usefulness) to draw water
Go into the casing water-in.Header tank by two lowest depth of independently drawing water is
Being lower than surperficial 3m pump system supplies water.Salt concn is 27ppt-31ppt.Water
Grizzly bar with 15mm before entering pump sieves.Water is not by casing once (no
Recirculation) and retention time be less than 1 hour.
The B casing is directly intake in main salt solution header tank.Ventilation: each case provides air by air diffuser separately from big agricultural gas blower.
The oxygen level that can effectively improve like this under the normal condition also will be in the event of failure of supplying water
Make fish continue a few hours of surviving under the barrier situation.Water level control: A is positioned at the external fixation pipe in the shared discharging pond adjacent with casing.
B external fixation pipe.Jump net (jump netting): around casing and the predation line be provided with 200mm high 85
% covering net (shade netting).The thrashing indication:
Low-water level buoyancy aid switch is installed in each casing.Be connected and whole day 24 with the center warning horn
Hour monitor.Automatic feeding:
Each case is all installed a timing that can be suspended in the 3kg capacity of water surface top, casing edge
Feeding apparatus.
Also with automatic feeding machine as a supplement come fish carried out 3 time feeding by artificial every day.The about 50% whole day food ration of calculating according to standard merchandise raising table is by manually providing.For increasing the body weight of fish,, can suitably adjust feeding speed in weekly.
Their body weight separately and definite cause of the death are taken out and write down to the fish of death at once.Anyly in process of the test be considered to essential disease treatment and should in all fish boxes, carry out, to reduce because the difference between the case that treatment may cause.
The current that keep the process casing are to guarantee that minimum dissolved oxygen level is 7.0mg/L.Detect the content of oxygen every day, and can will regulate current if desired to keep balance between fish box.Regularly scrub fish box with prevent tip long-pending and too much suspended solids.
Write down water temperature every day.
Adopt the following method fish of weighing:
Close the current that enter casing and make the depth of water reduce to 20cm.Utilization is installed in the intravital scatterer of case and keeps oxygen level.Then narcotic (being dissolved in the parathesin in the methylated spirit) is added to the water and makes the fish calmness.With net fish is dragged for to volume and to be 40L and to be equipped with in the well-bucket of 15L water, weigh with Salter 50kg suspension type spring balance in batches.Stress level and physical injury all remain on minimum like this.
The food of fish is as follows: food A-55ppm astaxanthin food B-55ppm astaxanthin+Corbinol (ethane-1-hexadecanoyl-1,1
-di 2 ethylhexyl phosphonic acid) food C-standard Trouw 75ppm astaxanthin (blank).
Divide 350 fishes equally in 5 casees (70 in every case).Case 1 and 3 usefulness food A feedings; Case 2 and 4 usefulness food B feedings (all being the A molding box); Sea water tank food C feeding (Type B case)
The pellet sizes of fish food is 6.5cm.
This test was carried out 36 days.
The gross weight of fish in each case of weighing when on-test and off-test.Carry out the sampling of the fish sample of corpse analysis after 4 weeks.Sample in the following time:
Get 10 fishes during on-test as base value:
In each case, get 10 fishes after 4 weeks;
When 36 days times finish, get all fishes that survive and make sample.
Utilize the astaxanthin level of HPLC analytic sample after selected immediately.
Therefore analyze after the 4th week, the 1st group of chromogenesis that demonstrates maximum range selected more fish and analyzed with HPLC from organizing 1.Get that 25% fish carries out that HPLC measures and all fishes carry out Roche Fan score value and determine.
Table 1 is listed the statistic by trial sheet.
Accompanying drawing 7 representative is with the diagram of the fish of each nursing of the three kinds of foods weight when the off-test.
Accompanying drawing 8 representative is with the diagram of the fish of each nursing of the three kinds of foods RocheFan score value when the off-test.
Result shown in the accompanying drawing 7 and 8 calculates with standard differentiate (derivation) method, and draws the difference of comparing the fish quantity of feeding with food A and B with the fish number of feeding with blank food.
Accompanying drawing 7 shows with nutrient substance (astaxanthin) and the common fish of raising of organic-phosphorus compound (Corbinol) has bigger increase than the weight with the fish that does not contain organic phosphorus compound food nursing.
Accompanying drawing 8 is represented to show higher Roche Fan score value with nutrient substance (astaxanthin) and the common fish ratio of raising of organic-phosphorus compound (Corbinol) with the fish that does not contain organic phosphorus compound food nursing.
Food kgs 15.8 14.2 15.5 18.0 0 efficiency of food conversion 0.92 0.96 1.17 0.91 0 mean temperatures 7.9 foods that average weight 1.393 1.421 1.373 1.517 1.230% increments 21.3 17.5 16.1 22.8 25.5 consumed than growth rate (% days) 0.54 0.45 0.410 0.57 0.63 when weight 00000 weight of gross weight 97.5 99.5 96.1 106.2 86.1 death increased by 17.1 14.8 13.3 19.7 17.5 initial average weights 1.149 1.210 1.183 1.236 0.980 end when quantity 70 70 70 70 70 initial gross weights 80.4 84.7 82.8 86.5 68.6 finished when the test statistics measuring tank 1234 seawater bath food A B A B C from date 27.2.95 Close Date 4.4.95 fates 36 36 36 36 36 starting quantities 70 70 70 70 70 dead quantity 00000 of table 1 embodiment 9 finished: A Trouw65,55ppm astaxanthin
B Trouw 65,55ppm astaxanthin+corbinol
The blank Trouw65 of C, the 75ppm astaxanthin
Food is directly provided by Trouw.
Corhinol (ethane-1-hexadecanoyl-1,1-di 2 ethylhexyl phosphonic acid)
Claims (16)
1. the organic phospho acid compound that has following formula:
Wherein:
N=0 or 1
R
3=contain＞alkyl of 10 carbon atoms
R
4=H or CH
3
2. the organic phospho acid compound in the claim 1, wherein R
4Be methyl.
3. the organic phospho acid in the claim 2, it has following formula:
4. the organic phospho acid in the claim 2, it has following formula:
5. the organic phospho acid in the claim 2, it has following formula:
6. the organic phospho acid in the claim 1, it has following formula:
7. the organic phospho acid in the claim 2, it has following formula:
8. method for preparing the described organic phospho acid compound of claim 1, be included in the non-aqueous media and low temperature under make the acyl chlorides of longer chain fatty acid react, wash with water and dry with the alkyl phosphonic acid derivative that contains active amino or hydroxyl.
9. the method for preparing the organic phospho acid compound in the claim 8, wherein non-aqueous media is a chloroform.
10. the method for preparing the organic phospho acid compound in the claim 8 or 9, wherein temperature remains on below 5 ℃.
11. the method for preparing the organic phospho acid compound in the claim 10, wherein temperature range is 3-5 ℃.
12. each the method for preparing the organic phospho acid compound among the claim 8-11 contains in the chain of wherein said long-chain fat isoxazolecarboxylic acid and is less than 20 carbon atoms.
13. the method for preparing the organic phospho acid compound in the claim 12, wherein acyl chlorides is n-Hexadecane acyl chlorides or dodecane acyl chlorides.
14. each the method for preparing the organic phospho acid compound among the claim 8-13, wherein phosphonate derivative is ethane-1-hydroxyl-1,1-di 2 ethylhexyl phosphonic acid (Etidonic acid) or 1 or 2-amino-ethyl phosphonic acids.
15. each the method for preparing the organic phospho acid compound among the claim 8-14, wherein reaction reagent uses by stoichiometric ratio.
16. each organic phospho acid compound among the claim 1-7, it as the animal foodstuff additive, improve the pigment picked-up of aquatic products thing or be used for the medicine ultra micro that drug disposition discharges and seal.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9607583.3A GB9607583D0 (en) | 1996-04-12 | 1996-04-12 | Organo phosphorous compounds |
| GB9607583.3 | 1996-04-12 | ||
| GB9617729.0 | 1996-08-23 | ||
| GB9617729A GB2311991B (en) | 1996-04-12 | 1996-08-23 | Organo phosphorus compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1218477A true CN1218477A (en) | 1999-06-02 |
Family
ID=26309109
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97194522A Pending CN1218477A (en) | 1996-04-12 | 1997-04-14 | Organo phosphorous compounds |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0892806A1 (en) |
| CN (1) | CN1218477A (en) |
| BR (1) | BR9708660A (en) |
| GB (1) | GB2323089B (en) |
| NO (1) | NO984671L (en) |
| WO (1) | WO1997039004A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107602610A (en) * | 2017-09-09 | 2018-01-19 | 南通意特化工有限公司 | It is a kind of can reuse sulfuric acid wastewater containing organic phospho acid production technology |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0400988D0 (en) * | 2004-01-16 | 2004-02-18 | Oxoid Ltd | Therapeutically useful antibacterial compounds |
| DE102004032781A1 (en) | 2004-01-23 | 2005-08-11 | Mcs Micro Carrier Systems Gmbh | New lipid-modified bis-phosphonic acid derivatives, useful e.g. for transporting therapeutic or diagnostic agents, with affinity for bone, also as corrosion inhibitors |
| US8901333B2 (en) | 2008-10-03 | 2014-12-02 | Life Technologies Corporation | Nanocrystals with functional ligands |
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|---|---|---|---|---|
| US2304156A (en) * | 1940-03-07 | 1942-12-08 | Du Pont | Organic compound and process of preparing the same |
| DE2530139C3 (en) * | 1975-04-30 | 1979-06-21 | Joh. A. Benckiser Gmbh, 6700 Ludwigshafen | N-acyl-1-aminoalkane-1,1-diphosphonic acids, their preparation and use |
| DE2651048A1 (en) * | 1976-11-09 | 1978-05-18 | Hoechst Ag | PLASTIC DISPERSION WITH HIGH WET ADHESION AND METHOD FOR THEIR PRODUCTION |
| JP2612619B2 (en) * | 1988-12-14 | 1997-05-21 | 財団法人相模中央化学研究所 | Transdermal absorption enhancer consisting of phosphorus-containing compound |
| EP0550385A1 (en) * | 1991-12-19 | 1993-07-07 | Ciba-Geigy Ag | Oral pharmaceutical compositions containing derivatives of methane-diphosphonic acid and 18-crown-6 ethers |
| GB2267033B (en) * | 1992-03-07 | 1996-01-24 | David Garnett | Lysophospholipid Animal Feed Supplement |
| US5523430A (en) * | 1994-04-14 | 1996-06-04 | Bristol-Myers Squibb Company | Protein farnesyl transferase inhibitors |
-
1996
- 1996-08-23 GB GB9726184A patent/GB2323089B/en not_active Expired - Fee Related
-
1997
- 1997-04-14 WO PCT/GB1997/001020 patent/WO1997039004A1/en not_active Application Discontinuation
- 1997-04-14 EP EP97916556A patent/EP0892806A1/en not_active Ceased
- 1997-04-14 BR BR9708660-6A patent/BR9708660A/en not_active Application Discontinuation
- 1997-04-14 CN CN97194522A patent/CN1218477A/en active Pending
-
1998
- 1998-10-06 NO NO984671A patent/NO984671L/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107602610A (en) * | 2017-09-09 | 2018-01-19 | 南通意特化工有限公司 | It is a kind of can reuse sulfuric acid wastewater containing organic phospho acid production technology |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2323089A8 (en) | 1998-09-24 |
| GB2323089B (en) | 1999-02-10 |
| NO984671L (en) | 1998-12-04 |
| GB2323089A (en) | 1998-09-16 |
| NO984671D0 (en) | 1998-10-06 |
| WO1997039004A1 (en) | 1997-10-23 |
| GB9726184D0 (en) | 1998-02-11 |
| EP0892806A1 (en) | 1999-01-27 |
| BR9708660A (en) | 2000-01-04 |
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