US20120101234A1 - Process for the preparation of sevelamer - Google Patents
Process for the preparation of sevelamer Download PDFInfo
- Publication number
- US20120101234A1 US20120101234A1 US13/319,821 US201013319821A US2012101234A1 US 20120101234 A1 US20120101234 A1 US 20120101234A1 US 201013319821 A US201013319821 A US 201013319821A US 2012101234 A1 US2012101234 A1 US 2012101234A1
- Authority
- US
- United States
- Prior art keywords
- sevelamer
- process according
- polyallylamine
- epichlorohydrin
- bicarbonate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- AQGXJVKWSPKOHF-UHFFFAOYSA-N CCC(CN)CC(C)CNCC(O)CNCC(C)CC(CC)CN Chemical compound CCC(CN)CC(C)CNCC(O)CNCC(C)CC(CC)CN AQGXJVKWSPKOHF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C08F26/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen
- C08F26/02—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen by a single or double bond to nitrogen
-
- 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
-
- 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
- C08F8/18—Introducing halogen atoms or halogen-containing groups
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2339/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen; Derivatives of such polymers
Definitions
- Sevelamer or poly(allylamine-co-N,N′-diallyl-1,3-diamino-2-hydroxypropane), is a polymer compound having the formula
- Sevelamer is marketed as the hydrochloride salt under the trade name Renagel® for controlling hyperphosphatemia (increase in the level of phosphates in the blood) in adult patients undergoing dialysis or hemodialysis.
- Renagel® the sevelamer carbonate/bicarbonate salt
- Polyallylamine is a polymer compound known in the art with the CAS RN 71550-12-4 and is obtained by allylamine polymerization.
- U.S. Pat. No. 6,180,754 in the name of The Dow Chemical Company describes a process for the synthesis of sevelamer that provides for the use of a LIST reactor to perform the cross-linking step.
- This reactor produced by the company LIST Inc., is a reactor specifically designed for processing high viscosity materials. It is easily understood that this reactor is not commonly used and that its use requires specific and economically important investments, unjustified for the preparation of a single active ingredient.
- the patent application WO01/18072 describes a process for the preparation of sevelamer hydrochloride comprising partial salification of a solution of polyallylamine hydrochloride, removal of salts through ion exchange or electrodeionization and by means of subsequent optional nanofiltration or ultrafiltration of the partially desalified polyallylamine, and then causing it to react with epichlorohydrin.
- WO01/18072 for example pages 4 and 5
- a substantial quantity of salts is produced during desalification of the polyallylamine hydrochloride with metal hydroxides a substantial quantity of salts is produced.
- the aim of the present invention is to provide a process for the preparation of sevelamer which overcomes the drawbacks of the prior art.
- the invention relates to a process for the preparation of sevelamer which comprises partially salifying, preferably with hydrochloric acid, a polyallylamine aqueous solution having a concentration between 10% and 14.5% (w/w) and reacting it with epichlorohydrin, in the absence of any organic solvents.
- the invention relates to a process comprising the steps of:
- the polyallylamine is partially salified with hydrochloric acid and the sevelamer obtained in step (d) is sevelamer hydrochloride.
- the initial polyallylamine aqueous solution is commercially available. This polyallylamine can be suitably diluted with water to the desired concentration.
- the concentration of the polyallylamine aqueous solution is between 11% and 14.5%, preferably between 12.5 and 14.5%, advantageously this concentration is around 13-14%.
- the epichlorohydrin used according to the present invention is also commercially available.
- the polyallylamine aqueous solution is loaded into a common reactor, hydrochloric acid is added to reach the degree of salification required and epichlorohydrin is dosed, preferably controlling the temperature as the reaction is exothermic.
- the temperature of the reaction mixture is maintained around 20-25° C. during the step of acid addition.
- the quantity of acid to add to the polyallylamine depends on the degree of salification required.
- the polyallylamine is salified to 25-40%, for example around 30-35%. Therefore, by way of example, salification can be achieved using a “allylamine unit”/“hydrochloric acid” molar ratio of around 3-3.5/1.
- the hydrochloric acid is preferably added in an aqueous solution.
- the “allylamine unit”/“epichlorohydrin” ratio is advantageously around 8-11/1, preferably around 9/1.
- the mixture is maintained under stirring for some time, for example a few hours, and the reaction mixture is then heated to a temperature between 65 and 85° C., preferably between 75 and 83° C.
- the cross-linking reaction is normally complete in a few hours.
- the sevelamer obtained according to the process of the invention can be directly filtered and dried according to methods known in the art.
- a water miscible solvent advantageously isopropanol
- isopropanol can be added to the reaction mass and maintained under stirring for some time, and the sevelamer thus obtained can then be filtered and dried.
- the sevelamer obtained with the process described above can be converted into sevelamer carbonate/bicarbonate according to known techniques, for example by reaction with gaseous carbon dioxide or other carbonating agents, such as carbonates of alkaline or alkaline-earth metals.
- reaction can be conducted in a basic aqueous solvent, such as in a sodium hydroxide solution or also in solid phase, i.e. without using solvents.
- a basic aqueous solvent such as in a sodium hydroxide solution or also in solid phase, i.e. without using solvents.
- PAA Solution PAA PAA (mol HCl washing 14.0% 100% allylamine epichlorohydrin epichlorohydrin HCl 38.2% isopropanol (g) (g) units) (mol) (g) (mol) (g) (g) 16650 2344 41.1 4.6 426.5 11.9 1137 14630
- a conventional reactor, with blade stirrer, is used.
- HCl is added to the polyallylamine loaded into the reactor in two batches dosed at a distance of 15 minutes.
- dosing of epichlorohydrin begins and continues for around 10 minutes.
- heating to 78° C.-83° C. begins and continues for 3 hours, at the end of which the product, after cooling to room temperature, is washed with isopropanol. Washing is performed by maintaining the product under stirring with isopropanol for 1 hour, then the product is centrifuged and vacuum dried at 60° C. for 3 hours, finally obtaining 2.94 kg of product in the form of a whitish solid.
- the analytical evaluations are performed according to methods known in the art and conventionally used for sevelamer.
- PAA PAA PAA (mol epi- epi- HCl Solution 100% allylamine chlorohydrin chlorohydrin HCl 38.2% 30% (g) (g) units) (mol) (g) (mol) (g) 483.5 145 2.54 0.28 26 0.79 77.5
- example 1 The process of example 1 is repeated. After adding one part of epichlorohydrin a vitreous and intractable gel is obtained, which blocked stirring.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Processes Of Treating Macromolecular Substances (AREA)
- Compositions Of Macromolecular Compounds (AREA)
- Saccharide Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI2009A000816A IT1394299B1 (it) | 2009-05-12 | 2009-05-12 | Procedimento per la preparazione di sevelamer |
ITMI2009A000816 | 2009-05-12 | ||
PCT/IB2010/001071 WO2010131092A1 (en) | 2009-05-12 | 2010-05-10 | Process for the preparation of sevelamer |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2010/001071 A-371-Of-International WO2010131092A1 (en) | 2009-05-12 | 2010-05-10 | Process for the preparation of sevelamer |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/173,898 Continuation US9303105B2 (en) | 2009-05-12 | 2014-02-06 | Process for the preparation of sevelamer |
Publications (1)
Publication Number | Publication Date |
---|---|
US20120101234A1 true US20120101234A1 (en) | 2012-04-26 |
Family
ID=41257151
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/319,821 Abandoned US20120101234A1 (en) | 2009-05-12 | 2010-05-10 | Process for the preparation of sevelamer |
US14/173,898 Expired - Fee Related US9303105B2 (en) | 2009-05-12 | 2014-02-06 | Process for the preparation of sevelamer |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/173,898 Expired - Fee Related US9303105B2 (en) | 2009-05-12 | 2014-02-06 | Process for the preparation of sevelamer |
Country Status (13)
Country | Link |
---|---|
US (2) | US20120101234A1 (pt) |
EP (1) | EP2430078B1 (pt) |
JP (1) | JP5658744B2 (pt) |
CY (1) | CY1114915T1 (pt) |
DK (1) | DK2430078T3 (pt) |
EA (1) | EA021074B1 (pt) |
ES (1) | ES2453114T3 (pt) |
HR (1) | HRP20140241T1 (pt) |
IT (1) | IT1394299B1 (pt) |
PL (1) | PL2430078T3 (pt) |
PT (1) | PT2430078E (pt) |
SI (1) | SI2430078T1 (pt) |
WO (1) | WO2010131092A1 (pt) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10479865B2 (en) * | 2017-11-01 | 2019-11-19 | Strides Shasun Limited | Process for the preparation of sevelamer carbonate |
CN115260355A (zh) * | 2022-05-16 | 2022-11-01 | 江苏中天药业有限公司 | 一种阴离子交换树脂、其制备方法、该树脂与药物的复合物和其掩味制剂 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101853260B1 (ko) * | 2016-11-29 | 2018-06-14 | 주식회사 퍼슨 | 세벨라머 카보네이트의 제조방법 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6180754B1 (en) * | 1999-09-03 | 2001-01-30 | The Dow Chemical Company | Process for producing cross-linked polyallylamine polymer |
US7220406B2 (en) * | 2002-10-22 | 2007-05-22 | Genzyme Corporation | Method for promoting bone formation |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3541511A1 (de) * | 1985-11-19 | 1987-05-21 | Grace W R Ab | Promoter fuer die papierleimung, verfahren zu dessen herstellung und dessen verwendung |
US6423754B1 (en) * | 1997-06-18 | 2002-07-23 | Geltex Pharmaceuticals, Inc. | Method for treating hypercholesterolemia with polyallylamine polymers |
EP1175451B1 (en) * | 1999-04-16 | 2007-07-04 | Abbott Laboratories | Process for producing cross-linked polyallylamine hydrochloride |
US6362266B1 (en) * | 1999-09-03 | 2002-03-26 | The Dow Chemical Company | Process for reducing cohesiveness of polyallylamine polymer gels during drying |
US6600011B2 (en) * | 2001-10-09 | 2003-07-29 | Genzyme Corporation | Process for purification and drying of polymer hydrogels |
US7459502B2 (en) * | 2003-11-03 | 2008-12-02 | Ilypsa, Inc. | Pharmaceutical compositions comprising crosslinked polyamine polymers |
JP2005138540A (ja) * | 2003-11-10 | 2005-06-02 | Konica Minolta Photo Imaging Inc | インクジェット記録材料 |
WO2008005217A2 (en) * | 2006-07-05 | 2008-01-10 | Genzyme Corporation | Iron(ii)-containing treatments for hyperphosphatemia |
BRPI0717008A2 (pt) * | 2006-09-01 | 2014-01-21 | Usv Ltd | Processo para o preparo de cloridrato de sevelamer e formulação do mesmo |
-
2009
- 2009-05-12 IT ITMI2009A000816A patent/IT1394299B1/it active
-
2010
- 2010-05-10 PL PL10727834T patent/PL2430078T3/pl unknown
- 2010-05-10 PT PT107278343T patent/PT2430078E/pt unknown
- 2010-05-10 EP EP10727834.3A patent/EP2430078B1/en active Active
- 2010-05-10 ES ES10727834.3T patent/ES2453114T3/es active Active
- 2010-05-10 WO PCT/IB2010/001071 patent/WO2010131092A1/en active Application Filing
- 2010-05-10 DK DK10727834.3T patent/DK2430078T3/en active
- 2010-05-10 US US13/319,821 patent/US20120101234A1/en not_active Abandoned
- 2010-05-10 EA EA201101613A patent/EA021074B1/ru not_active IP Right Cessation
- 2010-05-10 SI SI201030544T patent/SI2430078T1/sl unknown
- 2010-05-10 JP JP2012510378A patent/JP5658744B2/ja not_active Expired - Fee Related
-
2014
- 2014-02-06 US US14/173,898 patent/US9303105B2/en not_active Expired - Fee Related
- 2014-02-27 CY CY20141100161T patent/CY1114915T1/el unknown
- 2014-03-14 HR HRP20140241AT patent/HRP20140241T1/hr unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6180754B1 (en) * | 1999-09-03 | 2001-01-30 | The Dow Chemical Company | Process for producing cross-linked polyallylamine polymer |
US7220406B2 (en) * | 2002-10-22 | 2007-05-22 | Genzyme Corporation | Method for promoting bone formation |
Non-Patent Citations (1)
Title |
---|
Chemistry, The Central Science; Brown, LeMay and Bursten; 7th Edition; Page 126 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10479865B2 (en) * | 2017-11-01 | 2019-11-19 | Strides Shasun Limited | Process for the preparation of sevelamer carbonate |
CN115260355A (zh) * | 2022-05-16 | 2022-11-01 | 江苏中天药业有限公司 | 一种阴离子交换树脂、其制备方法、该树脂与药物的复合物和其掩味制剂 |
Also Published As
Publication number | Publication date |
---|---|
ES2453114T3 (es) | 2014-04-04 |
PT2430078E (pt) | 2014-02-11 |
JP5658744B2 (ja) | 2015-01-28 |
PL2430078T3 (pl) | 2014-06-30 |
EP2430078A1 (en) | 2012-03-21 |
IT1394299B1 (it) | 2012-06-06 |
EP2430078B1 (en) | 2014-01-01 |
SI2430078T1 (sl) | 2014-04-30 |
DK2430078T3 (en) | 2014-03-24 |
ITMI20090816A1 (it) | 2010-11-13 |
EA021074B1 (ru) | 2015-03-31 |
CY1114915T1 (el) | 2016-12-14 |
US20140213736A1 (en) | 2014-07-31 |
WO2010131092A1 (en) | 2010-11-18 |
US9303105B2 (en) | 2016-04-05 |
HRP20140241T1 (hr) | 2014-04-11 |
JP2012526887A (ja) | 2012-11-01 |
EA201101613A1 (ru) | 2012-04-30 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: LABORATORIO CHIMICO INTERNAZIONALE S.P.A., ITALY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:VILLANI, FLAVIO;DE ANGELIS, BRUNO;NARDI, ANTONIO;AND OTHERS;REEL/FRAME:027596/0770 Effective date: 20111122 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |