CN113045693A - Preparation method of sevelamer carbonate - Google Patents
Preparation method of sevelamer carbonate Download PDFInfo
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- CN113045693A CN113045693A CN202110319199.4A CN202110319199A CN113045693A CN 113045693 A CN113045693 A CN 113045693A CN 202110319199 A CN202110319199 A CN 202110319199A CN 113045693 A CN113045693 A CN 113045693A
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/44—Preparation of metal salts or ammonium salts
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Abstract
The invention relates to a preparation method of sevelamer carbonate, which comprises the following steps of (1) decoloring allylamine hydrochloride, performing filter pressing, and adjusting the pH value of filtrate by using hydrochloric acid; (2) performing five times of polymerization reaction on the allylamine hydrochloride filtrate and azodiisobutyl amidine hydrochloride, cooling, alkalifying, distilling and concentrating after the polymerization is finished to obtain polyacrylamide hydrochloride; (3) crosslinking reaction is carried out on polyacrylamide hydrochloride and epoxy chloropropane, and jelly is obtained after the reaction is finished and the temperature is reduced and the solidification is carried out; (4) the jelly is crushed and washed by alkali twice, and the sevelamer alkali is obtained by water washing; (5) adding sevelamer alkali into purified water, heating, and introducing carbon dioxide into the sevelamer alkali for salt forming reaction; centrifuging, washing and drying after the reaction is finished to obtain sevelamer carbonate; the invention is suitable for industrial production, has simple operation and can reduce the cost.
Description
Technical Field
The invention belongs to the technical field of production of medical products, and particularly relates to production of sevelamer carbonate.
Background
Calcium and phosphorus are indispensable elements of the human body, and they are kept in balance in the human body, absorbed and discharged according to the needs of the human body through strict control of the kidney, endocrine system and skeleton. Problems arise when the body functions are abnormal and cannot be controlled. For example, patients with renal failure inevitably ingest phosphorus but cannot discharge phosphorus well, so that the phosphorus in the blood is excessive, hyperphosphatemia is caused, and the death risk is 27% higher than that of normal people. Diet control is currently the most basic treatment, and phosphorus binders must be taken to control hyperphosphatemia.
Sevelamer carbonate is an aliphatic polyamine polymer, a phosphate conjugate that is calcium-free and not absorbed by the human body. Can be used for treating hyperphosphatemia. It contains many NH in its molecule2In the intestinal tract, cationic polymers are formed, and are combined with phosphate released in the digestive tract, and the combined phosphate cannot be absorbed again and is excreted in the manner of feces, so that the phosphorus concentration in blood is reduced. Can be used for treating hyperphosphatemia.
Disclosure of Invention
The invention provides a preparation method of sevelamer carbonate, which comprises the following steps
(1) Decoloring allylamine hydrochloride, performing filter pressing, and adjusting the pH value of filtrate by using hydrochloric acid;
(2) carrying out five times of polymerization reaction on the allylamine hydrochloride filtrate obtained in the step (1) and azo diisobutyl amidine hydrochloride, cooling, alkalifying, distilling and concentrating after the polymerization is finished to obtain polyacrylamide hydrochloride;
(3) crosslinking reaction is carried out on the polyacrylamide hydrochloride obtained in the step (2) and epoxy chloropropane, and cooling and curing are carried out after the reaction is finished to obtain jelly;
(4) the jelly is crushed and washed by alkali twice, and the sevelamer alkali is obtained by water washing;
(5) adding sevelamer alkali into purified water, heating, and introducing carbon dioxide into the sevelamer alkali for salt forming reaction; and centrifuging, washing and drying after the reaction is finished to obtain the sevelamer carbonate.
In the step (1), the weight ratio of the allylamine hydrochloride to the activated carbon is 1: 0.05-0.1, the decoloring condition is 50-70 ℃, and the pH value is adjusted to 0.1-0.5 by hydrochloric acid.
In the step (2), the weight of the azodiisobutyl amidine hydrochloride added in each reaction is 0.004-0.005 time of that of allyl amine hydrochloride, the temperature of single polymerization reaction is controlled at 50-80 ℃, and the polymerization reaction is carried out for 24 hours.
And (3) in the step (2), the concentration condition is that the temperature is 60-70 ℃, the vacuum is less than or equal to-0.08 MPa, and the distillation is carried out until the required concentration is reached.
In the step (3), the weight ratio of the polyacrylamide hydrochloride to the epoxy chloropropane is 1: 0.1-0.2, and the reaction time is 3-5 minutes.
In the step (3), the curing temperature is 20-50 ℃, and the curing time is 15-20 hours.
In the step (4), the single alkali washing temperature is 30-50 ℃, and the alkali washing time is 1 hour.
And (3) introducing carbon dioxide and polyacrylamide hydrochloride in a weight ratio of 1: 0.1-0.3, the drying temperature is 50-80 ℃, and the drying time is 6-8 hours.
The invention aims to provide a synthesis method of sevelamer carbonate, which is suitable for industrial production and is simple to operate. The method can reduce labor cost.
Detailed Description
In order to enable those skilled in the art to better understand the technical solutions in the present application, the technical solutions in the present application will be clearly and completely described below with reference to specific embodiments of the present application, and it is obvious that the described embodiments are only a part of the embodiments in the present application, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present application without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
380g of allylamine hydrochloride and 19g of activated carbon were added to the reaction flask, the temperature was raised to 50 ℃ and decolorized for 1 hour. Filtering, adding the filtrate into another reaction bottle, slowly dropwise adding hydrochloric acid into the filtrate, and adjusting the pH to 0.1. Controlling the temperature of a reaction bottle to be 50 ℃, adding 7.6g of azobisisobutylamidine hydrochloride into the reaction bottle in batches for polymerization, cooling the reaction liquid to 25 ℃ after the reaction is finished, and adding 133g of liquid alkali into the reaction liquid. Controlling the temperature at 60 ℃ and the vacuum degree at-0.08 MPa, and distilling the reaction liquid under reduced pressure to the required concentration to obtain the polyacrylamide hydrochloride solution.
Weighing 80g of polyacrylamide hydrochloride solution, adding into a reaction bottle, adding 8g of epoxy chloropropane into the reaction bottle, heating to 15 ℃, and reacting for 3 minutes. The reaction solution was transferred to a beaker, and the temperature of the beaker was maintained at 20 ℃ and left to stand for 15 hours. The resulting condensate was crushed and added to a sodium hydroxide solution, and stirred for 1 hour at a temperature of 30 ℃. Suction filtration is carried out, and the filter cake is added into the sodium hydroxide solution again and stirred for 1 hour. And (5) carrying out suction filtration and washing to obtain sevelamer alkali.
Adding the obtained sevelamer alkali into a reaction bottle, adding purified water into the reaction bottle, heating to 25 ℃, introducing 8g of carbon dioxide into the reaction liquid for reaction, performing suction filtration after the reaction is finished, and drying the filter cake at 50 ℃ for 6 hours to obtain sevelamer carbonate.
Example 2
380g of allylamine hydrochloride and 28g of activated carbon were added to the reaction flask, the temperature was raised to 60 ℃ and decolorized for 1 hour. And (3) carrying out suction filtration, adding the filtrate into another reaction bottle, slowly dropwise adding hydrochloric acid into the filtrate, adjusting the pH to 0.3, controlling the temperature of the reaction bottle to be 65 ℃, adding 8.6g of azobisisobutylamidine hydrochloride into the reaction bottle in batches, carrying out polymerization reaction, cooling the reaction liquid to 25 ℃ after the reaction is finished, and adding 133g of liquid caustic soda into the reaction liquid. Controlling the temperature to 65 ℃ and the vacuum degree to be-0.08 MPa, and distilling the reaction liquid under reduced pressure to the required concentration to obtain the polyacrylamide hydrochloride solution.
Weighing 80g of polyacrylamide hydrochloride solution, adding the solution into a reaction bottle, adding 12g of epoxy chloropropane into the reaction bottle, and heating to 25 ℃ for reaction for 4 minutes. The reaction solution was transferred to a beaker, and the temperature of the beaker was kept at 35 ℃ for 18 hours. The resulting condensate was crushed and added to a sodium hydroxide solution, and stirred for 1 hour at a temperature of 40 ℃. Suction filtration is carried out, and the filter cake is added into the sodium hydroxide solution again and stirred for 1 hour. And (5) carrying out suction filtration and washing to obtain sevelamer alkali.
Adding the obtained sevelamer alkali into a reaction bottle, adding purified water into the reaction bottle, heating to 30 ℃, introducing 10g of carbon dioxide into the reaction liquid for reaction, performing suction filtration after the reaction is finished, and drying a filter cake at 65 ℃ for 6 hours to obtain sevelamer carbonate.
Example 3
380g of allylamine hydrochloride and 38g of activated carbon were added to the reaction flask, the temperature was raised to 70 ℃ and decolorized for 1 hour. And (3) carrying out suction filtration, adding the filtrate into another reaction bottle, slowly dropwise adding hydrochloric acid into the filtrate, adjusting the pH to 0.5, controlling the temperature of the reaction bottle to be 80 ℃, adding 9.5g of azobisisobutylamidine hydrochloride into the reaction bottle in batches, carrying out polymerization reaction, cooling the reaction liquid to 25 ℃ after the reaction is finished, and adding 133g of liquid caustic soda into the reaction liquid. Controlling the temperature at 70 ℃ and the vacuum degree at-0.08 MPa, and distilling the reaction liquid under reduced pressure to the required concentration to obtain the polyacrylamide hydrochloride solution.
Weighing 80g of polyacrylamide hydrochloride solution, adding the polyacrylamide hydrochloride solution into a reaction bottle, adding 16g of epoxy chloropropane into the reaction bottle, and heating to 15 ℃ for reaction for 5 minutes. The reaction solution was transferred to a beaker, and the temperature of the beaker was maintained at 50 ℃ and left to stand for 20 hours. The resulting condensate was crushed and added to a sodium hydroxide solution, and stirred for 1 hour at a temperature of 50 ℃. Suction filtration is carried out, and the filter cake is added into the sodium hydroxide solution again and stirred for 1 hour. And (5) carrying out suction filtration and washing to obtain sevelamer alkali.
Adding the obtained sevelamer alkali into a reaction bottle, adding purified water into the reaction bottle, heating to 35 ℃, introducing 8g of carbon dioxide into the reaction liquid for reaction, performing suction filtration after the reaction is finished, and drying a filter cake at 80 ℃ for 6 hours to obtain sevelamer carbonate.
Claims (8)
1. The preparation method of sevelamer carbonate is characterized by comprising the following steps
(1) Decoloring allylamine hydrochloride, performing filter pressing, and adjusting the pH value of filtrate by using hydrochloric acid;
(2) carrying out five times of polymerization reaction on the allylamine hydrochloride filtrate obtained in the step (1) and azo diisobutyl amidine hydrochloride, cooling, alkalifying, distilling and concentrating after the polymerization is finished to obtain polyacrylamide hydrochloride;
(3) crosslinking reaction is carried out on the polyacrylamide hydrochloride obtained in the step (2) and epoxy chloropropane, and cooling and curing are carried out after the reaction is finished to obtain jelly;
(4) the jelly is crushed and washed by alkali twice, and the sevelamer alkali is obtained by water washing;
(5) adding sevelamer alkali into purified water, heating, and introducing carbon dioxide into the sevelamer alkali for salt forming reaction; and centrifuging, washing and drying after the reaction is finished to obtain the sevelamer carbonate.
2. The method for preparing sevelamer carbonate according to claim 1, wherein in the step (1), the weight ratio of allylamine hydrochloride to activated carbon is 1: 0.05-0.1, the decoloring condition is 50-70 ℃, and the pH is adjusted to 0.1-0.5 by hydrochloric acid.
3. The method for preparing sevelamer carbonate according to claim 1, wherein the weight of the azodiisobutyl amidine hydrochloride added in each reaction in the step (2) is 0.004 to 0.005 times of that of the allylamine hydrochloride, and the temperature of the single polymerization reaction is controlled to be 50 to 80 ℃ and the polymerization reaction is carried out for 24 hours.
4. The method for preparing sevelamer carbonate according to claim 1, wherein the concentration in step (2) is carried out at 60-70 deg.C under vacuum of-0.08 MPa, and distilling to desired concentration.
5. The method for preparing sevelamer carbonate according to claim 1, wherein the weight ratio of the polyacrylamide hydrochloride to the epichlorohydrin in the step (3) is 1: 0.1-0.2, and the reaction time is 3-5 minutes.
6. The method for preparing sevelamer carbonate according to claim 1, wherein the curing temperature in step (3) is 20-50 ℃ and the curing time is 15-20 hours.
7. The method for preparing sevelamer carbonate according to claim 1, wherein the single alkali washing in step (4) is carried out at 30-50 ℃ for 1 hour.
8. The method for preparing sevelamer carbonate according to claim 1, wherein the step (5) is performed by introducing carbon dioxide and polyallylamine hydrochloride in a weight ratio of 1: 0.1-0.3, the drying temperature is 50-80 ℃, and the drying time is 6-8 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110319199.4A CN113045693A (en) | 2021-03-25 | 2021-03-25 | Preparation method of sevelamer carbonate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202110319199.4A CN113045693A (en) | 2021-03-25 | 2021-03-25 | Preparation method of sevelamer carbonate |
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| CN113045693A true CN113045693A (en) | 2021-06-29 |
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| CN202110319199.4A Pending CN113045693A (en) | 2021-03-25 | 2021-03-25 | Preparation method of sevelamer carbonate |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159880A (en) * | 2011-12-14 | 2013-06-19 | 上海亿法医药科技有限公司 | Preparation method for sevelamer carbonate |
| CN105732865A (en) * | 2016-03-04 | 2016-07-06 | 扬州天和药业有限公司 | Preparation process of sevelamer carbonate |
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- 2021-03-25 CN CN202110319199.4A patent/CN113045693A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159880A (en) * | 2011-12-14 | 2013-06-19 | 上海亿法医药科技有限公司 | Preparation method for sevelamer carbonate |
| CN105732865A (en) * | 2016-03-04 | 2016-07-06 | 扬州天和药业有限公司 | Preparation process of sevelamer carbonate |
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