CN109232883A - It is a kind of than Sha Luomu post-processing approach - Google Patents
It is a kind of than Sha Luomu post-processing approach Download PDFInfo
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- CN109232883A CN109232883A CN201710555419.7A CN201710555419A CN109232883A CN 109232883 A CN109232883 A CN 109232883A CN 201710555419 A CN201710555419 A CN 201710555419A CN 109232883 A CN109232883 A CN 109232883A
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
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Abstract
Easy to operate the invention discloses a kind of post-processing approach than Sha Luomu, the chlorinty of product is low, and swelling ratio is low, and phosphate binding capacity is suitable with Japan's listing preparation.It comprises the concrete steps that: after the reaction was completed, reaction residual being added in purified water, is stirred, is crushed, washing is drying to obtain；The washing step is successively with anhydrous methanol, dilute hydrochloric acid, sodium hydroxide solution and purifying water washing.
Description
Technical field
The present invention relates to a kind of post-processing approach, and in particular to a kind of post-processing approach than Sha Luomu.Belong to medical skill
Art field.
Background technique
Chronic kidney disease disease incidence is up to 10%, it has also become threatens the stealthy killer of human health.Hyperphosphatemia is chronic
Kidney trouble, the especially common complication of End-stage renal disease patient, it is seen that in 80% dialysis patient.Hyperphosphatemia is dystopy
An important factor for calcification, secondary hyperparathyroidism and renal osteodystrophy.Effectively control serum paraoxonase level be
The key of patients with chronic kidney disease prognosis.Most patients can not reach control standard by middle phosphorus intake of keeping on a diet, because
And it needs to reach control purpose by application phosphate binder.Even if when the chronic renal disease later period starts dialysis treatment, still
It needs that phosphate binder auxiliary is cooperated to reduce serum phosphorus levels.
It is more entitled N, N, N than the chemistry of Sha Luomu ', N '-four (3- aminopropyl)-Putriscine-epihalohydrin copolymer,
It is a kind of anion exchange resin, belongs to the novel phosphate binder of non-calcium non-aluminum, is not easy to cause serum calcium, aluminium raising, adverse reaction
It is relatively small.
Chinese patent CN100551951C discloses two kinds of preparation methods than Sha Luomu, and a kind of method is with toluene and water
For reaction dissolvent, another method is using water as reaction dissolvent, and reaction route is as follows:
Its specific method is:
One, using toluene and water as reaction dissolvent
Prepare stock solution: the concentrated hydrochloric acid of 2 molar equivalents be added to the N of 1 molar equivalent, N, N through 2 hours first ',
In N '-four (3- aminopropyl)-Putriscine, then by water and surfactant (branched dodecylbenzene sulfonic acid sodium, 30 weights
Amount % aqueous solution) it is added in the solution, form resulting solution with following weight %: BTA41.8 weight %, HCl9.4
Weight %, 41.1 weight % of water, surfactant (30 weight % aqueous solution) 7.7 weight %.The reactor used is an appearance
Product is the round-bottomed flask that 0.25L has baffle with three mouthfuls and four sides.The flask is returned using oil bath heating and equipped with a water cooling
The mechanical agitator of flow condenser and 1 inch spiral paddle.25g stock solution and 75g toluene are added to the reaction first
In device.In another container, solution of the epoxychloropropane of 40 weight % in toluene is prepared.With syringe pump by the desired amount of ring
Oxygen chloropropane was added in reactor through 90 minutes.Reaction carries out 2 hours, then starts to be dehydrated with Dean and Stark apparatus.When
When all water is removed from the system, reaction reaches terminal.Bead is purified by the following steps.Remove toluene, with methanol,
Wash again with 20%NaOH aqueous solution (removal surfactant), then protonating bead thus with HCl, resulting particle is again
It is washed with deionized and removes excessive HCl at least twice.Particle is 3 days dry under freezing, becomes white powder.
Two, using water as reaction dissolvent
Prepare stock solution: the concentrated hydrochloric acid of 2 molar equivalents be added to the N of 1 molar equivalent, N, N through two hours first ',
In N '-four (3- aminopropyl)-Putriscine, the solution is then added water to, so that solution reaches following quality composition: N, N,
N ', N '-four (3- aminopropyl)-Putriscine accounts for 45%, HCl and accounts for 10%, and water accounts for 45%.In 24 hole reactors, use
Simultaneously 0.6g stock solution is added in the reaction flask of 5mL, and epoxychloropropane is added, and heats 80 DEG C and maintains 9 hours, then makes reactor cold
But, add water-swellable, the gel is then crushed to micron order, with methanol, again with 20%NaOH aqueous solution (removal surface-active
Agent) washing, then with HCl make bead protonation thus resulting particle be washed with deionized again remove at least twice it is excessive
HCl.Particle is 3 days dry under freezing, becomes white powder.
Two lines post processing mode is first then to use salt pickling with alkali cleaning, is finally washed, applicant's difference experiment investigation
Both methods is as a result as follows:
The chlorinty of one products obtained therefrom of method is high, swelling ratio is high, phosphate binding capacity is low, and method two can obtain solid production
Object, the product swelling ratio (being the grams of every gram of dry cross-linked polymer institute lyosoption when balancing in aqueous environments) is low, about
Less than 2.5, but the phosphate binding capacity of product, it is below and lists preparation (trade name: キ ッ Network リ Application than Sha Luomu Japanカ
プ セ Le 250mg, Astellas Pharma Inc.), and the chlorinty of products obtained therefrom is higher, there is more serious amplification effect
It answers.
Summary of the invention
The purpose of the present invention is to overcome above-mentioned the deficiencies in the prior art, provide a kind of post-processing approach than Sha Luomu.
To achieve the above object, the present invention adopts the following technical solutions:
A kind of post-processing approach than Sha Luomu, comprises the concrete steps that: by N, N, N ', N '-four (3- aminopropyl)-Isosorbide-5-Nitrae-fourth two
Amine is dissolved in purified water, and epoxychloropropane is added dropwise, and after the reaction was completed, reaction residual is added in purified water, is stirred, is crushed,
Washing, is drying to obtain.
The washing step is successively with anhydrous methanol, dilute hydrochloric acid, sodium hydroxide solution and purifying water washing.
It is finally washed twice with purified water in the washing step.
N, N, N ', (3- the aminopropyl) -1,4- butanediamine of N '-four and anhydrous methanol, dilute hydrochloric acid, sodium hydroxide solution and purifying
The mass volume ratio of water is 1g:20mL.
The dilute hydrochloric acid mass concentration is 1%.
The sodium hydroxide solution mass concentration is 5%.
N, N, N ', the mass ratio of (3- the aminopropyl) -1,4- butanediamine of N '-four and dissolution purified water is 1:1；With post-processing
It is 1g:20mL with the mass volume ratio of purified water.
Washing step of the invention is finally washed again using first pickling by alkali cleaning, can remove extra sodium hydroxide and generation
Sodium chloride, thus make chlorinty with Japan listing preparation it is suitable.If pickling after first alkali cleaning, due to hydrochloric acid can with amino at
Salt can not wash removing, it is easy to cause chlorinty in product excessively high (10% or more).
Beneficial effects of the present invention:
Post-processing approach provided by the invention than Sha Luomu, easy to operate, the chlorinty of product is low, and swelling ratio is low, phosphorus
Hydrochlorate binding capacity is suitable with Japan's listing preparation, especially suitable for industrialized production.
Specific embodiment
Below with reference to embodiment, the present invention will be further elaborated, it should explanation, following the description merely to
It explains the present invention, its content is not defined.
Reaction route of the invention is following (reaction condition is shown in each embodiment):
The detection method of chlorinty of the present invention, swelling ratio and phosphate binding capacity is as follows:
Chlorinty
Product to be tested about 1.0g is taken, accurately weighed, silver nitrate titration liquid (0.1mol/L) 10mL, water 50mL and nitre is added in precision
Sour 2mL boils 10 minutes, cooling, adds nitrobenzene 3mL and ammonium ferric sulfate indicator 2mL, shakes up, with ammonium thiocyanate titrating solution
(0.1mol/L) is titrated to the aobvious red of solution, and the result of titration is corrected with blank test.Every 1mL silver nitrate titration liquid
(0.1mol/L) is equivalent to the Cl of 3.545mg.
Swelling ratio
Product to be tested about 0.04g is taken, precise weighing (W is set1, g) the stirring cup with stirring rotator in, it is accurately weighed
(W2, g), then the accurate buffer that is added (takes sodium chloride 1.75g and BES (bis- (2- the ethoxy) -2-aminoethanesulfonic acids of N, N-)
19.19g adds water 200mL to make to dissolve, and adjusts pH value to 7.0 with 1mol/L sodium hydroxide, is diluted with water to 300mL) 2mL, it is close
Envelope is inverted, is stirred 30 minutes on magnetic stirring apparatus, then with 4500 turns of speed per minute centrifugation 60 minutes, discards filtrate, essence
Close weighed (W3, g), it records and calculates, takes three parts of this product to be measured, the RSD of measurement result must not exceed 5% three times.
Calculation formula:
Phosphate binding capacity
The preparation of reference substance solution: 105 DEG C of dryings are taken to the potassium dihydrogen phosphate about 2.72g of constant weight, sodium chloride about
4.68g, BES (N, N- bis- (2- ethoxy) -2-aminoethanesulfonic acid) about 21.32g, it is accurately weighed, add water 900mL to make to dissolve, uses
It is saturated sodium hydroxide solution and adjusts pH value to 6.0, add water to be settled to 1000mL, shake up, as reference substance solution.
Measuring method: taking product to be tested about 70mg, accurately weighed, sets in 50mL measuring bottle, reference substance solution is added to be diluted to scale, stir
1h is mixed, is filtered, precision measures subsequent filtrate 1mL, sets in 100mL measuring bottle, is diluted with water to scale, shakes up, and precision measures 20 μ l, note
Enter ion chromatograph, records chromatogram.Another accurate measurement reference substance solution 7mL, sets in 10mL measuring bottle, is diluted with water to scale,
It shakes up, then accurate measurement 1mL, sets in 100mL measuring bottle, be diluted with water to scale, shake up, as standard solution, be measured in the same method.It presses
Following formula calculates phosphate Percentage bound.
Calculation formula:
C is the concentration of reference substance solution, mg/mL in formula；
ASampleFor the peak area of test solution；
AIt is rightFor the peak area of standard solution
W is test sample sample weighting amount, mg；
LOD is loss on drying, %.
Embodiment 1
By 15g (47.4mmol) N, N, N ', N '-four (3- aminopropyl)-Putriscine is dissolved in 15g purified water, cooling
It to 15~20 DEG C, is added dropwise epoxychloropropane 9.21g (99.5mmol), temperature control is no more than 25 DEG C, is heated to after being added dropwise
It 80 DEG C, reacts 9 hours, is down to room temperature, reaction residual is added in purified water 300mL and be stirred, is crushed, and with anhydrous methanol,
1wt% dilute hydrochloric acid, 5wt% sodium hydrate aqueous solution, purified water, each 300mL of purified water are washed, constant pressure and dry 24 hours at 50 DEG C
Obtain product 15g, yield 61.9%.
Embodiment 2
By 150g (0.474mol) N, N, N ', N '-four (3- aminopropyl)-Putriscine is dissolved in 150g purified water, drop
Temperature is added dropwise epoxychloropropane 96.46g (1.04mol) to 15~20 DEG C, and temperature control is no more than 25 DEG C, and rear heat temperature raising is added dropwise
It to 80 DEG C, reacts 10 hours, is down to room temperature, reaction residual is added in purified water 3000mL and be stirred, is crushed, and with no water beetle
Alcohol, 1wt% dilute hydrochloric acid, 5wt% sodium hydrate aqueous solution, purified water, each 3000mL of purified water are washed, the constant pressure and dry 35 at 50 DEG C
Hour obtains product 155g, yield 62.9%.
Embodiment 3
By 1.5kg (4.74mol) N, N, N ', N '-four (3- aminopropyl)-Putriscine is dissolved in 1.5kg purified water, drop
Temperature is added dropwise epoxychloropropane 1.01kg (10.9mol) to 15~20 DEG C, and temperature control is no more than 25 DEG C, and rear heat temperature raising is added dropwise
It to 80 DEG C, reacts 9 hours, is down to room temperature, reaction residual is added in purified water 30L and be stirred, is crushed, and with anhydrous methanol,
1wt% dilute hydrochloric acid, 5wt% sodium hydrate aqueous solution, purified water, each 30L of purified water are washed, and are obtained within constant pressure and dry 48 hours at 50 DEG C
To product 1.57kg, yield 62.5%.
Embodiment 4
By 15kg (47.4mol) N, N, N ', N '-four (3- aminopropyl)-Putriscine is dissolved in 15kg purified water, cooling
It to 15~20 DEG C, is added dropwise epoxychloropropane 10.08kg (109mol), temperature control is no more than 25 DEG C, is heated to after being added dropwise
It 80 DEG C, reacts 10 hours, is down to room temperature, reaction residual is added in purified water 300L and be stirred, is crushed, and with anhydrous methanol,
1wt% dilute hydrochloric acid, 5wt% sodium hydrate aqueous solution, purified water, each 300L of purified water are washed, constant pressure and dry 48 hours at 50 DEG C
Obtain product 15.6kg, yield 62.2%.
Comparative example
By 15g (47.4mmol) N, N, N ', N '-four (3- aminopropyl)-Putriscine is dissolved in 15g purified water, cooling
It to 15~20 DEG C, is added dropwise epoxychloropropane 9.21g (99.5mmol), temperature control is no more than 25 DEG C, is heated to after being added dropwise
It 80 DEG C, reacts 9 hours, is down to room temperature, reaction residual is added in purified water 300mL and be stirred, is crushed, and with anhydrous methanol,
5wt% sodium hydrate aqueous solution, 1wt% dilute hydrochloric acid, purified water, each 300mL of purified water are washed, constant pressure and dry 24 hours at 50 DEG C
Obtain product 14.5g, yield 59.8%.
The elemental analysis of Examples 1 to 4 and comparative example product the results are shown in Table 1..
The elemental analysis result of 1. Examples 1 to 4 of table and comparative example
| C/% | H/% | N/% | C/N | |
| Embodiment 1 | 52.78 | 10.38 | 16.57 | 3.18 |
| Embodiment 2 | 52.60 | 10.37 | 16.44 | 3.20 |
| Embodiment 3 | 54.40 | 10.43 | 16.64 | 3.27 |
| Embodiment 4 | 54.10 | 10.45 | 16.50 | 3.28 |
| Comparative example | 52.50 | 10.41 | 16.48 | 3.18 |
In than Sha Luomu Japan offering circular, N, N, N ', N '-four (3- aminopropyl)-Putriscine: epoxy chloropropionate
Alkane=1:2.1~2.4, i.e. y/x=2.1~2.4, calculating carbon-nitrogen ratio are (192x+36y)/84x=3.18~3.31.It can by table 1
Know, the carbon-nitrogen ratio of Examples 1 to 4 and comparative example meets range.
It determines Examples 1 to 4, comparative example, method one and method two and obtains product, and Japan's listing preparation (キ ッ Network
リンカ プ セ Le 250mg, Astellas Pharma Inc., L061F01) chlorinty, swelling ratio and phosphate combines
Amount, the results are shown in Table 2..
Chlorinty, swelling ratio and the phosphate binding capacity of 2. different product of table
| Chlorinty (%) | Swelling ratio (g/g) | Phosphate binding capacity (mmol/g) | |
| Embodiment 1 | 1.2 | 2.2 | 4.5 |
| Embodiment 2 | 1.3 | 2.0 | 4.9 |
| Embodiment 3 | 1.2 | 2.1 | 5.1 |
| Embodiment 4 | 1.1 | 1.9 | 5.5 |
| Comparative example | 1.2 | 2.3 | 3.7 |
| Method one | 12 | 3.0 | 3.5 |
| Method two | 13 | 2.5 | 3.5 |
| Japan's listing preparation | 1.3 | 2.2 | 4.9 |
Note: in method one and method two, N, N, N ', the object of N '-four (3- aminopropyl)-Putriscine and epoxychloropropane
The ratio between amount of matter is 1:2.2.
From Table 2, it can be seen that the chlorinty of two product of method one and method is respectively 12% and 13%, Examples 1 to 4
It is 1.1~1.3%, lists preparation quite (1.3%) with Japan.The swelling ratio of one product of method is 3.0g/g, and method two is
2.5g/g, Examples 1 to 4 are 1.9~2.2g/g, quite (2.2g/g) with listing preparation.The phosphorus of two product of method one and method
Hydrochlorate binding capacity is 3.5mmol/g, and comparative example 3.7mmol/g, Examples 1 to 4 is 4.5~5.5mmol/g, with listing preparation
Quite (4.9mmol/g).
Above-mentioned, although specific embodiments of the present invention have been described, not to the limit of the scope of the present invention
System, based on the technical solutions of the present invention, those skilled in the art do not need to make the creative labor can make it is each
Kind modification or deformation are still within protection scope of the present invention.
Claims (7)
1. a kind of post-processing approach than Sha Luomu, which is characterized in that comprise the concrete steps that: by N, N, N ', (the 3- ammonia third of N '-four
Base)-Putriscine is dissolved in purified water, and epoxychloropropane is added dropwise, purified water is added in reaction residual after the reaction was completed
In, it stirs, crushes, washing is drying to obtain.
2. a kind of post-processing preparation method than Sha Luomu according to claim 1, which is characterized in that the purge step
It suddenly is successively with anhydrous methanol, dilute hydrochloric acid, sodium hydroxide solution and purifying water washing.
3. a kind of preparation method than Sha Luomu according to claim 3, which is characterized in that in the washing step most
It is washed twice afterwards with purified water.
4. a kind of preparation method than Sha Luomu according to claim 3 or 4, which is characterized in that N, N, N ', (3- of N '-four
Aminopropyl) -1,4- butanediamine and anhydrous methanol, dilute hydrochloric acid, sodium hydroxide solution and purified water mass volume ratio be 1g:
20mL。
5. a kind of preparation method than Sha Luomu according to claim 3, which is characterized in that the dilute hydrochloric acid quality is dense
Degree is 1%.
6. a kind of preparation method than Sha Luomu according to claim 3, which is characterized in that the sodium hydroxide solution
Mass concentration is 5%.
7. a kind of preparation method than Sha Luomu according to claim 1, which is characterized in that N, N, N ', (the 3- ammonia of N '-four
Propyl) mass ratio of -1,4- butanediamine and dissolution purified water is 1:1；Mass volume ratio with post-processing purified water is 1g:
20mL。
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710555419.7A CN109232883A (en) | 2017-07-10 | 2017-07-10 | It is a kind of than Sha Luomu post-processing approach |
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| CN201710555419.7A CN109232883A (en) | 2017-07-10 | 2017-07-10 | It is a kind of than Sha Luomu post-processing approach |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1878822A (en) * | 2003-11-03 | 2006-12-13 | 伊立普萨公司 | Anion-binding polymers and uses thereof |
| US20080085259A1 (en) * | 2006-05-05 | 2008-04-10 | Huval Chad C | Amine condensation polymers as phosphate sequestrants |
| CN106432719A (en) * | 2015-08-06 | 2017-02-22 | 山东诚创医药技术开发有限公司 | Preparation method of bixalomer |
-
2017
- 2017-07-10 CN CN201710555419.7A patent/CN109232883A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1878822A (en) * | 2003-11-03 | 2006-12-13 | 伊立普萨公司 | Anion-binding polymers and uses thereof |
| US20080085259A1 (en) * | 2006-05-05 | 2008-04-10 | Huval Chad C | Amine condensation polymers as phosphate sequestrants |
| CN106432719A (en) * | 2015-08-06 | 2017-02-22 | 山东诚创医药技术开发有限公司 | Preparation method of bixalomer |
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