WO2002102779A1 - Methode de preparation de 4-chloropyridine-n-oxydes - Google Patents

Methode de preparation de 4-chloropyridine-n-oxydes Download PDF

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Publication number
WO2002102779A1
WO2002102779A1 PCT/NL2002/000379 NL0200379W WO02102779A1 WO 2002102779 A1 WO2002102779 A1 WO 2002102779A1 NL 0200379 W NL0200379 W NL 0200379W WO 02102779 A1 WO02102779 A1 WO 02102779A1
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WO
WIPO (PCT)
Prior art keywords
oxide
pyridine
process according
stands
base
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.)
Ceased
Application number
PCT/NL2002/000379
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English (en)
Inventor
Ronus Bode De
Constantinus Simon Maria Liebregts
Wilhelmus Zwaan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Koninklijke DSM NV
DSM IP Assets BV
Original Assignee
DSM IP Assets BV
DSM NV
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by DSM IP Assets BV, DSM NV filed Critical DSM IP Assets BV
Publication of WO2002102779A1 publication Critical patent/WO2002102779A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom

Definitions

  • the invention relates to a process for the preparation of 4- chloropyridine-N-oxide of formula (1)
  • R 1 , R 2 en R 3 each independently stand for H, an alkyl group or an alkoxy group and R 4 stands for an alkyl group or an alkoxy group, in which the corresponding 4-H-pyridine-N-oxide is subjected to a treatment with Cl 2 , resulting in the formation of the 4-Cl-pyridine-N-oxide.
  • 4-CI-pyridine-N-oxides can be used as intermediate products in the preparation of important pharmaceuticals such as omeprazol, pantoprazol, rabeprazol and lansoprazol. As a rule this involves their conversion into 4-alkoxy- pyridine-N-oxides, for example 4-methoxy-2,3,5-trimethyl-pyridine, 3,4-dimethoxy- 2-methyl-pyridine, 4-(3-methoxy-propyloxy) or 4(2-trifluorethyl)2,3- dimethylpyridine.
  • a disadvantage of the known processes is that the pyridine N- oxide is reduced in the chiorination, so that for the subsequent steps to 4-alkoxy or 4-aryloxy substituted pyridines an extra oxidation step is necessary to obtain the corresponding pyridine N-oxide.
  • Examples of suitable compounds that can be prepared with the process according to the invention are 4-chloro-pyridine-N-oxides of formula (1) where R 1 , R 2 and R 3 stand for H, an alkyl group with 1-3 C atoms or an alkoxy group with 1-3 C atoms, and where R 4 stands for an alkyl group with 1-3 C atoms or an alkoxy group with 1-3 C atoms.
  • R 3 and R 4 each independently stand for an alkyl group or an alkoxy group
  • R 1 stands for H and R 2 for H, an alkyl group or an alkoxy group
  • the alkyl and or alkoxy groups in R 1 , R 2 , R 3 or R 4 may optionally be substituted .
  • the temperature at which the chiorination takes place is not very critical and for example lies between -20 and 100 °C, preferably between 10 and 50°C.
  • the pressure at which the reaction is carried out may in practice for example lie between 0.1 and 10 Pa. For practical reasons atmospheric pressure will often be chosen where possible. Higher pressures are advantageous for keeping Cl 2 gas in solution.
  • the chiorination reaction can be carried out in a solvent.
  • solvent in principle all solvents can be considered in which the reactants dissolve to an acceptable degree and that are inert under the reaction conditions.
  • suitable solvents are halogenated hydrocarbons, in particular dichloromethane or dichlorobenzene and alkane carboxylic acids with for example 1-10 C atoms, in particular acetic acid.
  • the quantity of chlorine gas applied is preferably larger than 0.5 equivalent, calculated relative to the quantity of 4-H-pyridine-N-oxide.
  • the non-converted 4-H-pyridine-N- oxide is preferably recycled.
  • use is preferably made of more than 1 equivalent of chlorine gas, calculated relative to the quantity of 4-H- pyridine-N-oxide.
  • the optimum excess depends for example on the quantity of dichloropyridine-N-oxide that can be formed, for example when R 1 , R 2 and/or R 3 represent hydrogen. This optimum can easily be determined by one skilled in the art for his specific situation.
  • the reaction is carried out with chlorine gas in the presence of a base.
  • a base for example (earth) alkali metal hydroxides or carbonates and alkali metal salts, in particular Na or K, of carboxylic acids, in particular sodium acetate.
  • the quantity of base to be applied preferably lies between 0.5 and 10 equivalents, calculated relative to the quantity of 4-H-pyridine-N-oxide, in particular between 1 and 3 equivalents.
  • the chiorination reaction is carried out in the presence of water.
  • the quantity of water preferably lies between 0 and 10 equivalents, calculated relative to the quantity of 4-H-pyridine-N-oxide. As more water is present in the reaction mixture, more chlorine bleach liquor can be formed, which may adversely affect the reaction.
  • the resulting 4-Cl-pyridine-N-oxide can, if desired after recovery, be used in the preparation of the corresponding N- alkoxy-pyridine or N-aryloxy-pyridine.
  • Suitable bases that can be applied in the preparation of the 4-alkoxy-pyridine-N-oxide are for example alkali metals and alkali metal hydroxides, hydrides or alcoholates, where alkali metal generally stands for Na or K.
  • Suitable solvents that can be applied if desired are aromatic hydrocarbons, in particular toluene or xylene; ethers, for example tetrahydrofuran (THF); dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO).
  • THF tetrahydrofuran
  • DMF dimethyl formamide
  • DMSO dimethyl sulfoxide
  • Chlorine gas (100 g; 1.4 mol) was introduced for 2-3 hours into a solution of 2,3-Lutidine-N-oxide (343.4 g; 2.79 mol) in dichloromethane (1200 ml) which was meanwhile being stirred and cooled (25-30 °C).
  • dichloromethane (1200 ml)
  • sodium hydroxide solution 223.2 g; 2.79 mol
  • chlorine gas was again introduced for 3-4 hours at 25-30 °C until the conversion was >98%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne une méthode de préparation de 4-chloropyridine-N-oxyde de la formule (I) dans laquelle R?1, R2 et R3¿ sont chacun, indépendamment, H, un groupe alkyle ou un groupe alcoxy; et R4 est un groupe alkyle ou un groupe alcoxy dans lequel le 4-H-pyridine-N-oxyde correspondant est soumis à un traitement avec Cl¿2? dont le résultat est la formation de 4-Cl-pyridine-N-oxyde. De préférence, R?1¿ est H; R2 est H ou méthyle; et R3 et R4 sont tous deux CH¿3?, ou R?1 et R2¿ sont tous deux H; R3 est méthoxy; et R4 est méthyle. De préférence, la chloration s'effectue en présence d'une base (par exemple un hydroxyde alcalino-(terreux) ou un carbonate) et d'eau, et 1 à 3 équivalents de la base sont utilisés, calculés relativement à la quantité de 4-H-pyridine-N-oxyde. Le 4-Cl-pyridine-N-oxyde obtenu peut subséquemment être soumis à un traitement réalisé avec un alcool substitué ou insubstitué en présence d'une base. Les composés résultants peuvent être utilisés dans la préparation de produits pharmaceutiques, tels que oméprazole, pantoprazole, rabéprazole et lansoprasole.
PCT/NL2002/000379 2001-06-15 2002-06-11 Methode de preparation de 4-chloropyridine-n-oxydes Ceased WO2002102779A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NL1018295A NL1018295C2 (nl) 2001-06-15 2001-06-15 Werkwijze voor de bereiding van 4-chloor-pyridine-n-oxiden.
NL1018295 2001-06-15

Publications (1)

Publication Number Publication Date
WO2002102779A1 true WO2002102779A1 (fr) 2002-12-27

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/NL2002/000379 Ceased WO2002102779A1 (fr) 2001-06-15 2002-06-11 Methode de preparation de 4-chloropyridine-n-oxydes

Country Status (2)

Country Link
NL (1) NL1018295C2 (fr)
WO (1) WO2002102779A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB958877A (en) * 1963-03-20 1964-05-27 Leuna Werke Veb Process for the production of chloropyridines and their alkyl-substituted homologues
US5045552A (en) * 1986-11-13 1991-09-03 Eisai Co., Ltd. Pyridine derivatives having anti-ulcerative activity
KR910006983B1 (ko) * 1989-12-09 1991-09-14 주식회사 중외제약 피리딘 유도체의 제조방법

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB958877A (en) * 1963-03-20 1964-05-27 Leuna Werke Veb Process for the production of chloropyridines and their alkyl-substituted homologues
US5045552A (en) * 1986-11-13 1991-09-03 Eisai Co., Ltd. Pyridine derivatives having anti-ulcerative activity
KR910006983B1 (ko) * 1989-12-09 1991-09-14 주식회사 중외제약 피리딘 유도체의 제조방법

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 199246, Derwent World Patents Index; Class B03, AN 1992-379292, XP002190094 *
T.C. KUEHLER ET AL.: "Structure-activity relationship of 2-[[(2-pyridyl)methyl]thio]-1H-benzimidazoles as anti Helicobacter pylori agents in vitro and evaluation of their in vivo efficacy", JOURNAL OF MEDICINAL CHEMISTRY., vol. 41, no. 11, 1998, AMERICAN CHEMICAL SOCIETY. WASHINGTON., US, pages 1777 - 1788, XP002190093, ISSN: 0022-2623 *
YA.P. NIZHNIK ET AL.: "Acridine N-oxide reaction with chlorine", RUSSIAN JOURNAL OF ORGANIC CHEMISTRY., vol. 34, no. 6, 1998, CONSULTANTS BUREAU., US, pages 908, XP002190092, ISSN: 1070-4280 *

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NL1018295C2 (nl) 2002-12-17

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