WO1998022426A1 - New manufacturing process of metoprolol - Google Patents
New manufacturing process of metoprolol Download PDFInfo
- Publication number
- WO1998022426A1 WO1998022426A1 PCT/SE1997/001926 SE9701926W WO9822426A1 WO 1998022426 A1 WO1998022426 A1 WO 1998022426A1 SE 9701926 W SE9701926 W SE 9701926W WO 9822426 A1 WO9822426 A1 WO 9822426A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- metoprolol
- methoxyethyl
- epichlorohydrin
- base
- resulting
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
Definitions
- the present invention relates to an improved method for the manufacture of metoprolol base l-(isopropylamino)-3-[p-(2-methoxyethyl)-phenoxy]-2-propanol) via the route of reacting p-(2-methoxyethyl)-phenol (A) and epichlorohydrin (B) and then reacting the obtained l-(2,3-epoxypropoxy)-4-(2-methoxyethyl)-benzene (AB) with isopropylamine (C).
- the crude metoprolol base is then purified.
- Swedish patents 354 851 and 368 004 disclose the reaction of p-(2-methoxyethyl)-phenol and epichlorohydrin where the epichlorohydrin is used not only as a building block in the reaction but also as solvent.
- metoprolol can be prepared in a manner that is fast, environmentally sound and gives a good yield and high purity using reactants that are known p_er se.
- the difference from the prior art is that the new method uses no other solvents than water for the reaction of A and B. From an environmental as well as an occupational hazard point of view it is a great advantage to be able to replace a hazardous organic solvent with an non-noxious solvent such as water.
- p-(2-Methoxyethyl)phenol (A) and epichlorohydrin (B, 1.4-2.0 eqv.) are reacted in water, at least 1.5 kg, preferably about 2 kg of water per kg of phenol, during the addition of sodium (or potassium) hydroxide solution, (1.3-1.7 eqv.) to form l-(2,3-epoxypropoxy)-4- (2-methoxyethyl)benzene; (p-methoxyethyl-epoxypropoxybenzene).
- the reaction is preferably performed at a temperature of 50 - 70 °C.
- the two phases are separated, and the p-methoxyethylepoxy-propoxybenzene is isolated by distillation under reduced pressure. More particular, the excess of epichlorohydrin is evaporated, and the epoxide is distilled under reduced pressure to obtain a product with a purity of about 96-98%. If desired, before distilling the main fraction of the epoxide, a prefraction/forecut (2-8 %, preferably 4-6 %) thereof could be distilled.
- the isolation by destination of the epoxide under reduced pressure is an important part of the process and essential for the quality of the end product.
- the epoxide is reacted with isopropylamine preferably in isopropyl alcohol to form metoprolol base.
- the amount of isopropylamine in relation to epoxide is at least 1 eqvivalent, preferably 3-6 eqvivalents.
- the reaction mixture is then treated in order to eliminate the excess of isopropylamine.
- the animation with isopropylamine is carried out in a pressurized system without isopropyl alcohol at 70 ⁇ 10°C at pressures of 2.8-3.2 kg / 275-315 kPa.
- the resulting metoprolol is dissolved in toluene, isobutyl methyl ketone or butyl acetate and extracted with dilute hydrochloric acid or sulphuric acid, preferably at pH 4-6.
- the phases are separated and the chosen solvent with sodium or potassium hydroxide solution to adjust the pH to 11 - 13 is added to the aqueous phase.
- the two phases are separated, and the organic phase is evaporated in vacuo to an oily residue of metoprolol base which is dissolved in acetone.
- Purified metoprolol base is then obtained by conventional means.
- the batch was stirred for another hour at approximately 60°C, then cooled to approximately 50°C and the phases were separated and the product washed with water.
- the reaction mixture was then concentrated at atmospheric pressure until the inner temperature reached ⁇ 100°C. Water was added to the batch and then distilled off in vacuo until the inner temperature reached ⁇ 100°C to form a concentrate.
- the resulting concentrate was diluted with isobutyl methyl ketone (-0.6 kg) and water (-2.2 kg), and concentrated sulphuric acid was added, to adjust the pH to 4-6. After separation, isobutyl methyl ketone ( ⁇ 1 kg) was added to the water layer, and concentrated sodium hydroxide solution was added to adjust the pH to 13.
- the organic layer was concentrated in vacuo at ⁇ 80°C, until distillation ceased, and the concentrated batch was redissolved in acetone (-1.6 kg) and filtered, to yield metoprolol base solution.
- the assay of metoprolol base in the solution was determined by titration. Yield: -1.2 kg metoprolol base (100 %) -95 % of theory. The purity of the metoprolol base was 96 %.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Hematology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Epoxy Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (20)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ335213A NZ335213A (en) | 1996-11-20 | 1996-11-18 | Metoprolol and a method of preparing metoprolol by reacting p-(2-methoxyethyl)phenol and epichlorohydrin and isopropylamine |
US08/973,144 US6252113B1 (en) | 1996-11-20 | 1996-11-20 | Manufacturing process of metoprolol |
IL12974797A IL129747A (en) | 1996-11-20 | 1997-11-18 | Process for manufacturing metoprolol |
SI9730512T SI0942899T1 (en) | 1996-11-20 | 1997-11-18 | Manufacturing process of metoprolol |
EEP199900202A EE03761B1 (en) | 1996-11-20 | 1997-11-18 | A new process for the production of metoprolol |
SK564-99A SK281990B6 (en) | 1996-11-20 | 1997-11-18 | New manufacturing process of metoprolol |
DE69719788T DE69719788T2 (en) | 1996-11-20 | 1997-11-18 | MANUFACTURING METHOD FOR METOPROLOL |
HU0002445A HUP0002445A3 (en) | 1996-11-20 | 1997-11-18 | Manufacturing process of metoprolol |
JP51107298A JP4039640B2 (en) | 1996-11-20 | 1997-11-18 | A novel method for producing metoprolol |
AT97913641T ATE234273T1 (en) | 1996-11-20 | 1997-11-18 | PRODUCTION PROCESS FOR METOPROLOL |
DK97913641T DK0942899T3 (en) | 1996-11-20 | 1997-11-18 | Method of Preparation of Metoprolol. |
BR9713370A BR9713370A (en) | 1996-11-20 | 1997-11-18 | Processes for the manufacture of metoprolol and a pharmaceutical preparation, and, metoprolol |
CA002269941A CA2269941A1 (en) | 1996-11-20 | 1997-11-18 | New manufacturing process of metoprolol |
PL333541A PL191392B1 (en) | 1996-11-20 | 1997-11-18 | Novel method of obtaining methoprolol |
AU50776/98A AU728270B2 (en) | 1996-11-20 | 1997-11-18 | New manufacturing process of metoprolol |
EP97913641A EP0942899B1 (en) | 1996-11-20 | 1997-11-18 | Manufacturing process of metoprolol |
UA99042412A UA66769C2 (en) | 1996-11-20 | 1997-11-18 | A novel method for the manufacture of metoprolol |
IS5034A IS1964B (en) | 1996-11-20 | 1999-04-26 | A new method of producing metoprolol |
NO19992401A NO311352B1 (en) | 1996-11-20 | 1999-05-19 | New method for the preparation of metoprolol |
HK00101688A HK1022684A1 (en) | 1996-11-20 | 2000-03-20 | Manufacturing process of metoprolol |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9604253-6 | 1996-11-20 | ||
SE9604253A SE9604253D0 (en) | 1996-11-20 | 1996-11-20 | New manufacturing process metoprolol |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998022426A1 true WO1998022426A1 (en) | 1998-05-28 |
Family
ID=20404680
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/SE1997/001926 WO1998022426A1 (en) | 1996-11-20 | 1997-11-18 | New manufacturing process of metoprolol |
Country Status (36)
Country | Link |
---|---|
US (1) | US6252113B1 (en) |
EP (1) | EP0942899B1 (en) |
JP (1) | JP4039640B2 (en) |
KR (1) | KR100544560B1 (en) |
CN (1) | CN1128786C (en) |
AR (1) | AR010069A1 (en) |
AT (1) | ATE234273T1 (en) |
AU (1) | AU728270B2 (en) |
BR (1) | BR9713370A (en) |
CA (1) | CA2269941A1 (en) |
CZ (1) | CZ174499A3 (en) |
DE (1) | DE69719788T2 (en) |
DK (1) | DK0942899T3 (en) |
EE (1) | EE03761B1 (en) |
EG (1) | EG21158A (en) |
ES (1) | ES2193365T3 (en) |
HK (1) | HK1022684A1 (en) |
HU (1) | HUP0002445A3 (en) |
ID (1) | ID21505A (en) |
IL (1) | IL129747A (en) |
IN (1) | IN187175B (en) |
IS (1) | IS1964B (en) |
MY (1) | MY119303A (en) |
NO (1) | NO311352B1 (en) |
NZ (1) | NZ335213A (en) |
PL (1) | PL191392B1 (en) |
PT (1) | PT942899E (en) |
RU (1) | RU2210565C2 (en) |
SA (1) | SA97180599B1 (en) |
SE (1) | SE9604253D0 (en) |
SK (1) | SK281990B6 (en) |
TR (1) | TR199901115T2 (en) |
TW (1) | TW412513B (en) |
UA (1) | UA66769C2 (en) |
WO (1) | WO1998022426A1 (en) |
ZA (1) | ZA9710005B (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007141593A3 (en) * | 2005-12-23 | 2008-02-28 | Medichem Sa | Process for the preparation of metoprolol and its salts |
CN102432476A (en) * | 2010-09-29 | 2012-05-02 | 湖南康普医药研究院 | Method for preparing metoprolol succinate on scale |
US8680303B2 (en) | 2010-03-01 | 2014-03-25 | Massachusetts Institute Of Technology | Epoxidation catalysts |
CN103980134A (en) * | 2014-05-30 | 2014-08-13 | 安徽省新星药物开发有限责任公司 | Preparation method of succinic acid S-metoprolol |
US8877930B2 (en) | 2009-11-04 | 2014-11-04 | Massachusetts Institute Of Technology | Continuous flow synthesis of amino alcohols using microreactors |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050107635A1 (en) * | 2003-11-14 | 2005-05-19 | Mehra Janakraj K. | Metoprolol manufacturing process |
US20080107726A1 (en) * | 2006-11-01 | 2008-05-08 | Pramod Kharwade | Compositions comprising beta-adrenergic receptor antagonists and diuretics |
CN101607918B (en) * | 2008-06-16 | 2014-02-19 | 北京德众万全药物技术开发有限公司 | Method for preparing metoprolol |
CN102381995B (en) * | 2010-08-31 | 2015-04-15 | 扬子江药业集团北京海燕药业有限公司 | Preparation method of metoprolol |
CN102503843B (en) * | 2011-10-28 | 2013-10-23 | 山东阿如拉药物研究开发有限公司 | Preparation method for metoprolol salt |
KR101379383B1 (en) * | 2012-03-23 | 2014-04-02 | 주식회사 알에스텍 | A process for preparing high purity of ⒮―Metoprolol |
CN105820057B (en) * | 2016-04-22 | 2017-09-29 | 上海应用技术学院 | A kind of method for preparing Metoprolol |
CN106543015A (en) * | 2016-11-07 | 2017-03-29 | 上海应用技术大学 | A kind of preparation method of metoprolol |
CN108299279B (en) * | 2018-02-09 | 2021-03-23 | 北京梅尔森医药技术开发有限公司 | Substituted arylaminol compounds, methods of making, and uses thereof |
US10744087B2 (en) | 2018-03-22 | 2020-08-18 | Incarda Therapeutics, Inc. | Method to slow ventricular rate |
CN111018724B (en) * | 2019-12-27 | 2022-11-08 | 江西美晶科技有限公司 | Metoprolol and preparation method thereof |
CN112645827A (en) * | 2020-12-25 | 2021-04-13 | 浙江普洛家园药业有限公司 | Method for continuously synthesizing metoprolol and salt thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2011584A6 (en) * | 1989-05-26 | 1990-01-16 | Esteve Quimica Sa | Industrial process for obtaining an aryloxypropanolamine |
WO1992016197A1 (en) * | 1991-03-18 | 1992-10-01 | Sepracor Inc. | Composition and method containing optically pure (s) metoprolol |
-
1996
- 1996-11-18 NZ NZ335213A patent/NZ335213A/en unknown
- 1996-11-20 US US08/973,144 patent/US6252113B1/en not_active Expired - Lifetime
- 1996-11-20 SE SE9604253A patent/SE9604253D0/en unknown
-
1997
- 1997-10-23 TW TW086115698A patent/TW412513B/en active
- 1997-11-06 ZA ZA9710005A patent/ZA9710005B/en unknown
- 1997-11-12 SA SA97180599A patent/SA97180599B1/en unknown
- 1997-11-13 IN IN3275DE1997 patent/IN187175B/en unknown
- 1997-11-18 ES ES97913641T patent/ES2193365T3/en not_active Expired - Lifetime
- 1997-11-18 SK SK564-99A patent/SK281990B6/en unknown
- 1997-11-18 WO PCT/SE1997/001926 patent/WO1998022426A1/en not_active Application Discontinuation
- 1997-11-18 TR TR1999/01115T patent/TR199901115T2/en unknown
- 1997-11-18 CZ CZ991744A patent/CZ174499A3/en unknown
- 1997-11-18 PL PL333541A patent/PL191392B1/en not_active IP Right Cessation
- 1997-11-18 DE DE69719788T patent/DE69719788T2/en not_active Expired - Fee Related
- 1997-11-18 EP EP97913641A patent/EP0942899B1/en not_active Expired - Lifetime
- 1997-11-18 RU RU99109477/04A patent/RU2210565C2/en not_active IP Right Cessation
- 1997-11-18 IL IL12974797A patent/IL129747A/en not_active IP Right Cessation
- 1997-11-18 KR KR1019997004401A patent/KR100544560B1/en not_active IP Right Cessation
- 1997-11-18 UA UA99042412A patent/UA66769C2/en unknown
- 1997-11-18 CA CA002269941A patent/CA2269941A1/en not_active Abandoned
- 1997-11-18 ID IDW990343D patent/ID21505A/en unknown
- 1997-11-18 AT AT97913641T patent/ATE234273T1/en not_active IP Right Cessation
- 1997-11-18 HU HU0002445A patent/HUP0002445A3/en unknown
- 1997-11-18 CN CN97199796A patent/CN1128786C/en not_active Expired - Lifetime
- 1997-11-18 AU AU50776/98A patent/AU728270B2/en not_active Ceased
- 1997-11-18 PT PT97913641T patent/PT942899E/en unknown
- 1997-11-18 EE EEP199900202A patent/EE03761B1/en not_active IP Right Cessation
- 1997-11-18 BR BR9713370A patent/BR9713370A/en not_active Application Discontinuation
- 1997-11-18 EG EG122697A patent/EG21158A/en active
- 1997-11-18 JP JP51107298A patent/JP4039640B2/en not_active Expired - Fee Related
- 1997-11-18 DK DK97913641T patent/DK0942899T3/en active
- 1997-11-19 MY MYPI97005544A patent/MY119303A/en unknown
- 1997-11-19 AR ARP970105420A patent/AR010069A1/en unknown
-
1999
- 1999-04-26 IS IS5034A patent/IS1964B/en unknown
- 1999-05-19 NO NO19992401A patent/NO311352B1/en unknown
-
2000
- 2000-03-20 HK HK00101688A patent/HK1022684A1/en not_active IP Right Cessation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2011584A6 (en) * | 1989-05-26 | 1990-01-16 | Esteve Quimica Sa | Industrial process for obtaining an aryloxypropanolamine |
WO1992016197A1 (en) * | 1991-03-18 | 1992-10-01 | Sepracor Inc. | Composition and method containing optically pure (s) metoprolol |
Non-Patent Citations (3)
Title |
---|
CHEMICAL ABSTRACTS, Volume 112, No. 21, 21 May 1990, (Columbus, Ohio, USA), page 658, Abstract No. 197820c; & PL,A,144 036 (ZJAWIONY, JORDANET et al.), 30 April 1988. * |
CHEMICAL ABSTRACTS, Volume 113, No. 21, 19 November 1990, (Columbus, Ohio, USA), page 677, Abstract No. 190900r; & ES,A,2 011 584 (ORANIAS OLSINA, GLORIA et al.), 16 January 1990. * |
CHEMICAL ABSTRACTS, Volume 119, No. 19, 8 November 1993, (Columbus, Ohio, USA), page 683, Abstract No. 203128w; & PL,A,158 497 (ZJAWIONY, JORDAN et al.), 30 Sept. 1992. * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007141593A3 (en) * | 2005-12-23 | 2008-02-28 | Medichem Sa | Process for the preparation of metoprolol and its salts |
US8877930B2 (en) | 2009-11-04 | 2014-11-04 | Massachusetts Institute Of Technology | Continuous flow synthesis of amino alcohols using microreactors |
US8680303B2 (en) | 2010-03-01 | 2014-03-25 | Massachusetts Institute Of Technology | Epoxidation catalysts |
US9169277B2 (en) | 2010-03-01 | 2015-10-27 | Massachusetts Institute Of Technology | Epoxidation catalysts |
CN102432476A (en) * | 2010-09-29 | 2012-05-02 | 湖南康普医药研究院 | Method for preparing metoprolol succinate on scale |
CN103980134A (en) * | 2014-05-30 | 2014-08-13 | 安徽省新星药物开发有限责任公司 | Preparation method of succinic acid S-metoprolol |
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