EP0000453B1 - Verfahren zur Herstellung von Thienopyridinderivaten. - Google Patents

Verfahren zur Herstellung von Thienopyridinderivaten. Download PDF

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Publication number
EP0000453B1
EP0000453B1 EP78400029A EP78400029A EP0000453B1 EP 0000453 B1 EP0000453 B1 EP 0000453B1 EP 78400029 A EP78400029 A EP 78400029A EP 78400029 A EP78400029 A EP 78400029A EP 0000453 B1 EP0000453 B1 EP 0000453B1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
solvent
aryl
chloro
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.)
Expired
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EP78400029A
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English (en)
French (fr)
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EP0000453A1 (de
Inventor
Emile Braye
André Bousquet
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Sanofi SA
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Sanofi SA
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • 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
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • the present invention relates to a process for the preparation of thienopyridine derivatives.
  • this process does not make it possible to prepare thienopyridine derivatives substituted in position 4 using the Pictet Spengler reaction by the action of an aldehyde on a thienylethylamine derivative.
  • the object of the present invention is to remedy these drawbacks by providing a process which makes it possible both to access the derivatives substituted in position 4, and to obtain significantly higher yields and conversion rates.
  • reaction between the compound of formula II and the compound of formula III is carried out in an inert solvent at a temperature between 0 ° C and 150 ° C, but preferably between room temperature and the boiling point of the most compound volatile which is generally one of the solvents used.
  • This reaction probably involves the formation of an intermediate compound which is not isolated, but cyclized in situ, as will be explained below.
  • the cyclization of this intermediate compound requires the presence of an acid which is either generated in the medium by the reaction of formation of the intermediate, or is added when this reaction of formation of the intermediate does not provide any.
  • the formation of acid in situ depends on the nature of the compound of formula III, thus for the compounds of formula III of types a, b, c, we observe the formation of such an acid of formula XH which serves as an agent. cyclization, whereas for the compounds of formula III of types d, e, and f, no acid is formed.
  • the reaction is most often quick, but it does. can sometimes be advantageous to heat at the end of the reaction to speed it up.
  • the reaction is carried out in a solvent inert with respect to the reagents, in particular the compounds of formula III.
  • This solvent must be anhydrous because water breaks down the compounds of formula III.
  • an aprotic solvent is used which can be polar in nature, such as dimethylformamide, dimethylsulfoxide, hexamethyl phosphorotriamide or another solvent, such as benzene, toluene, a chlorinated solvent, such as a chlorinated hydrocarbon or light ethers.
  • the compounds of formula II and III are reacted in stoichiometric amounts, or optionally with a molar excess of the compound of formula III of up to approximately 50%.
  • Cyclization therefore takes place with the formation of an alcohol, a mercaptan, an amine or water.
  • the group R 4 is an aryl group such as the phenyl group, a heterocyclic group such as the 2-thienyl group, an aliphatic or cycloaliphatic radical or a functional group such as alkoxycarbonyl, carboxy.
  • the mixture is heated to reflux (41 ° C.) and 156 g of dimethyl sulfoxide are added slowly. Throughout the addition, there is a significant release of gas consisting of SO 2 and HCl. A slight heating must be maintained to keep the medium at reflux. At the end of the addition of dimethyl sulfoxide, a stream of nitrogen is passed to remove the dissolved hydrochloric acid.
  • the reaction medium (333 g) is used as it is in the cyclization operation described below.
  • the crude product thus obtained contains from 1 to 2% of impurities and can be made analytically pure by recrystallization from ethanol.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Claims (6)

1. Verfahren zur Herstellung von Thienopyridinderivaten der allgemeinen Formel
Figure imgb0023
worin R, Wasserstoff, Alkyl, Aryl oder gegebenenfalls substituiertes Aralkyl bedeutet, R2 und R3 gleich oder verschieden sind und jeweils Wasserstoff, nied. Alkyl, Aryl oder eine heterocyclische Gruppe darstellen und R4 Wasserstoff, Alkyl, Cycloalkyl, Alkoxy-carbonyl, Carboxy, Aryl oder eine heterocyclische Gruppe ist, dadurch gekennzeichnet, daß man eine Verbindung de allgemeinen Formel
Figure imgb0024
worin R,, R2 und R3 die obige Bedeutung haben, mit einer Verbindung der allgemeinen Formel
Figure imgb0025
worin R4 die obige Bedeutung hat, X Halogen, gegebenenfalls substituiertes Alkoxy, gegebenenfalls substituiertes Thioalkyl oder gegebenenfalls substituiertes Amino bedeutet und Y gegebenenfalls substituiertes Alkoxy, gegebenenfalls substituiertes Thioalkyl, gegebenenfalls substituiertes Amino oder eine Gruppe der Formel
Figure imgb0026
darstellt, wobei R nied. Alkyl oder Aryl ist, oder X und Y zusammen mit dem Kohlenstoffatom, an dem sie hängen, einen sechsgliedrigen heterocyclischen Hexahydro-S-triazin-, Trioxan-oder Trithianring bilden, in einem inerten Lösungsmittel das, wenn X ist nicht Halogen, eine Mineralsäure oder eine organische Carbon- oder Sulfosäure enthält, bei einer Temperatur von 0 bis 150°C und in wasserfreiem Medium umsetzt und gegebenenfalls die Base freisetzt.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man die Reaktion bei Umbebungstemperatur bis zum Siedepunkt der flüchtigeren Verbindung durchfürht.
3. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man als inertes Lösungsmittel ein aprotisches polares Lösungsmittel, wie Dimethylformamid, Dimethylsulfoxyd, Hexamethylphosphortriamid oder Benzol, oder ein Chlorlösungsmittel, wie einen Chlorkohlenwasserstoff, oder einen niederen Äther einsetzt.
4. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man als Säure Salzsäure oder Methansulfonsäure einsetzt.
5. Verfahren nach Anspruch 3, dadurch gekennzeichnet, daß man ein Lösungsmittel einsetzt, das das Halogenid der Verbindung der Formel (I) nicht löst.
6. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß Man die Verbindung der Formel (111) in stöchiometrischer Menge bis zu einem molaren überschß von 50%, bezogen auf die Verbindung der Formel (11), einsetzt.
EP78400029A 1977-07-12 1978-06-21 Verfahren zur Herstellung von Thienopyridinderivaten. Expired EP0000453B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7721517A FR2397417A1 (fr) 1977-07-12 1977-07-12 Procede de preparation de derives de la thienopyridine
FR7721517 1977-07-12

Publications (2)

Publication Number Publication Date
EP0000453A1 EP0000453A1 (de) 1979-01-24
EP0000453B1 true EP0000453B1 (de) 1980-07-23

Family

ID=9193307

Family Applications (1)

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EP78400029A Expired EP0000453B1 (de) 1977-07-12 1978-06-21 Verfahren zur Herstellung von Thienopyridinderivaten.

Country Status (32)

Country Link
US (1) US4174448A (de)
EP (1) EP0000453B1 (de)
JP (1) JPS5419994A (de)
AR (1) AR224501A1 (de)
AT (1) AT366691B (de)
AU (1) AU516506B2 (de)
BE (1) BE868866A (de)
CA (1) CA1113469A (de)
CH (1) CH633013A5 (de)
DD (1) DD136838A5 (de)
DE (1) DE2860056D1 (de)
DK (1) DK155285C (de)
ES (1) ES471403A1 (de)
FI (1) FI67852C (de)
FR (1) FR2397417A1 (de)
GB (1) GB1599728A (de)
GR (1) GR64796B (de)
HU (1) HU181928B (de)
IE (1) IE46929B1 (de)
IL (1) IL54886A (de)
IT (1) IT1105084B (de)
LU (1) LU79823A1 (de)
MX (1) MX4884E (de)
NO (1) NO152844C (de)
NZ (1) NZ187834A (de)
PH (1) PH14288A (de)
PL (1) PL115368B1 (de)
PT (1) PT68251A (de)
RO (1) RO74931A (de)
SU (1) SU900813A3 (de)
YU (1) YU41832B (de)
ZA (1) ZA783296B (de)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4906756A (en) * 1988-05-10 1990-03-06 Syntex (U.S.A.) Inc. 2-(2-nitrovinyl)thiophene reduction and synthesis of thieno[3,2-c]pyridine derivatives
FR2664596B1 (fr) * 1990-07-10 1994-06-10 Sanofi Sa Procede de preparation d'un derive n-phenylacetique de tetrahydrothieno [3,2-c] pyridine et son intermediaire de synthese.
HUT74685A (en) * 1994-02-02 1997-01-28 Lilly Co Eli Hiv protease inhibitors and intermediates piperidine derivatives condensed with heterocycles as intermediates for hiv protease inhibitors
PT707007E (pt) * 1994-10-14 2002-06-28 Merck Patent Gmbh Derivados amino(tio)eter como agentes activos no snc
US6043368A (en) * 1996-09-04 2000-03-28 Poli Industria Chimica, S.P.A. Method of making thieno-pyridine derivatives
WO1999045013A1 (en) * 1998-03-06 1999-09-10 Novo Nordisk A/S 4,5,6,7-TETRAHYDRO-THIENO[3,2-c]PYRIDINE DERIVATIVES
CN102241690B (zh) 2010-05-13 2015-08-12 天津药物研究院 一类含腈基的噻吩并吡啶酯类衍生物、其制备方法和用途
EP3677535A1 (de) 2015-10-09 2020-07-08 Devi-Group B.V. Verfahren zur montage einer treppenliftführungsschiene und ein kit

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2215948B1 (de) * 1973-02-01 1976-05-14 Centre Etd Ind Pharma
FR2312246A1 (fr) * 1975-05-28 1976-12-24 Parcor Derives de la tetrahydro-4,5,6,7 thieno (3,2-c) pyridine, leur procede de preparation et leurs applications
FR2312247A1 (fr) * 1975-05-30 1976-12-24 Parcor Derives de la thieno-pyridine, leur procede de preparation et leurs applications
FR2315274A1 (fr) * 1975-06-27 1977-01-21 Parcor Nouveaux derives de la thieno (2,3-c) pyridine, leur preparation et leurs applications

Also Published As

Publication number Publication date
AT366691B (de) 1982-04-26
GR64796B (en) 1980-06-02
FR2397417A1 (fr) 1979-02-09
DK155285B (da) 1989-03-20
HU181928B (en) 1983-11-28
NO152844C (no) 1985-11-27
PL115368B1 (en) 1981-03-31
IE781155L (en) 1979-01-12
PT68251A (fr) 1978-08-01
IE46929B1 (en) 1983-11-02
FI67852B (fi) 1985-02-28
IT7850225A0 (it) 1978-07-10
US4174448A (en) 1979-11-13
DK155285C (da) 1989-07-24
IT1105084B (it) 1985-10-28
FI67852C (fi) 1985-06-10
YU148278A (en) 1982-08-31
ES471403A1 (es) 1979-01-16
CA1113469A (en) 1981-12-01
CH633013A5 (fr) 1982-11-15
BE868866A (fr) 1979-01-10
FI782044A (fi) 1979-01-13
NO152844B (no) 1985-08-19
NO782411L (no) 1979-01-15
SU900813A3 (ru) 1982-01-23
IL54886A0 (en) 1978-08-31
DK311078A (da) 1979-01-13
AU516506B2 (en) 1981-06-04
YU41832B (en) 1988-02-29
GB1599728A (en) 1981-10-07
ATA468978A (de) 1981-09-15
MX4884E (es) 1982-12-02
AU3794078A (en) 1980-01-17
PH14288A (en) 1981-05-04
DE2860056D1 (en) 1980-11-13
DD136838A5 (de) 1979-08-01
EP0000453A1 (de) 1979-01-24
NZ187834A (en) 1981-05-01
FR2397417B1 (de) 1980-04-18
LU79823A1 (fr) 1978-12-07
ZA783296B (en) 1979-07-25
JPS6339598B2 (de) 1988-08-05
RO74931A (ro) 1980-10-30
AR224501A1 (es) 1981-12-15
IL54886A (en) 1981-11-30
PL208318A1 (pl) 1979-05-07
JPS5419994A (en) 1979-02-15

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