WO1994020493A1 - Procede de preparation de n-methyl (pyridyl-3)-2 tetrahydrothiopyrannecarbothioamide-2-oxyde-1-(1r,2r) - Google Patents
Procede de preparation de n-methyl (pyridyl-3)-2 tetrahydrothiopyrannecarbothioamide-2-oxyde-1-(1r,2r) Download PDFInfo
- Publication number
- WO1994020493A1 WO1994020493A1 PCT/FR1994/000221 FR9400221W WO9420493A1 WO 1994020493 A1 WO1994020493 A1 WO 1994020493A1 FR 9400221 W FR9400221 W FR 9400221W WO 9420493 A1 WO9420493 A1 WO 9420493A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pyridyl
- methyl
- oxide
- process according
- salt
- Prior art date
Links
- 0 *C(*N*)(*CCC1)S1O Chemical compound *C(*N*)(*CCC1)S1O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- PROCESS FOR THE PREPARATION OF N-METHYL PYRIDYL-3.-2 T ⁇ TRAHYDROTHIOPYRANNECARBOTHIOAMIDE-2-OXIDE- 1 -O R.2R
- the present invention relates to a process for the preparation of N-methyl (3-pyridyl) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1- (1R, 2R) of formula:
- R represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms
- Het represents a heterocyclic radical of aromatic character
- Y represents a valence bond or a methylene radical.
- (1S.2S) UR, 2R) is useful as an antihypertensive agent (EP-0 097 584) and, particularly the isomer (1R, 2R), as a cardiac protector (EP-0 429 324) at doses for which the antihypertensive effect does not manifest itself .
- N-methyl (pyridyl-3) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1- (1R . 2R) can be isolated from a mixture of the forms (1R.2R) and (1S.2S), in particular from the racemic mixture , by chiral phase chromatography (EP-0 097 584) or can be prepared by stereoselective methods (EP-0 426 557). These methods require the use of large quantities of solvents or else the carrying out of a large number of steps.
- N-methyl (3-pyridyl) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1- (1R.2R) can be obtained at starting from a salt of the mixture of trans isomers (1R, 2R) and (1S.2S) and in particular of the racemic mixture with an optically active acid.
- the method according to the invention consists in selectively precipitating in a suitable solvent a salt of the trans isomer (1R.2R) with an optically active acid and then in liberating the trans isomer (1R.2R) from its salt.
- an optically active acid chosen from (-) - camphanic acid and (+) - 3-bromo-10 camphor-10 sulfonic acid.
- the solvents which are particularly suitable for the selective crystallization of the salt of the trans isomer (1R.2R) with an optically active acid are preferably chosen from water, aliphatic alcohols containing 1 to 4 carbon atoms such as methanol , ethanol or isopropanol, and hydro-alcoholic mixtures.
- (1R.2R) is released from its salt by means of an inorganic or organic base, operating in water or in a mixture consisting of water and an immiscible solvent in which the trans isomer (1R, 2R ) is soluble.
- mineral base hydroxides or carbonates of alkali metals (sodium hydroxide, potassium hydroxide, sodium carbonate) are preferably used.
- organic base tertiary aliphatic amines (triethylamine) or pyridine can be used, the basicity of which is strong enough to release the optically active acid from its salt.
- potash is used in a hydroorganic medium such as a water-halogenated aliphatic hydrocarbon mixture such as a water-methylene chloride mixture: in this way, the isomer trans (1R, 2R) passes into solution in the organic solvent as it is formed, the salt of the optically active acid remaining in aqueous solution.
- a hydroorganic medium such as a water-halogenated aliphatic hydrocarbon mixture such as a water-methylene chloride mixture
- N-methyl (3-pyridyl) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1- (1R.2R) is separated from its solution according to the usual methods and it can be purified according to known techniques, for example by crystallization.
- the mixture of trans isomers (1R.2R) and (1S.2S) of N-methyl (pyridyl-3) -2 tetrahydrothiopyrannecarbothioamide-2-oxide-1, and more particularly the racemic mixture, can be prepared under the conditions described in European patent EP-0 097 584.
- the following examples illustrate the present invention.
- the enantiomeric excess is close to 100%.
- the yield is 33.4%.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU61445/94A AU6144594A (en) | 1993-03-02 | 1994-02-28 | Method for preparing n-methyl 2-(3-pyridyl) (1r,2r)-2-tetrahydrothiopyrancarbothioamide-1-oxide |
EP94908384A EP0687264A1 (fr) | 1993-03-02 | 1994-02-28 | Procede de preparation de n-methyl (pyridyl-3)-2 tetrahydrothiopyrannecarbothioamide-2-oxyde-1-(1r,2r) |
KR1019950703729A KR960701046A (ko) | 1993-03-02 | 1994-02-28 | N-메틸 2-(3-피리딜)(1r, 2r)-2-테트라히드로티오피란카르보티오아미드-1- 옥사이드의 제조방법(method for preparing n-methyl 2-(3-pyridyl)(1r,2r)-2-tetrahydrothiopyrancarbothioamide-1-oxide) |
JP6519651A JPH08507304A (ja) | 1993-03-02 | 1994-02-28 | (1r,2r)−n−メチル−2−(3−ピリジル)テトラヒドロチオピラン−2−カルボチオアミド1−オキシドの製造方法 |
SK1071-95A SK107195A3 (en) | 1993-03-02 | 1994-02-28 | Method for preparing (1r,2r)-n-methyl-2-(3-pyridyl) tetrahydrothiopyran-2-carbothioamide-1-oxide |
PL94310440A PL310440A1 (en) | 1993-03-02 | 1994-02-28 | Method of obtaining (2r)-n-methyl-2-(pyridyl-3)-tetrahydrothiopyrano-carbothiamide-2(1r)-1-oxide |
NO953386A NO953386D0 (no) | 1993-03-02 | 1995-08-29 | Fremgangsmåte for fremstilling av N-metyl-2-(3-pyridyl)-(1R,2R)-2-tetrahydrotiopyrankarbotioamid-1-oksyd |
FI954110A FI954110A0 (fi) | 1993-03-02 | 1995-09-01 | Menetelmä (1R,2R)-N-metyyli-2-(3-pyridyyli)-2-tetrahydrotiopyrankarbotiamodi-1-oksidin valmistamiseksi |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR93/02369 | 1993-03-02 | ||
FR9302369A FR2702213B1 (fr) | 1993-03-02 | 1993-03-02 | Procédé de préparation de N-méthyl (pyridyl-3)-2 tétrahydrothiopyrannecarbothioamide-2-oxyde-1-(1R,2R). |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1994020493A1 true WO1994020493A1 (fr) | 1994-09-15 |
Family
ID=9444564
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR1994/000221 WO1994020493A1 (fr) | 1993-03-02 | 1994-02-28 | Procede de preparation de n-methyl (pyridyl-3)-2 tetrahydrothiopyrannecarbothioamide-2-oxyde-1-(1r,2r) |
Country Status (16)
Country | Link |
---|---|
US (1) | US5688956A (fr) |
EP (1) | EP0687264A1 (fr) |
JP (1) | JPH08507304A (fr) |
KR (1) | KR960701046A (fr) |
AU (1) | AU6144594A (fr) |
CA (1) | CA2153577A1 (fr) |
CZ (1) | CZ223895A3 (fr) |
FI (1) | FI954110A0 (fr) |
FR (1) | FR2702213B1 (fr) |
HU (1) | HUT71923A (fr) |
IL (1) | IL108785A0 (fr) |
NO (1) | NO953386D0 (fr) |
PL (1) | PL310440A1 (fr) |
SK (1) | SK107195A3 (fr) |
WO (1) | WO1994020493A1 (fr) |
ZA (1) | ZA941367B (fr) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0426557A1 (fr) * | 1989-10-31 | 1991-05-08 | Rhone-Poulenc Sante | Procédé de préparation de (pyridyl-3)-2 tétrahydrothiopyrannecarbothioamide-2-oxydes-1-(1R,2R), les (pyridyl-3)-2 tÀ©trahydrothiopyrannecarbothioamide-2-oxydes-1-(1R,2R) ainsi obtenus et les compositions pharmaceutiques qui les contiennent |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IE81170B1 (en) * | 1988-10-21 | 2000-05-31 | Zeneca Ltd | Pyridine derivatives |
-
1993
- 1993-03-02 FR FR9302369A patent/FR2702213B1/fr not_active Expired - Fee Related
-
1994
- 1994-02-28 WO PCT/FR1994/000221 patent/WO1994020493A1/fr not_active Application Discontinuation
- 1994-02-28 JP JP6519651A patent/JPH08507304A/ja active Pending
- 1994-02-28 CZ CZ952238A patent/CZ223895A3/cs unknown
- 1994-02-28 IL IL10878594A patent/IL108785A0/xx unknown
- 1994-02-28 HU HU9502571A patent/HUT71923A/hu unknown
- 1994-02-28 CA CA002153577A patent/CA2153577A1/fr not_active Abandoned
- 1994-02-28 ZA ZA941367A patent/ZA941367B/xx unknown
- 1994-02-28 PL PL94310440A patent/PL310440A1/xx unknown
- 1994-02-28 KR KR1019950703729A patent/KR960701046A/ko not_active Application Discontinuation
- 1994-02-28 EP EP94908384A patent/EP0687264A1/fr not_active Withdrawn
- 1994-02-28 AU AU61445/94A patent/AU6144594A/en not_active Abandoned
- 1994-02-28 SK SK1071-95A patent/SK107195A3/sk unknown
-
1995
- 1995-08-15 US US08/515,421 patent/US5688956A/en not_active Expired - Fee Related
- 1995-08-29 NO NO953386A patent/NO953386D0/no unknown
- 1995-09-01 FI FI954110A patent/FI954110A0/fi not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0426557A1 (fr) * | 1989-10-31 | 1991-05-08 | Rhone-Poulenc Sante | Procédé de préparation de (pyridyl-3)-2 tétrahydrothiopyrannecarbothioamide-2-oxydes-1-(1R,2R), les (pyridyl-3)-2 tÀ©trahydrothiopyrannecarbothioamide-2-oxydes-1-(1R,2R) ainsi obtenus et les compositions pharmaceutiques qui les contiennent |
Non-Patent Citations (2)
Title |
---|
SAMUEL H. WILEN ET AL: "Tables of resolving agents and optical resolutions", 1972, UNIVERSITY OF NOTRE DAME PRESS, LONDON * |
THOMAS J. BROWN ET AL: "Synthesis and biological activity of trans (+-)-N-methyl-2-(3-pyridyl)-2-tetrahydrothiopyrancarbothioamide 1-oxide (RP 49356) and analogues: A new class of potassium channel opener", JOURNAL OF MEDICINAL CHEMISTRY, vol. 35, no. 20, 1 October 1992 (1992-10-01), WASHINGTON US, pages 3613 - 3624 * |
Also Published As
Publication number | Publication date |
---|---|
KR960701046A (ko) | 1996-02-24 |
EP0687264A1 (fr) | 1995-12-20 |
ZA941367B (en) | 1994-10-03 |
IL108785A0 (en) | 1994-06-24 |
JPH08507304A (ja) | 1996-08-06 |
NO953386L (no) | 1995-08-29 |
FR2702213B1 (fr) | 1995-04-07 |
US5688956A (en) | 1997-11-18 |
FI954110A (fi) | 1995-09-01 |
CZ223895A3 (en) | 1995-12-13 |
HUT71923A (en) | 1996-02-28 |
FR2702213A1 (fr) | 1994-09-09 |
SK107195A3 (en) | 1995-12-06 |
HU9502571D0 (en) | 1995-10-30 |
PL310440A1 (en) | 1995-12-11 |
NO953386D0 (no) | 1995-08-29 |
CA2153577A1 (fr) | 1994-09-15 |
AU6144594A (en) | 1994-09-26 |
FI954110A0 (fi) | 1995-09-01 |
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