WO1994000433A1 - Process for making phenylthiomethylpyridinylalkenoates - Google Patents

Process for making phenylthiomethylpyridinylalkenoates Download PDF

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Publication number
WO1994000433A1
WO1994000433A1 PCT/US1993/006177 US9306177W WO9400433A1 WO 1994000433 A1 WO1994000433 A1 WO 1994000433A1 US 9306177 W US9306177 W US 9306177W WO 9400433 A1 WO9400433 A1 WO 9400433A1
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WO
WIPO (PCT)
Prior art keywords
formula
phenyl
halo
lower alkoxy
group
Prior art date
Application number
PCT/US1993/006177
Other languages
English (en)
French (fr)
Inventor
Robert A. Daines
Original Assignee
Smithkline Beecham Corporation
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 Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to US08/356,353 priority Critical patent/US5700943A/en
Priority to JP50263894A priority patent/JP3181917B2/ja
Priority to AU46557/93A priority patent/AU678979B2/en
Priority to CA002138955A priority patent/CA2138955A1/en
Priority to EP93916841A priority patent/EP0649408A4/en
Publication of WO1994000433A1 publication Critical patent/WO1994000433A1/en
Priority to KR1019940704738A priority patent/KR950702184A/ko

Links

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
    • C07D213/04—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 having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—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 having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D213/04—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 having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—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 having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • 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
    • C07D213/04—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 having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—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 having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5

Definitions

  • the field of this invention is that of a process for making certain thioethers by coupling a chloromethyl pyridyl compound with thiophenols and related mercaptans.
  • the products of this coupling, the thioethers and their related sulfoxides and sulfones are useful for treating diseases arising from or related to leukotrienes, particularly leukotriene B4. As such there utility lies in antagonizing the affects of leukotrienes.
  • This invention relates to a process for making these compounds and other compounds of a similar nature where a chloromethylpridine is coupled with a thiophenol or benzylic mercaptan.
  • This invention covers a method for making a compound of formula I
  • R j contains an ⁇ , ⁇ -unsaturated carbonyl group and the designation (R) n indicates hydrogen or one or more non-hydrogen radicals capable of being covalently bonded on the pyridyl and phenyl rings and m is 0 -5; which method comprises coupling a chloromethylpyridine of formula II with a thiol of formula HI in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) under an inert gas at a temperature between about ambient and 100° C for a period sufficient to effect the coupling.
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • Formula II Formula II Formula HI where Ri is defined above and (R) n is hydrogen or one or more radicals which can be substituted on either the pyridyl or phenyl ring and m is 0 - 5.
  • the imdefined carbonyl function valence can be a carbon- carbon bond, a carbon-heteroatom bond wherein the heteroatom is oxygen, nitrogen, sulfur or the like, including phosphorus.
  • This invention is intended to cover all the enventualities where a thiol of the type illustrated is reacted with a pyridyl derivative which has an ⁇ , ⁇ -unsaturated carbonyl system at the 2-position which can undergo a Michael addition reaction with the thiol.
  • the (R) n designation is used here to indicate that one or more groups may be present on either the pyridyl ring or the phenyl ring. This invention also includes the case where each of these R groups is hydrogen. It is expected that any number and combination of substituents may be present on either ring. The only limitation envisioned is that the one of these groups must not interfere with the coupling reaction to a degree as to render the reaction impractical, ie, it does not occur at all, the yield is vanishing small, the wrong product is obtained in an undesirable amount.
  • a given group may be in protected form, for example a carboxylate function may be present in the form of an ester, the acid being regenerated by hydrolytic, catalytic or enzymatic means once the coupling reaction is completed.
  • the invention is that of the use of DBU to affect the coupling of the chloro and the thiol to achieve the thioether and is to be viewed as only so limited.
  • aliphatic is intended to include saturated and unsaturated radicals. This includes normal and branched chains, saturated or mono or poly unsaturated chains where both double and triple bonds may be present in any combination.
  • lower alkyl means an alkyl group of 1 to 6 carbon atoms in any isomeric form, but particularly the normal or linear form.
  • Lower alkoxy means the group lower alkyl-O-.
  • Acyl-lower alkyl refers to the group (O)C-lower alkyl where the carbonyl carbon is counted as one of the carbons of the 1 to 6 carbons noted under the definition of lower alkyl.
  • Halo refers to and means fluoro, chloro, bromo or iodo. The phenyl ring may be substituted with one or more of these radicals.
  • substituents may be the same or different, such as where there are three chloro groups, or a combination of chloro and alkyl groups and further where this latter combination may have different alkyl radicals in the chloro/alkyl pattern.
  • Oxides of the pyridyl ring nitrogen may be prepared by means known in the art and as illustrated herein. These are to be considered part of the invention.
  • Compounds with a -chiral center may be administered as a racemic mixture or the racemates may be separated and the individual enantiomer used alone.
  • the compound l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is available from Aldrich.
  • DBU diazabicyclo[5.4.0]undec-7-ene
  • the thiol or mercaptan is dissolved in a dry polar solvent like acetonitrile to which is added about an equivalent of the chloromethylpyridine adduct to be coupled.
  • a dry polar solvent like acetonitrile
  • 2 to 5 equivalents of DBU as measured against the thiol or mercaptan are added.
  • About 3 equivalents of DBU are preferred. Dry conditions are maintained throughout the course of setting up and running the reaction.
  • An inert atmosphere is used, preferably argon. The reaction is stirred at between about ambient temperature and 100° C for several hours.
  • the reaction can be made to go in a useful manner by heating the stirred reactants for 2 to 4 hours under an argon gas at a temperature of about 50° C. Thereafter the reaction is cooled and the product, the thioether, is recovered and purified by conventional means.
  • Preferred products of this reaction are those compounds of formula
  • Cio-alip atic where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is Cj to C20-aliphatic-O-, or R is unsubstituted or substituted phenyl-Ci to CiQ-al ⁇ hatic-O- where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo;
  • R2 is H, lower alkoxy, halo, -CN, -(CH2) n R4 where n is 0 - 5, lower alkyl, or CF3;
  • R3 is H, lower alkoxy, halo, lower alkyl, CF3, -CN, -(CH2) n R4 where n is 0 - 5,
  • R4 is tetrazol-5-yl or COR5; and R5 is lower alkoxy, C ⁇ O- ⁇ 0 or phenyl(CH2) ⁇ -3CO.
  • R2 and R3 are both hydrogen, both halo, both methyl, or both methoxy.
  • Another preferred set of compounds are those where R2 is COR5 and R3 is hydrogen.
  • the 2,6- dichloro is a preferred product.
  • Specific preferred products are: (E)-methyl 3-[3-[4-(4-methoxyphenyl)butyloxy]-6-[(2,6- dichlorophenylthio)methyl]-2-pyridinyl]-2-propenoate,
  • the first step was to make the intermediates needed for forming those R groups where the intermediates were not available commercially.
  • This chemistry is illustrated for the case of the substituted phenyl-Ci to C ⁇ o-aliphatic-0- groups.
  • the same or similar chemistry has been disclosed in published patent applications, for example PCT international application numbers PCT/US91/03772, PCT/US91/03940, and PCT/US91/03399.
  • the chemistries set out in those documents can be used in place of or in conjunction with those given here to prepare the R groups of formula I.
  • the substituted chloromethylpyridine is prepared next, as opposed to the thiol intermediate, but this is not critical to the practice of the invention.
  • Base or acid
  • a free acid can be obtained from the salt by aridifying a solution of the salt.
  • Esters and amides can be prepared using standard reaction conditions and reagents. Tetrazoles are prepared from the corresponding acid halide, e.g., the acid chloride, by literature methods.
  • Trmlring the right hand portion of formula I can be purchased from o commercial sources.
  • a fist is as follows: 2,5-dichlorothiophenol, 2,6-dimethylthiophenol,2-chloro-6-fluorobenzyl mercaptan, and 2,4-difluorobenzyl thiol.
  • Other thiols can be made by published chemistry; that chemistry involves converting a haloalkylphenyl (the bromo form is preferred) compound to the corresponding mercaptan by treating the bromo compound with thiourea followed by base hydrolysis.
  • the thiophenols can be prepared by thermal rearrangement of the corresponding thiocarbamate followed by hydrolysis.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/US1993/006177 1992-06-30 1993-06-30 Process for making phenylthiomethylpyridinylalkenoates WO1994000433A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US08/356,353 US5700943A (en) 1993-06-30 1993-06-30 Process for making phenylthiomethylpyridinylalkenoates
JP50263894A JP3181917B2 (ja) 1992-06-30 1993-06-30 フェニルチオメチルピリジニルアルケノアート類の製造方法
AU46557/93A AU678979B2 (en) 1992-06-30 1993-06-30 Process for making phenylthiomethylpyridinylalkenoates
CA002138955A CA2138955A1 (en) 1992-06-30 1993-06-30 Process for making phenylthiomethylpyridinylalkenoates
EP93916841A EP0649408A4 (en) 1992-06-30 1993-06-30 METHOD FOR THE PRODUCTION OF PHENYLTHIOMETHYLPYRIDINYLALKENOATS.
KR1019940704738A KR950702184A (ko) 1992-06-30 1994-12-24 페닐티오메틸피리디닐알케노에이트의 제조방법(Process for making phenylthi omethypyridinylalkenoates)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US90695192A 1992-06-30 1992-06-30
US07/906,951 1992-06-30
US2520093A 1993-03-02 1993-03-02
US08/025,200 1993-03-02

Publications (1)

Publication Number Publication Date
WO1994000433A1 true WO1994000433A1 (en) 1994-01-06

Family

ID=26699426

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/006177 WO1994000433A1 (en) 1992-06-30 1993-06-30 Process for making phenylthiomethylpyridinylalkenoates

Country Status (10)

Country Link
EP (1) EP0649408A4 (enrdf_load_stackoverflow)
JP (1) JP3181917B2 (enrdf_load_stackoverflow)
KR (1) KR950702184A (enrdf_load_stackoverflow)
CN (1) CN1095713A (enrdf_load_stackoverflow)
AU (1) AU678979B2 (enrdf_load_stackoverflow)
CA (1) CA2138955A1 (enrdf_load_stackoverflow)
MX (1) MX9303972A (enrdf_load_stackoverflow)
NZ (1) NZ254473A (enrdf_load_stackoverflow)
TW (1) TW247907B (enrdf_load_stackoverflow)
WO (1) WO1994000433A1 (enrdf_load_stackoverflow)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996033174A1 (en) * 1995-04-21 1996-10-24 Smithkline Beecham Plc New form of (e)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl]-2-propenoic acid
EP0733044A4 (en) * 1993-12-08 1997-03-05 Smithkline Beecham Corp CHEMICAL COMPOUNDS

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1314666C (zh) * 2005-12-19 2007-05-09 华中师范大学 微波辅助合成硫醚类化合物的方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3810379A1 (de) * 1988-03-26 1989-10-12 Hoechst Ag Azaneophyl- und silazaneophylsulfide, verfahren zu ihrer herstellung, sie enthaltende mittel und ihre verwendung als schaedlingsbekaempfungsmittel
AU7982591A (en) 1990-06-07 1991-12-31 Smithkline Beecham Corporation Amide linked pyridyle-benzoic acid derivatives for treating leukotriene-related diseases
FI925544L (fi) 1990-06-07 1992-12-07 Smithkline Beecham Corp Bensoesyraderivat foer behandling av leukotrienassocierade sjukdomar
WO1991018601A1 (en) * 1990-06-07 1991-12-12 Smithkline Beecham Corporation Benzoic acid derivatives
WO1992005156A1 (en) * 1990-09-13 1992-04-02 Smithkline Beecham Corporation Pyridylthio or pyridyloxy alkanoic acids
WO1993006085A1 (en) * 1991-09-19 1993-04-01 Smithkline Beecham Corporation Pyridine compounds for treating leukotriene-related diseases

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J. Org. Chem., Vol. 53, issued 1988, TROST et al., "Tetra-N-Butylammonium Oxone. Oxidations under Anhydrous Conditions", pages 532-537, esp. pg. 535, see entire document. *
See also references of EP0649408A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0733044A4 (en) * 1993-12-08 1997-03-05 Smithkline Beecham Corp CHEMICAL COMPOUNDS
WO1996033174A1 (en) * 1995-04-21 1996-10-24 Smithkline Beecham Plc New form of (e)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl]-2-propenoic acid
US6093828A (en) * 1995-04-21 2000-07-25 Smithkline Beecham P.L.C. Form of (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridi nyl]-2-propenoic acid

Also Published As

Publication number Publication date
NZ254473A (en) 1996-11-26
TW247907B (enrdf_load_stackoverflow) 1995-05-21
AU678979B2 (en) 1997-06-19
CN1095713A (zh) 1994-11-30
JPH07508283A (ja) 1995-09-14
AU4655793A (en) 1994-01-24
JP3181917B2 (ja) 2001-07-03
EP0649408A1 (en) 1995-04-26
KR950702184A (ko) 1995-06-19
CA2138955A1 (en) 1994-01-06
EP0649408A4 (en) 1995-06-21
MX9303972A (es) 1994-04-29

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