WO2003082812A2 - Process for the preparation of 2-ethoxy-3-[4-(2-{methanesulphonyloxyphenyl}ethoxy) phenil] propanoic acid - Google Patents
Process for the preparation of 2-ethoxy-3-[4-(2-{methanesulphonyloxyphenyl}ethoxy) phenil] propanoic acid Download PDFInfo
- Publication number
- WO2003082812A2 WO2003082812A2 PCT/GB2003/001395 GB0301395W WO03082812A2 WO 2003082812 A2 WO2003082812 A2 WO 2003082812A2 GB 0301395 W GB0301395 W GB 0301395W WO 03082812 A2 WO03082812 A2 WO 03082812A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- ethoxy
- group
- protecting group
- Prior art date
Links
- CXGTZJYQWSUFET-UHFFFAOYSA-N CCOC(Cc(cc1)ccc1OCCc(cc1)ccc1OS(C)(=O)=O)C(O)=O Chemical compound CCOC(Cc(cc1)ccc1OCCc(cc1)ccc1OS(C)(=O)=O)C(O)=O CXGTZJYQWSUFET-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/30—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reactions not involving the formation of esterified sulfo groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to an improved process for the preparation of the compound 2-ethoxy-3-[4-(2- ⁇ 4-methanesulfonyloxyphenyl ⁇ ethoxy)phenyl]propanoic acid, as shown in formula I below
- the above compound is intended for therapeutic use in the Insulin Resistance Syndrome (IRS) including type 2 diabetes mellitus, which refers to a cluster of manifestations including insulin resistance with accompanying hyperinsulinaemia, possible type 2 diabetes mellitus, arterial hypertension, central (visceral) obesity, dyslipidaemia observed as deranged lipoprotein levels typically characterised by elevated VLDL (very low density lipoproteins), small dense LDL particles and reduced HDL (high density lipoprotein) concentrations and reduced fibrinolysis.
- IRS Insulin Resistance Syndrome
- the compound of formula I is disclosed in PCT Publication Number WO99/62872.
- Two alternative processes are disclosed for the preparation of the compound of formula I in Examples 1 and 2 of the application. We have discovered an improvement in relation to one of the processes disclosed.
- the present invention provides a process for the preparation of a compound of formula I
- R represents H or an acid protecting group which comprises reacting a compound of formula II
- X is a suitable leaving group in the presence of a base using water as the diluent.
- the process is carried out at a temperature in the range 0°C to 250°C and preferably in the range 50°C to 150°C. More preferably the process is carried out at a temperature in the range of 80°C to 130°C and most preferably in the range of 90°C to 110°C.
- acid protecting group means that the acid is protected from reaction by forming a suitable acid derivative such as an ester or amide or by other means of protection of carboxylic acid groups known in the art.
- suitable means of protection and acid derivatives may be found in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York, 1999.
- the nature of the ester is not important in the performance of the process since its function is to act as a protecting group.
- the improvements relate to the application of phase transfer catalysis to the process.
- R is H, benzyl or a (l-4C)alkyl group, such as methyl, ethyl or propyl. More preferably R is a (l-4C)alkyl group. Most preferably R is ethyl.
- X is halo, for example bromo, chloro or iodo, an optionally substituted phenylsulfonyloxy group, in particular (4-methylphenyl)sulfonyloxy group or 2,4,6- triisopropylphenylsulfonyloxy group or an alkylsulphonyloxy group for example methanesulphonyloxy.
- X is a methanesulphonyloxy group.
- Suitable bases include carbonates, hydrogen carbonates or hydroxides particularly of alkali metals.
- the base is sodium carbonate, sodium hydrogen carbonate, potassium carbonate or potassium hydrogen carbonate.
- the molar ratio of the compound of formula IJJ. to the compound of formula LT is in the range of 0.5 to 10 , preferably in the range 0.8 to 4 and more preferably in the range of 1.0 to 3 and most preferably is in the range of 1.2 to 1.8 for example 1.2 to 1.6.
- the molar ratio of the base to the compound of formula II is in the range of 0.5 to 10 , preferably in the range 0.8 to 7 for example 0.8 to 4 and more preferably in the range of 1.0 to 5 and most preferably is in the range of 1.2 to 4.2.
- the process of the invention has the following advantages.
- the reaction times are more rapid than the reactions known in the prior art and therefore the process is less costly to run.
- the process gives higher yields and the product is of a higher purity than previously disclosed processes for the preparation of the compound of formula I.
- it is a considerable advantage in terms of waste disposal, environmental reasons and cost to use water as the diluent instead of an organic liquid. Further, the process is consistently reproducible and robust.
- Converting the acid ester derivative may be accomplished simply by hydrolysis (acidic or alkaline or enzymatic) of the ester to the acid, such a step being known to the skilled person, such as described in the examples below and in Example 2 i) of WO99/62872.
- the present invention provides a process for the preparation of a compound of formula I
- R represents an acid protecting group with a compound of formula TJI
- X is a suitable leaving group in the presence of a base and using water as the diluent to give a compound of formula I in which R is an acid protecting group and then removing the protecting group to give a compound of formula I in which R is H.
- the protecting group is an ester and the protecting group removal step comprises a hydrolysis step.
- the hydrolysis step may be acid or base catalysed.
- the base is lithium hydroxide.
- an organic liquid may be present in the hydrolysis step for example acetone, 2-butanone, methanol, ethanol, tetrahydrofuran or dioxane.
- the process provides the S-enantiomer of the compound of formula I in which R is H by using the S-enantiomer of the compound of formula II in which R represents H or an acid protecting group followed by hydrolysis when R is an acid protecting group.
- the compound of formula I in which R is H may be purified by recrystallisation.
- Suitable recrystallisation solvents include one or more of the following ethanol, water, isopropyl acetate, isopropanol, isooctane and toluene.
- the invention is illustrated by the following non-limiting examples.
- Acetic acid was added to the water mixture after phase-separation and the pH was corrected to 1-3 using sulphuric acid in water.
- the crude title compound was crystallized by seeding. The identity of the product was confirmed by HPLC and gave a relative area of 76%.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- General Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Endocrinology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Semiconductor Lasers (AREA)
- Glass Compositions (AREA)
- Iron Core Of Rotating Electric Machines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
- Separation By Low-Temperature Treatments (AREA)
Abstract
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BR0308297-0A BR0308297A (en) | 2002-04-02 | 2003-03-28 | Process for the preparation of a compound |
SI200330411T SI1492764T1 (en) | 2002-04-02 | 2003-03-28 | Process |
AU2003226523A AU2003226523A1 (en) | 2002-04-02 | 2003-03-28 | Process for the preparation of 2-ethoxy-3-[4-(2-{methanesulphonyloxyphenyl}ethoxy)phenil] propanoic acid |
DE60306506T DE60306506T2 (en) | 2002-04-02 | 2003-03-28 | METHOD |
KR10-2004-7015590A KR20050002918A (en) | 2002-04-02 | 2003-03-28 | Process for the preparation of 2-ethoxy-3-[4-(2-{methanesulphonyloxyphenyl}ethoxy)phenyl]propanoic acid |
IL16433403A IL164334A0 (en) | 2002-04-02 | 2003-03-28 | Process for the preparation of 2-ethoxy-3-Ä4-(2-ämethanesulfonyloxyphenylüethoxy)phenylÜpropanoic acid |
CA002478650A CA2478650A1 (en) | 2002-04-02 | 2003-03-28 | Process for the preparation of 2-ethoxy-3-[4-(2-{methanesulphonyloxyphenyl}ethoxy) phenil] propanoic acid |
JP2003580280A JP2005521725A (en) | 2002-04-02 | 2003-03-28 | New method |
MXPA04009686A MXPA04009686A (en) | 2002-04-02 | 2003-03-28 | Process for the preparation of 2-ethoxy-3-[4-(2-{methanesulphonyloxyphenyl}ethoxy) phenil] propanoic acid. |
NZ534989A NZ534989A (en) | 2002-04-02 | 2003-03-28 | Process for the preparation of 2-ethoxy-3-[4-(2-{4-methanesulphonyloxyphenyl}ethoxy)phenyl]propanoic acid |
US10/509,654 US20050215808A1 (en) | 2002-04-02 | 2003-03-28 | New process |
EP03745340A EP1492764B1 (en) | 2002-04-02 | 2003-03-28 | Process |
NO20044045A NO20044045L (en) | 2002-04-02 | 2004-09-24 | New procedure |
HK05104064A HK1071353A1 (en) | 2002-04-02 | 2005-05-13 | Process |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE0201005-6 | 2002-04-02 | ||
SE0201005A SE0201005D0 (en) | 2002-04-02 | 2002-04-02 | New Process |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2003082812A2 true WO2003082812A2 (en) | 2003-10-09 |
WO2003082812A3 WO2003082812A3 (en) | 2004-01-08 |
Family
ID=20287470
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2003/001395 WO2003082812A2 (en) | 2002-04-02 | 2003-03-28 | Process for the preparation of 2-ethoxy-3-[4-(2-{methanesulphonyloxyphenyl}ethoxy) phenil] propanoic acid |
Country Status (19)
Country | Link |
---|---|
US (1) | US20050215808A1 (en) |
EP (1) | EP1492764B1 (en) |
JP (1) | JP2005521725A (en) |
KR (1) | KR20050002918A (en) |
CN (1) | CN1285571C (en) |
AT (1) | ATE331704T1 (en) |
AU (1) | AU2003226523A1 (en) |
BR (1) | BR0308297A (en) |
CA (1) | CA2478650A1 (en) |
DE (1) | DE60306506T2 (en) |
ES (1) | ES2266842T3 (en) |
HK (1) | HK1071353A1 (en) |
IL (1) | IL164334A0 (en) |
MX (1) | MXPA04009686A (en) |
NO (1) | NO20044045L (en) |
NZ (1) | NZ534989A (en) |
SE (1) | SE0201005D0 (en) |
WO (1) | WO2003082812A2 (en) |
ZA (1) | ZA200406589B (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999062872A1 (en) * | 1998-06-04 | 1999-12-09 | Astrazeneca Ab | New 3-aryl-2-hydroxypropionic acid derivative (i) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6358850B1 (en) * | 1999-12-23 | 2002-03-19 | International Business Machines Corporation | Slurry-less chemical-mechanical polishing of oxide materials |
-
2002
- 2002-04-02 SE SE0201005A patent/SE0201005D0/en unknown
-
2003
- 2003-03-28 JP JP2003580280A patent/JP2005521725A/en not_active Withdrawn
- 2003-03-28 ES ES03745340T patent/ES2266842T3/en not_active Expired - Lifetime
- 2003-03-28 CA CA002478650A patent/CA2478650A1/en not_active Abandoned
- 2003-03-28 CN CNB038076853A patent/CN1285571C/en not_active Expired - Fee Related
- 2003-03-28 EP EP03745340A patent/EP1492764B1/en not_active Expired - Lifetime
- 2003-03-28 AT AT03745340T patent/ATE331704T1/en not_active IP Right Cessation
- 2003-03-28 NZ NZ534989A patent/NZ534989A/en unknown
- 2003-03-28 BR BR0308297-0A patent/BR0308297A/en not_active IP Right Cessation
- 2003-03-28 US US10/509,654 patent/US20050215808A1/en not_active Abandoned
- 2003-03-28 KR KR10-2004-7015590A patent/KR20050002918A/en not_active Application Discontinuation
- 2003-03-28 DE DE60306506T patent/DE60306506T2/en not_active Expired - Fee Related
- 2003-03-28 WO PCT/GB2003/001395 patent/WO2003082812A2/en active IP Right Grant
- 2003-03-28 MX MXPA04009686A patent/MXPA04009686A/en not_active Application Discontinuation
- 2003-03-28 IL IL16433403A patent/IL164334A0/en unknown
- 2003-03-28 AU AU2003226523A patent/AU2003226523A1/en not_active Abandoned
-
2004
- 2004-08-18 ZA ZA200406589A patent/ZA200406589B/en unknown
- 2004-09-24 NO NO20044045A patent/NO20044045L/en unknown
-
2005
- 2005-05-13 HK HK05104064A patent/HK1071353A1/en not_active IP Right Cessation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999062872A1 (en) * | 1998-06-04 | 1999-12-09 | Astrazeneca Ab | New 3-aryl-2-hydroxypropionic acid derivative (i) |
Non-Patent Citations (2)
Title |
---|
J.F.W. KEANA, ET AL.: "New mono- and difunctional 2,2,5,5-tetramethylpyrrolidine- and delta3-pyrroline-1-oxyl nitroxide spin labels" CANADIAN JOURNAL OF CHEMISTRY, vol. 60, no. 12, 15 June 1982 (1982-06-15), pages 1439-1447, XP002256848 NATIONAL RESEARCH COUNCIL, OTTAWA, CA * |
R.W. KIERSTEAD, ET AL.: "beta1-Selective adrenoceptor antagonists. 1. Synthesis and beta-adrenergic blocking activity of a series of binary (aryloxy)propanolamines" JOURNAL OF MEDICINAL CHEMISTRY, vol. 26, no. 11, 1983, pages 1561-1569, XP002922416 AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, US ISSN: 0022-2623 * |
Also Published As
Publication number | Publication date |
---|---|
DE60306506T2 (en) | 2007-01-18 |
MXPA04009686A (en) | 2005-01-11 |
WO2003082812A3 (en) | 2004-01-08 |
SE0201005D0 (en) | 2002-04-02 |
CN1646487A (en) | 2005-07-27 |
ATE331704T1 (en) | 2006-07-15 |
BR0308297A (en) | 2004-12-28 |
ES2266842T3 (en) | 2007-03-01 |
IL164334A0 (en) | 2005-12-18 |
NO20044045L (en) | 2004-10-18 |
NZ534989A (en) | 2006-04-28 |
AU2003226523A1 (en) | 2003-10-13 |
KR20050002918A (en) | 2005-01-10 |
JP2005521725A (en) | 2005-07-21 |
CA2478650A1 (en) | 2003-10-09 |
DE60306506D1 (en) | 2006-08-10 |
US20050215808A1 (en) | 2005-09-29 |
EP1492764A2 (en) | 2005-01-05 |
HK1071353A1 (en) | 2005-07-15 |
CN1285571C (en) | 2006-11-22 |
ZA200406589B (en) | 2005-09-21 |
EP1492764B1 (en) | 2006-06-28 |
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