CA2138955A1 - Process for making phenylthiomethylpyridinylalkenoates - Google Patents
Process for making phenylthiomethylpyridinylalkenoatesInfo
- Publication number
- CA2138955A1 CA2138955A1 CA002138955A CA2138955A CA2138955A1 CA 2138955 A1 CA2138955 A1 CA 2138955A1 CA 002138955 A CA002138955 A CA 002138955A CA 2138955 A CA2138955 A CA 2138955A CA 2138955 A1 CA2138955 A1 CA 2138955A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- phenyl
- halo
- group
- lower alkoxy
- 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.)
- Abandoned
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
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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)
Abstract
This invention relates to a process of making a compound of formula (I) where R1 contains an .alpha.,.beta.-unsaturated carbonyl group and Rn is hydrogen or nonhydrogen radicals which do not have a functional group which interferes with the coupling reaction, which process comprises coupling a thiolphenol or phenylalkylmercaptan with a chloromethylpyridine in the pres-ence of DBU under an inert atmosphere. These compounds are leukotriene antagonists and as such can be used in treating various diseases associated with leukotrienes.
Description
~138`9~5 . 0 94/00433 ~ PCl'tUS93/06177 P~ ocess for makin~ phenylthiG, ,et~ ,~/ipyridinylalke.loal~s.
f'~c~-.e of l~a ~nv~ntinn The field of this illv~lllion i., that of a ~1 oCe86 for m~kir~E certain thioetherR by coupling a chloromethyl pyridyl co~ ,ound with thioph~nol~
5 and related mercaptans. The products of thi6 coupling, the thioet~ers and their related sl1lfoYi-les and RlllfoneR are uReful for treating liReaces ariaing from or related to leukotrieneR, particularly lellkotriene B4. AR such there utility lie6 in antag~i7ing the Affec~Q of leukotrieneR.
~q~k.,, <~ l Of ~ ~nV~n*~n A _erie6 of thioethers f~e~r--.te~l by the general formula R~
(CH2)~
have been diRco~cled to be u6eful in treating ~;ReA8eS involving the leukol,l ~n~ cA~c" 19, particularly those ~liReAQeE believed to be A~sor,i~te with or c~nRe-l by the dih~Lo.~le~lrotrienes (lellkotnene B4). These thioe~h~rg can be found in cel ~,a~ pllhlics~tionc~ particularly PCT
AppliCAtj~!n gerial nnmher PCT/US9V03772. A method for ~c~al;~g those novel tLe~l,e~l ;c agents is ~iiRrlose~ therein along with a description of utility and the hAr~. o~ d of the family of hioA~ive lipids known as the leukotrienes.
This invention relates to a process for mstkine theRe co ~ ldR and other cr.--~o~,llds of a RimilAr nature where a chloromethylpridine is coupled with a t~ti~p~tPnol or benzylic ll,el~t~.
~nmmstry of ~f~ Inv~nt:;- n This invention covers a method for m~king a co ~oulld of formula I
(R)n~
Rl N f7~(R)n (CH2)m~
where Rl contstinR an a~,~nn~At~l-ated calbollyl group and the rle~ ns~t;on (R)n in~lir~stteE Ly~ t:ll or one or more non-LyLo~ rA~3ir~ls c~p~hle of C~13895~.~ .. ~. ..
wo 94/00433 Pcr/usg3/o617 being covalently bon~ on the pyridyl and phenyl rings and m is 0 -5;
which mPt~oA c~l .;ses coupling a chloromethylpyridine of formula II with a thiol of formula III in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) under an inert gas at a te~ ~, ature between about ~mhient and 5 100 C for a period snffi~P-nt to effect the coupling.
(R)n ~1 HS(CH2)m~(R)n Formula II Formula m where R1 is ~içfine~l above and (R)n i8 hydrogen or one or more radicals 10 which can be substituted on either the pyridyl or phenyl ring and m is 0 - 5.
('~ner~l li~ml~G-~ ent~
The following definitions are used in describing this invention.
An ,~mRAtnrated calbGl~yl group is illustrated by -CH=CH-C(=O)-15 or -C~C-C(=O)-. The lm~fine~l carb(,nyl filnrt;on valence can be a carbon-call,oll bond, a calL,oll-heteroatom bond wherein the heteroatom ifi u~y~
iLlv~ l, sulfur or the like, inrln~ing ~lloslJllorus. This illvt:lllion is int~n~e~ to cover all the t:llve..~ itie_ where a thiol of the type illustrated i8 reacted with a pyridyl del;vaLive which has an a,~llns,qt--.~ted carbonyl 20 _ystem at the 2-poRit;on which can undergo a ~Uirh~el addition reAc~ion with the thiol.
The (R)n lisRign~tion is used here to indicate that one or more groups may be present on either the pyridyl ring or the phenyl ring. This tion also includes the case where each of these R groups is hyLo~
25 It is ~ le~l that any mlmher and CQ n)-in~;on of substituents may be ~-ese~t on either nng. The only limit~ n envi~ione~l i6 that the one of these groups must not int~r~,e with the coupling re~ n to a degree as to render the r~aC~ion i~f~ r~l, ie, it does not occur at all, the yield is v~ni~hing ~mall, the wrong product is obt~ine~l in an lmd~rirable amount.
30 It should be understood that a given group may be in protecte-l form, for r~ le a c&l,oAylate function may be present in the form of an ester, the acid being regenerated by hydrolytic, catalytic or enzymatic me~ns once the coupling reaction is complete-l The in~elltion is that of the use of DBU to affect the coupling of the chloro and the thiol to achieve the t~ioet~er and i8 35 to be viewed as only 80 limited ~ 1 3 8 ~ PCr/US93/06177 As for other terms, "~lirh~tic" is inten~lerl to include ssturated and s~t~rated rslAic~l~. Thi6 includeæ normal and br~n~he~ rh~inc, æaturated or mono or poly lmR~t~rat,ed chains where both double and triple bond6 may be present in any cQmhin~tio~. The phraæe "lower alkyl" mean6 5 an alkyl group of 1 to 6 carbon atomR in any iRomD~ric form, but particularly the noImal or linear form. "Lower alkoxy" mD~n~ the group lower alkyl-O-.
"Acyl-lower alkyl" referæ to the group (O)C-lower alkyl where the carbonyl c~boll iæ counted a6 one of the ~I,onæ of the 1 to 6 carbonæ noted under the def~nition of lower alkyl. "Halo" referæ to and mD~ns fluoro, chloro, 10 bromo or iodo. The phenyl ring may be æul~ led with one or more of theæe r~lir~læ. Mlll~irle ællhEtit~lent6 may be the æame or di~t~ Lt, 6uch a6 where there are three c-h~oro groups, or a cQmhin~tiQn of c-hloro and alkyl glo.ll 6 and further where thiæ latter comhin~tinn may have d~Tef~llt alkyl r~ir~l~ in the chloro/alkyl patterIl.
Oxides of the pyridyl ring ~llo~l, may be ~le~a,ed by m~n~ known in the art and as illustrated herein. These are to be consi~lDred part of the i~lve~ Qn If by æome cQmhin~tion of sllbEht~ tc~ a chiral center iæ created or another form of an i~o~neric center iæ created in a cu~uu-ld of thiæ
20 inventinn~ all forms of suc~ mer(6) are int~n~e~tl to be cu~,~,ed herein.
Co...l~- .".1~ with a chiral center may be ~lmini6tsred aæ a racemic ~; Y l ~ . e or the r~D-m~e-s may be separated and the individual enant;omer used alone.
The co~l,oulld 1,8-~i~7~hicyclot5.4.0]undec-7-ene (DBU) iæ availa~e 25 from Aldrich. To effect the coupling, t~e thiol or m~ ~n iæ diææolved in a dry polar solvent like ~cet(~ le to which iæ added about an equivalent of the chloromet-Lyll,~l;dine ~d~lllt t to be col~ple~ Then belwe~:ll 2 to 5 equ.valentæ of DBU aæ mea6ured a~in~t the thiol or ~ ~e,~ t~.. are P~ e~l-About 3 e~lui~,alents of DBU are l"afe,,~d. D~y cO~ ;o~ are m~int~in 30 throl~hl~ ~t the cour6e of ~et~ up and l~ g the r~D~r~ n An inert ~t~noæphsre is used, ~lefelably argon. The re~c~;n- iæ ~lirl~d at between ahout ~mhi-D-nt t~ e~ and 100 C for several hour6. The re~rtir~n can he _ade to go in a u6eful m~nnDr by h ~ti~ the bLl,ad re~nt~ for 2 to 4 hour6 under an argon gaæ st a t~;---l,e. Btula of about 50 C. Therea~er the 35 re~ctiQn iæ cooled and the product, the thioetl~er~ iæ l~cu~e,ed and purified by CO~ r~ ;ons~l m~D~n~.
I~efe~, od products of this re~r1;o~ are thoæe cu ~ of formula ~138955-wo 94/00433 Pcr/usg3/o617 R~
`(CH2)~ll~R2 Formula L~
or an N-o~cide, or a pharm~cell~ç~lly acceptable 6alt, where misO-5;
R iB Cl to C2o~ ph~tic) unsubstituted or substituted phenyl-C1 to C1o-~liph~tic where sll~E~ etl phenyl has one or more rA~li~lR selected from the group cQnRiFtin~ of lower alkoxy, lower alkyl, trih~lomethyl~ and halo, or R is Cl to C20-~liph~tic-O-, or R iB unsubstituted or su~s~ ul~ed phenyl-C1 to C1o-~liph~tiC-O- where 6ubstituted phenyl has one or more r~ s~lçcts~l from the group conRiFtin~ of lower alkoxy, lower alkyl, trih~lQm^~yl, and halo;
Rl iB -(CH2)XCH=CHCORy, or -(CH2)xCH=CHCHO, where x is 0 - 2 and Ry iB -OH or an ester thereof or NH2 or a su~ ed amide derivative thereof;
R2 is H, lower alkoy, halo, -CN, -(CH2)nR4 where n iB O - 5, lower alkyl, or CF3;
R3 is H, lower alko~y, halo, lower allyl, CF3, -CN, -(CH2)nR4 where nisO-5, R4 i6 tetrazol-5-yl or CORs; and Rs iB lower alkoy, CH3(CH2)0 6CO or phenyl(CH2)0 3CO.
The more l,lefe~led products are those where R iB 8UbBtitUted phenyl-C2 to C8 alkoy, particularly the ~nRll~.~ 1sll-phenyl(CH2)2 g-O-group, or the p-fluoro- or p-m~tl~Qsyphenyl(CH2)2 8-0- group, or CH3(CH2)7 g-O-; m is 0 - 5, most ~lerelably 0, 1, or 2; Rl iB H02C-CH=CH-, or HO2C-CH2CH2- or a salt, ester or amide derivative thereof.
Anothér sub-group of l,.efel,ed products are those where R2 and R3 are both llg~v~ , both halo, both methyl, or both mPt~ no~r l,.ef~lldd set of co ~yO~dR are those where R2 iB CORs and R3 iB h~drc~ e~. The 2,6-~irhloro i8 a ylefelled product. .~pe~ific l,refelldd products are:
(E)-~etLyl 3 [3 t4 (4 m~tll~rgphenyl)butyloxy]-6-~(2,6-~irhlorophenylthio)mel.hyl]-2-pyridinyl]-2-~lu~. .o~te, (E~methyl 3-t3-[4-(4-mpthn~ henyl)butyloxy]-6-[phe~llhiomethyl]
f'~c~-.e of l~a ~nv~ntinn The field of this illv~lllion i., that of a ~1 oCe86 for m~kir~E certain thioetherR by coupling a chloromethyl pyridyl co~ ,ound with thioph~nol~
5 and related mercaptans. The products of thi6 coupling, the thioet~ers and their related sl1lfoYi-les and RlllfoneR are uReful for treating liReaces ariaing from or related to leukotrieneR, particularly lellkotriene B4. AR such there utility lie6 in antag~i7ing the Affec~Q of leukotrieneR.
~q~k.,, <~ l Of ~ ~nV~n*~n A _erie6 of thioethers f~e~r--.te~l by the general formula R~
(CH2)~
have been diRco~cled to be u6eful in treating ~;ReA8eS involving the leukol,l ~n~ cA~c" 19, particularly those ~liReAQeE believed to be A~sor,i~te with or c~nRe-l by the dih~Lo.~le~lrotrienes (lellkotnene B4). These thioe~h~rg can be found in cel ~,a~ pllhlics~tionc~ particularly PCT
AppliCAtj~!n gerial nnmher PCT/US9V03772. A method for ~c~al;~g those novel tLe~l,e~l ;c agents is ~iiRrlose~ therein along with a description of utility and the hAr~. o~ d of the family of hioA~ive lipids known as the leukotrienes.
This invention relates to a process for mstkine theRe co ~ ldR and other cr.--~o~,llds of a RimilAr nature where a chloromethylpridine is coupled with a t~ti~p~tPnol or benzylic ll,el~t~.
~nmmstry of ~f~ Inv~nt:;- n This invention covers a method for m~king a co ~oulld of formula I
(R)n~
Rl N f7~(R)n (CH2)m~
where Rl contstinR an a~,~nn~At~l-ated calbollyl group and the rle~ ns~t;on (R)n in~lir~stteE Ly~ t:ll or one or more non-LyLo~ rA~3ir~ls c~p~hle of C~13895~.~ .. ~. ..
wo 94/00433 Pcr/usg3/o617 being covalently bon~ on the pyridyl and phenyl rings and m is 0 -5;
which mPt~oA c~l .;ses coupling a chloromethylpyridine of formula II with a thiol of formula III in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) under an inert gas at a te~ ~, ature between about ~mhient and 5 100 C for a period snffi~P-nt to effect the coupling.
(R)n ~1 HS(CH2)m~(R)n Formula II Formula m where R1 is ~içfine~l above and (R)n i8 hydrogen or one or more radicals 10 which can be substituted on either the pyridyl or phenyl ring and m is 0 - 5.
('~ner~l li~ml~G-~ ent~
The following definitions are used in describing this invention.
An ,~mRAtnrated calbGl~yl group is illustrated by -CH=CH-C(=O)-15 or -C~C-C(=O)-. The lm~fine~l carb(,nyl filnrt;on valence can be a carbon-call,oll bond, a calL,oll-heteroatom bond wherein the heteroatom ifi u~y~
iLlv~ l, sulfur or the like, inrln~ing ~lloslJllorus. This illvt:lllion is int~n~e~ to cover all the t:llve..~ itie_ where a thiol of the type illustrated i8 reacted with a pyridyl del;vaLive which has an a,~llns,qt--.~ted carbonyl 20 _ystem at the 2-poRit;on which can undergo a ~Uirh~el addition reAc~ion with the thiol.
The (R)n lisRign~tion is used here to indicate that one or more groups may be present on either the pyridyl ring or the phenyl ring. This tion also includes the case where each of these R groups is hyLo~
25 It is ~ le~l that any mlmher and CQ n)-in~;on of substituents may be ~-ese~t on either nng. The only limit~ n envi~ione~l i6 that the one of these groups must not int~r~,e with the coupling re~ n to a degree as to render the r~aC~ion i~f~ r~l, ie, it does not occur at all, the yield is v~ni~hing ~mall, the wrong product is obt~ine~l in an lmd~rirable amount.
30 It should be understood that a given group may be in protecte-l form, for r~ le a c&l,oAylate function may be present in the form of an ester, the acid being regenerated by hydrolytic, catalytic or enzymatic me~ns once the coupling reaction is complete-l The in~elltion is that of the use of DBU to affect the coupling of the chloro and the thiol to achieve the t~ioet~er and i8 35 to be viewed as only 80 limited ~ 1 3 8 ~ PCr/US93/06177 As for other terms, "~lirh~tic" is inten~lerl to include ssturated and s~t~rated rslAic~l~. Thi6 includeæ normal and br~n~he~ rh~inc, æaturated or mono or poly lmR~t~rat,ed chains where both double and triple bond6 may be present in any cQmhin~tio~. The phraæe "lower alkyl" mean6 5 an alkyl group of 1 to 6 carbon atomR in any iRomD~ric form, but particularly the noImal or linear form. "Lower alkoxy" mD~n~ the group lower alkyl-O-.
"Acyl-lower alkyl" referæ to the group (O)C-lower alkyl where the carbonyl c~boll iæ counted a6 one of the ~I,onæ of the 1 to 6 carbonæ noted under the def~nition of lower alkyl. "Halo" referæ to and mD~ns fluoro, chloro, 10 bromo or iodo. The phenyl ring may be æul~ led with one or more of theæe r~lir~læ. Mlll~irle ællhEtit~lent6 may be the æame or di~t~ Lt, 6uch a6 where there are three c-h~oro groups, or a cQmhin~tiQn of c-hloro and alkyl glo.ll 6 and further where thiæ latter comhin~tinn may have d~Tef~llt alkyl r~ir~l~ in the chloro/alkyl patterIl.
Oxides of the pyridyl ring ~llo~l, may be ~le~a,ed by m~n~ known in the art and as illustrated herein. These are to be consi~lDred part of the i~lve~ Qn If by æome cQmhin~tion of sllbEht~ tc~ a chiral center iæ created or another form of an i~o~neric center iæ created in a cu~uu-ld of thiæ
20 inventinn~ all forms of suc~ mer(6) are int~n~e~tl to be cu~,~,ed herein.
Co...l~- .".1~ with a chiral center may be ~lmini6tsred aæ a racemic ~; Y l ~ . e or the r~D-m~e-s may be separated and the individual enant;omer used alone.
The co~l,oulld 1,8-~i~7~hicyclot5.4.0]undec-7-ene (DBU) iæ availa~e 25 from Aldrich. To effect the coupling, t~e thiol or m~ ~n iæ diææolved in a dry polar solvent like ~cet(~ le to which iæ added about an equivalent of the chloromet-Lyll,~l;dine ~d~lllt t to be col~ple~ Then belwe~:ll 2 to 5 equ.valentæ of DBU aæ mea6ured a~in~t the thiol or ~ ~e,~ t~.. are P~ e~l-About 3 e~lui~,alents of DBU are l"afe,,~d. D~y cO~ ;o~ are m~int~in 30 throl~hl~ ~t the cour6e of ~et~ up and l~ g the r~D~r~ n An inert ~t~noæphsre is used, ~lefelably argon. The re~c~;n- iæ ~lirl~d at between ahout ~mhi-D-nt t~ e~ and 100 C for several hour6. The re~rtir~n can he _ade to go in a u6eful m~nnDr by h ~ti~ the bLl,ad re~nt~ for 2 to 4 hour6 under an argon gaæ st a t~;---l,e. Btula of about 50 C. Therea~er the 35 re~ctiQn iæ cooled and the product, the thioetl~er~ iæ l~cu~e,ed and purified by CO~ r~ ;ons~l m~D~n~.
I~efe~, od products of this re~r1;o~ are thoæe cu ~ of formula ~138955-wo 94/00433 Pcr/usg3/o617 R~
`(CH2)~ll~R2 Formula L~
or an N-o~cide, or a pharm~cell~ç~lly acceptable 6alt, where misO-5;
R iB Cl to C2o~ ph~tic) unsubstituted or substituted phenyl-C1 to C1o-~liph~tic where sll~E~ etl phenyl has one or more rA~li~lR selected from the group cQnRiFtin~ of lower alkoxy, lower alkyl, trih~lomethyl~ and halo, or R is Cl to C20-~liph~tic-O-, or R iB unsubstituted or su~s~ ul~ed phenyl-C1 to C1o-~liph~tiC-O- where 6ubstituted phenyl has one or more r~ s~lçcts~l from the group conRiFtin~ of lower alkoxy, lower alkyl, trih~lQm^~yl, and halo;
Rl iB -(CH2)XCH=CHCORy, or -(CH2)xCH=CHCHO, where x is 0 - 2 and Ry iB -OH or an ester thereof or NH2 or a su~ ed amide derivative thereof;
R2 is H, lower alkoy, halo, -CN, -(CH2)nR4 where n iB O - 5, lower alkyl, or CF3;
R3 is H, lower alko~y, halo, lower allyl, CF3, -CN, -(CH2)nR4 where nisO-5, R4 i6 tetrazol-5-yl or CORs; and Rs iB lower alkoy, CH3(CH2)0 6CO or phenyl(CH2)0 3CO.
The more l,lefe~led products are those where R iB 8UbBtitUted phenyl-C2 to C8 alkoy, particularly the ~nRll~.~ 1sll-phenyl(CH2)2 g-O-group, or the p-fluoro- or p-m~tl~Qsyphenyl(CH2)2 8-0- group, or CH3(CH2)7 g-O-; m is 0 - 5, most ~lerelably 0, 1, or 2; Rl iB H02C-CH=CH-, or HO2C-CH2CH2- or a salt, ester or amide derivative thereof.
Anothér sub-group of l,.efel,ed products are those where R2 and R3 are both llg~v~ , both halo, both methyl, or both mPt~ no~r l,.ef~lldd set of co ~yO~dR are those where R2 iB CORs and R3 iB h~drc~ e~. The 2,6-~irhloro i8 a ylefelled product. .~pe~ific l,refelldd products are:
(E)-~etLyl 3 [3 t4 (4 m~tll~rgphenyl)butyloxy]-6-~(2,6-~irhlorophenylthio)mel.hyl]-2-pyridinyl]-2-~lu~. .o~te, (E~methyl 3-t3-[4-(4-mpthn~ henyl)butyloxy]-6-[phe~llhiomethyl]
2-pyridinyl]-2-ylo~o~tç, 2138 !3 5~
. ~) 94/00433 PCI/US93/06177 tE~methyl 3-t3-t2-(4-me~QYYphenyl)ethyloxy]-6-[(2~6-dichlorophenylthio)-methyl]-2-pyridinyl]-2-propqnoAte, (E)-methyl 3-[3-t2-(4-fluoroPhenYl)ethYloxY]-6-[(2,6-dichlorophenylthio)methyl]-2-pyridinyl]-2-propenoAte, or 6 OE~methyl 3-[3-t8-(4-mPthnyyphenyl)octyloxy]-6-t(3-carbometh benzylthio)metllyl]-2-pyridinyl]-2-propçno~
~thPci~
a~ l methoA~ vari~ti-n~ on the same procegs, have been used for ~lel,al~g these c ~ 0!~ . In ~cllbl~l, the a~oach taken was to first make the intermP~liAtes nee~le-l to make the R group, then to prepare the phenyl interme~i~t,e neeAe~ for fol~g the core structure of formula I; the pyridyl interrnP~ e was then ~lel alcd and reacted with the phenyl interme.~ te to form the core structure. Salts, free acids, amides, alternative esters and the like were then l lc~alcd.
As noted, the first step was to make the interrne-lis.t~s neetle.1 for fo~g those R ~0~8 where the interme~liAt~ were not available cQmm~rcially. This rhamip~ry is illustrated for the case of the substituted phenyl-C1 to Clo-~liphAtic-o- groups. The same or fiimil~r rh~miFtry has been ~ clQ6e~l in pllhli~he-l patent A~lir~ti~ n~, for PYAmple PCT
in~rn~ti~)n~l ~p~liCAtiQn mlmhers PCTIUS9V03772, PCT/US91/03940, and PCT/US9V03399. The rhPmiQ~ries set out in those ~lo~ tQ can be used in place of or in cc~ rt;c!n with those given here to ~.el,are the R groups of formula I.
Usually the snl~ e~l chloromell,yl~yl;dine is ~ ,~ed neYt, as opposed to the thiol i~ s~ t~, but this is not cntical to the practice of the i~v~ on MAking the su~liluted 6-chloromethylpyridyl interme~ te can begin with the Bl~ l,illg ~ ~ou~d and the rhçmiFtry 13i~clo~efl in the PCT ~plirAti~n PCT/US9V03772 and the other PCT cases cited above.
The rhemiQ'ry set out in the '03772 case can be used to COllVel l the s~al lillgm~te~ l, 2~ *~line-a2~3-diol~ to, for e~A..~le, the 2-(E-2-ca.buA~,methylethenyl~3-[4~4-mPtt oYyphenyl)butyloxy~-6-~hloromell~yl~;dine. This is illustrated in ~rh~me I given below. Novel rh~-nig~ry~ both cQn~itir nc and the reagent DBU, are then used to couple 35 the thiophenol with the chloromethyl substituted pyridine in order to make the basic structure of formula I. Base, or acid, can then be used to hydrolyze any ester group, if 80 desi~cd. A free acid can be ohtoinsA from ~e salt by acidifying a solution of the salt. Esters and ~mitle~ can be d using Eton~rd re-A~i~n c~nditinn~ and reagents. Tetrazoles are 3 PCr/US93/0617.
prepared from the COl~eb~O~rling acid h~liAe, e.g., the acid c~oride, by literature mPt~OA~.
Using the ~ l sors ~ al ed as per the noted PCT applications or which have been pur~-h~e~ from a cQmmsrcial source, and the steps 5 olltlinp~3 in .~çhpme I, can be uged to ~lel,afe c~ oullds offormula I.
~rhPmP I
Cl p-MeOC6H4(CH2~ HS~
MeO2C~ N Cl HCI Cl \DBU
~
p-MeOC6H4(C~
MeO2C N '~ Cl S~
Cl/~
pMeOC6H4(CH2) aq LiOH ll l U 02C/~N ~ Cl S~
Cl A general dc~c.;l,Lon of the conditions and reagents which can be used for ~ll~rel lh-g the diol to the ~(chloromethyl)pyridine co~oul.d can be found in PCT ~ppli~t;nn nllmher PCT/US91/03772. That description of the generalized case for each step is incol~,Gl~ted herein by reference along with the Eperific chPn~ y set out in the ~y~mples of that ~prlir~ n A mlmhPr of thioph~Pnnl~: and tl io~lkylphenyl compounds useful for mslki~ the right hand portion of formula I can be purrh~ce~ from 213~95~
. ~) 94/00433 PCI/US93/06177 tE~methyl 3-t3-t2-(4-me~QYYphenyl)ethyloxy]-6-[(2~6-dichlorophenylthio)-methyl]-2-pyridinyl]-2-propqnoAte, (E)-methyl 3-[3-t2-(4-fluoroPhenYl)ethYloxY]-6-[(2,6-dichlorophenylthio)methyl]-2-pyridinyl]-2-propenoAte, or 6 OE~methyl 3-[3-t8-(4-mPthnyyphenyl)octyloxy]-6-t(3-carbometh benzylthio)metllyl]-2-pyridinyl]-2-propçno~
~thPci~
a~ l methoA~ vari~ti-n~ on the same procegs, have been used for ~lel,al~g these c ~ 0!~ . In ~cllbl~l, the a~oach taken was to first make the intermP~liAtes nee~le-l to make the R group, then to prepare the phenyl interme~i~t,e neeAe~ for fol~g the core structure of formula I; the pyridyl interrnP~ e was then ~lel alcd and reacted with the phenyl interme.~ te to form the core structure. Salts, free acids, amides, alternative esters and the like were then l lc~alcd.
As noted, the first step was to make the interrne-lis.t~s neetle.1 for fo~g those R ~0~8 where the interme~liAt~ were not available cQmm~rcially. This rhamip~ry is illustrated for the case of the substituted phenyl-C1 to Clo-~liphAtic-o- groups. The same or fiimil~r rh~miFtry has been ~ clQ6e~l in pllhli~he-l patent A~lir~ti~ n~, for PYAmple PCT
in~rn~ti~)n~l ~p~liCAtiQn mlmhers PCTIUS9V03772, PCT/US91/03940, and PCT/US9V03399. The rhPmiQ~ries set out in those ~lo~ tQ can be used in place of or in cc~ rt;c!n with those given here to ~.el,are the R groups of formula I.
Usually the snl~ e~l chloromell,yl~yl;dine is ~ ,~ed neYt, as opposed to the thiol i~ s~ t~, but this is not cntical to the practice of the i~v~ on MAking the su~liluted 6-chloromethylpyridyl interme~ te can begin with the Bl~ l,illg ~ ~ou~d and the rhçmiFtry 13i~clo~efl in the PCT ~plirAti~n PCT/US9V03772 and the other PCT cases cited above.
The rhemiQ'ry set out in the '03772 case can be used to COllVel l the s~al lillgm~te~ l, 2~ *~line-a2~3-diol~ to, for e~A..~le, the 2-(E-2-ca.buA~,methylethenyl~3-[4~4-mPtt oYyphenyl)butyloxy~-6-~hloromell~yl~;dine. This is illustrated in ~rh~me I given below. Novel rh~-nig~ry~ both cQn~itir nc and the reagent DBU, are then used to couple 35 the thiophenol with the chloromethyl substituted pyridine in order to make the basic structure of formula I. Base, or acid, can then be used to hydrolyze any ester group, if 80 desi~cd. A free acid can be ohtoinsA from ~e salt by acidifying a solution of the salt. Esters and ~mitle~ can be d using Eton~rd re-A~i~n c~nditinn~ and reagents. Tetrazoles are 3 PCr/US93/0617.
prepared from the COl~eb~O~rling acid h~liAe, e.g., the acid c~oride, by literature mPt~OA~.
Using the ~ l sors ~ al ed as per the noted PCT applications or which have been pur~-h~e~ from a cQmmsrcial source, and the steps 5 olltlinp~3 in .~çhpme I, can be uged to ~lel,afe c~ oullds offormula I.
~rhPmP I
Cl p-MeOC6H4(CH2~ HS~
MeO2C~ N Cl HCI Cl \DBU
~
p-MeOC6H4(C~
MeO2C N '~ Cl S~
Cl/~
pMeOC6H4(CH2) aq LiOH ll l U 02C/~N ~ Cl S~
Cl A general dc~c.;l,Lon of the conditions and reagents which can be used for ~ll~rel lh-g the diol to the ~(chloromethyl)pyridine co~oul.d can be found in PCT ~ppli~t;nn nllmher PCT/US91/03772. That description of the generalized case for each step is incol~,Gl~ted herein by reference along with the Eperific chPn~ y set out in the ~y~mples of that ~prlir~ n A mlmhPr of thioph~Pnnl~: and tl io~lkylphenyl compounds useful for mslki~ the right hand portion of formula I can be purrh~ce~ from 213~95~
4/00433 PC~/US93/06177 ~ o.nmercial sources. A list, not intsn~lecl to be çYh~ *ve, is aR follows:
2,5~i~hlorothiorhPn()l, 2,6-dimethylthio~Pr ol,~-chloro-6-fluorobenzyl mel ~pl~l, and 2,4-difluorobenzyl thiol. Other thiol6 can be made by pllhliRhP~l rhemi~try; that rhPmiFtry involves converl,ing a h~l?~lkylphenyl 5 (the bromo form i6 l,~fell~d) compound to the colle~yon~ling mel~tan by treating the bromo co~oulld with thiourea followed by baRe hydrolysis.
Alt~l"ati~,ely the thiophPnnlR can be l,la~a~ad by thermal leallOllgement of the co~leL~o-.lling t~iorA~ te followed by hydrolysis.
Coupling the thiol wit~ the chloromel~lyl~l;dyl cu~ ,o~d uRing a 10 novel mptbo~3 which employs l,8-~ 7~bicyclo[5.4.0]undec-7-ene (DBU) and an al,~lo~l;ate ~olvent, for e~ lc CH3CN. IUo:Ft~lre is excluded from the system and an inert gas is used, for ey~mple argon. A slightly elevated tçmpt l~tula is ~lafel~c:d, one that is about 50 C or 80; the coupling re~cf;on is comrlete in about 3 hours.
Once the core structure is ~ el any ester can be hydrolyzed with acid or base, base is preferred, or that acid can be collv~l ~ed to another ester, an amide or another salt.
r.~ ~m~ lim~.n~
The following e~-nples are given to illustrate how to make and use 20 the cu~poullds of tbis ~v~t n.~ . These F.~ 1e~ are just that, ~ les, and are not ;~te---lP~ to ~ ibe or otherwise limit the scope ofthis Reference is made to the claims for ~iP,finir~ what is ~G8~ d to tbe illve~ )lD.
F.~.. wle 1 (P'.~.i~h;.. 3 r3-r4-(4-m~t~ n~vh~yl)hntylm~yl-6-r(~ 6-(~irhlnrol?hP.Tu~ltt iû)mP~ -?-~ Vfn~tq ~ett~yl 3 r3 r4 (4 mPtlln~?h~nvl)hll~cylo~yl-6-r(~. 6-t~ .hlnro-vh~ t~;o)m~t~ --vy~ yn-~ v~ t~. 2,6-Dichlorotbiophenol (53mg, 0.297mmol, Aldrich) was dissolved in dry MeCN
(0.60~) and treated nth 2-(E-2-c~l,u~,- ethyletbenyl~3-[4~4-methoyphenyl)butylo~cy]-6-chlorometLyl~ ;dine l~dlochloride (11 5mg~
0.270mmel) and 1,8-~i~7~bicyclo[5.4.0]undec-7-ene (DBU, 0.142mL, - 35 0.949mmol). The re~ion was ~L"ed under an atmosphere of argon at 50 C for 3h. The re~;on solution was diluted with EtOAc and washed with H20 and brine and dried (MgSO4). Purific~t;orl by flash column chromatography (silica, EtOAc: CH2Cl2: hPY~nP~ 10: 15: 75) gave a colorless wasy solid: lH NMR (250~7 CDCl3) ~ 7.94 (d, J=15.7Hz, lH, 21389~5~ ``` ` `
vinyl),7.31 (d, J=7.6Hz, 2H, aryl), 7.13 (m, 4H, aryl, pyridyl), 7.11 ~a, J=8.4Hz, lH, pyridyl), 6.86 (d, J-8.7Hz, 2H, phenyl), 6.69 (d, J=15.7Hz, lH, vinyl), 4.14 (6, 2H, CH2-S), 3.97 (t, J=6.1Hz, 2H, CH2-O), 3.80 (6, 3H, OMe), 3.78 (~, 3H, methyl ester), 2.63 (t, J=7.2Hz, 2H, benzylic), 1.81 (m, 4H, 5 CH2CH2); analysi6 calcd. for C27H27Cl2NO4S: C, 60.90; H, 5.11; N, 2.63;
found: C, 60.61; H, 5.01; N, 2.57; MS (ES+): 532.0 (M+H).
Procee-lin~ in a 8imil~r -~A----e~', but sub6li~ul,i~g for the interme~i~te61isted in ~A and lB the &y~,op~;ate c~orome~lylyyl;dine and thiorhPnol or mercPptQ~lkylphenyl ~ ct6~ the following c~,myound6 10 can be l..el,a.cd:
(E)-methyl 3-[3-t8-(4-methosyphenyl)octyloxy]-6-[(3-c~l,o~ethoxybenzylthio)-methyl]-2-pyridinyl]-2-propeno~te, (E)-methyl 3-[3-[4-(4-methosyphenyl)butyloxy]-6-[phenylthiomethyl]
2-pyridinyl]-2-~loya..o~te, and (E~methyl 3-[3-[4-(4-metho,~ yl)butyloxy]-6-[(2,6-dichloro-phenylthio)methyl]-2-pyridinyl]-2-~.o~ te ~R (F) T.ithillm 3 r3 r4 (4 matht~s~harlyl)hl~ syl-6-r(~ 6-~irhloroph~ ylthio)m~th,~ -vyri~irlyll-~-vl~v~ t~. OE~MethYI 3-[3-[4-(4-m^~l o~yphenyl)butylosy]-6-[(2,6-~ hlorophenylthio)methyl]-2-py-ridinyl]-2-~u~ o~ts (65mg, 0.1~mmol) was dissolved in TH~ (1.0mL) and MeOH (0.50mL) and treated with 1.0M LiOH (0 ~5mT., O ~5mmol).
The re~ n was sli..ed under an argon atmosphere for 20h. The solvent was t ~d~.ated and the product p~rifiell by Reve~sed Phased MPLC (RP-18 25 silica, H2O-MeOH gradient). Lyo~ili7~t;or~ yielded a colorless amorphous solid: lH NMR (250~7, d4-MeOH) o 7.68 (d, J=15.7Hz, lH, vinyl), 7.37 (d, J=7.6Hz, 2H, aryl), 7.13 (m, 4H, aryl, pyridyl), 7.02 (d, J=8.4Hz, lH, pyridyl), 6.82 (d, J=15.7Hz, lH, vinyl), 6.81 (d, J=8.7Hz, 2H, phenyl), 4.13 (6, 2H, CH2-S), 4.00 (t, J=6.1Hz, 2H, CH2-O), 3.75 (8, 3H, OMe), 2.62 (t, 30 J=7.2Hz, 2H, benzylic), 1.80 (m, 4H, CH2CH2); analysis calcd. for C26H24Cl2NO4SLi 15/8H2O: C, 55.95; H, 5.01; N, 2.51; found: C, 55.75;
H, 4.58; N, 2.36; MS (ES+): 518.0 (M+H, free acid).
2,5~i~hlorothiorhPn()l, 2,6-dimethylthio~Pr ol,~-chloro-6-fluorobenzyl mel ~pl~l, and 2,4-difluorobenzyl thiol. Other thiol6 can be made by pllhliRhP~l rhemi~try; that rhPmiFtry involves converl,ing a h~l?~lkylphenyl 5 (the bromo form i6 l,~fell~d) compound to the colle~yon~ling mel~tan by treating the bromo co~oulld with thiourea followed by baRe hydrolysis.
Alt~l"ati~,ely the thiophPnnlR can be l,la~a~ad by thermal leallOllgement of the co~leL~o-.lling t~iorA~ te followed by hydrolysis.
Coupling the thiol wit~ the chloromel~lyl~l;dyl cu~ ,o~d uRing a 10 novel mptbo~3 which employs l,8-~ 7~bicyclo[5.4.0]undec-7-ene (DBU) and an al,~lo~l;ate ~olvent, for e~ lc CH3CN. IUo:Ft~lre is excluded from the system and an inert gas is used, for ey~mple argon. A slightly elevated tçmpt l~tula is ~lafel~c:d, one that is about 50 C or 80; the coupling re~cf;on is comrlete in about 3 hours.
Once the core structure is ~ el any ester can be hydrolyzed with acid or base, base is preferred, or that acid can be collv~l ~ed to another ester, an amide or another salt.
r.~ ~m~ lim~.n~
The following e~-nples are given to illustrate how to make and use 20 the cu~poullds of tbis ~v~t n.~ . These F.~ 1e~ are just that, ~ les, and are not ;~te---lP~ to ~ ibe or otherwise limit the scope ofthis Reference is made to the claims for ~iP,finir~ what is ~G8~ d to tbe illve~ )lD.
F.~.. wle 1 (P'.~.i~h;.. 3 r3-r4-(4-m~t~ n~vh~yl)hntylm~yl-6-r(~ 6-(~irhlnrol?hP.Tu~ltt iû)mP~ -?-~ Vfn~tq ~ett~yl 3 r3 r4 (4 mPtlln~?h~nvl)hll~cylo~yl-6-r(~. 6-t~ .hlnro-vh~ t~;o)m~t~ --vy~ yn-~ v~ t~. 2,6-Dichlorotbiophenol (53mg, 0.297mmol, Aldrich) was dissolved in dry MeCN
(0.60~) and treated nth 2-(E-2-c~l,u~,- ethyletbenyl~3-[4~4-methoyphenyl)butylo~cy]-6-chlorometLyl~ ;dine l~dlochloride (11 5mg~
0.270mmel) and 1,8-~i~7~bicyclo[5.4.0]undec-7-ene (DBU, 0.142mL, - 35 0.949mmol). The re~ion was ~L"ed under an atmosphere of argon at 50 C for 3h. The re~;on solution was diluted with EtOAc and washed with H20 and brine and dried (MgSO4). Purific~t;orl by flash column chromatography (silica, EtOAc: CH2Cl2: hPY~nP~ 10: 15: 75) gave a colorless wasy solid: lH NMR (250~7 CDCl3) ~ 7.94 (d, J=15.7Hz, lH, 21389~5~ ``` ` `
vinyl),7.31 (d, J=7.6Hz, 2H, aryl), 7.13 (m, 4H, aryl, pyridyl), 7.11 ~a, J=8.4Hz, lH, pyridyl), 6.86 (d, J-8.7Hz, 2H, phenyl), 6.69 (d, J=15.7Hz, lH, vinyl), 4.14 (6, 2H, CH2-S), 3.97 (t, J=6.1Hz, 2H, CH2-O), 3.80 (6, 3H, OMe), 3.78 (~, 3H, methyl ester), 2.63 (t, J=7.2Hz, 2H, benzylic), 1.81 (m, 4H, 5 CH2CH2); analysi6 calcd. for C27H27Cl2NO4S: C, 60.90; H, 5.11; N, 2.63;
found: C, 60.61; H, 5.01; N, 2.57; MS (ES+): 532.0 (M+H).
Procee-lin~ in a 8imil~r -~A----e~', but sub6li~ul,i~g for the interme~i~te61isted in ~A and lB the &y~,op~;ate c~orome~lylyyl;dine and thiorhPnol or mercPptQ~lkylphenyl ~ ct6~ the following c~,myound6 10 can be l..el,a.cd:
(E)-methyl 3-[3-t8-(4-methosyphenyl)octyloxy]-6-[(3-c~l,o~ethoxybenzylthio)-methyl]-2-pyridinyl]-2-propeno~te, (E)-methyl 3-[3-[4-(4-methosyphenyl)butyloxy]-6-[phenylthiomethyl]
2-pyridinyl]-2-~loya..o~te, and (E~methyl 3-[3-[4-(4-metho,~ yl)butyloxy]-6-[(2,6-dichloro-phenylthio)methyl]-2-pyridinyl]-2-~.o~ te ~R (F) T.ithillm 3 r3 r4 (4 matht~s~harlyl)hl~ syl-6-r(~ 6-~irhloroph~ ylthio)m~th,~ -vyri~irlyll-~-vl~v~ t~. OE~MethYI 3-[3-[4-(4-m^~l o~yphenyl)butylosy]-6-[(2,6-~ hlorophenylthio)methyl]-2-py-ridinyl]-2-~u~ o~ts (65mg, 0.1~mmol) was dissolved in TH~ (1.0mL) and MeOH (0.50mL) and treated with 1.0M LiOH (0 ~5mT., O ~5mmol).
The re~ n was sli..ed under an argon atmosphere for 20h. The solvent was t ~d~.ated and the product p~rifiell by Reve~sed Phased MPLC (RP-18 25 silica, H2O-MeOH gradient). Lyo~ili7~t;or~ yielded a colorless amorphous solid: lH NMR (250~7, d4-MeOH) o 7.68 (d, J=15.7Hz, lH, vinyl), 7.37 (d, J=7.6Hz, 2H, aryl), 7.13 (m, 4H, aryl, pyridyl), 7.02 (d, J=8.4Hz, lH, pyridyl), 6.82 (d, J=15.7Hz, lH, vinyl), 6.81 (d, J=8.7Hz, 2H, phenyl), 4.13 (6, 2H, CH2-S), 4.00 (t, J=6.1Hz, 2H, CH2-O), 3.75 (8, 3H, OMe), 2.62 (t, 30 J=7.2Hz, 2H, benzylic), 1.80 (m, 4H, CH2CH2); analysis calcd. for C26H24Cl2NO4SLi 15/8H2O: C, 55.95; H, 5.01; N, 2.51; found: C, 55.75;
H, 4.58; N, 2.36; MS (ES+): 518.0 (M+H, free acid).
Claims (3)
1. A process for making a compound of formula I
where the R1 contains an .alpha.,.beta.-unsaturated carbonyl group and the designation (R)n is hydrogen or one or more non-hydrogen radicals covalently bonded to the pyridyl and phenyl rings and m is 0-5; which process comprises coupling a chloromethylpyridine of formula II with a thiol of formula III in the presence of 2 to 5 equivalents of 1,8-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.
Formula II Formula III
where R1 is defined above, m is 0 - 5 and (R)n is hydrogen or one or more radicals which can be substituted on either the pyridyl or phenyl ring and which does not have a functional group which interferes with the coupling reaction.
where the R1 contains an .alpha.,.beta.-unsaturated carbonyl group and the designation (R)n is hydrogen or one or more non-hydrogen radicals covalently bonded to the pyridyl and phenyl rings and m is 0-5; which process comprises coupling a chloromethylpyridine of formula II with a thiol of formula III in the presence of 2 to 5 equivalents of 1,8-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.
Formula II Formula III
where R1 is defined above, m is 0 - 5 and (R)n is hydrogen or one or more radicals which can be substituted on either the pyridyl or phenyl ring and which does not have a functional group which interferes with the coupling reaction.
2. The process of claim 1 where about 3 equivalents of DBU is used and the reaction is carried out in acetonitrile under argon at a temperature of about 50° C for 2 to 4 hours.
3. The process of claim 2 wherein the product is a compound of formula IA
IA
or an N-oxide, or a pharmaceutically acceptable salt, where R is C1 to C20-aliphatic, unsubstituted or substituted phenyl-C1 to C10-aliphatic where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is C1 to C20-aliphatic-O-, or R is unsubstituted or substituted phenyl-C1 to C10-aliphatic-O- where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo;
R1 is -(CH2)xCH=CHCORy, or -(CH2)xCH=CHCHO, where x is 0 - 2 and Ry is -OH or an ester thereof or NH2 or a substituted amide derivative thereof;
R2 is H, lower alkoxy, halo, -CN, -(CH2)nR4 where n is 0 - 5, lower alkyl, or CF3;
R3 is H, lower alkoxy, halo, lower alkyl, CF3, -CN, -(CH2)nR4 where n is 0 - 5, R4 is tetrazol-5-yl or COR5; and R5 is lower alkoxy, CH3(CH2)0-6CO or phenyl(CH2)0-3CO.
IA
or an N-oxide, or a pharmaceutically acceptable salt, where R is C1 to C20-aliphatic, unsubstituted or substituted phenyl-C1 to C10-aliphatic where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is C1 to C20-aliphatic-O-, or R is unsubstituted or substituted phenyl-C1 to C10-aliphatic-O- where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo;
R1 is -(CH2)xCH=CHCORy, or -(CH2)xCH=CHCHO, where x is 0 - 2 and Ry is -OH or an ester thereof or NH2 or a substituted amide derivative thereof;
R2 is H, lower alkoxy, halo, -CN, -(CH2)nR4 where n is 0 - 5, lower alkyl, or CF3;
R3 is H, lower alkoxy, halo, lower alkyl, CF3, -CN, -(CH2)nR4 where n is 0 - 5, R4 is tetrazol-5-yl or COR5; and R5 is lower alkoxy, CH3(CH2)0-6CO or phenyl(CH2)0-3CO.
Applications Claiming Priority (5)
| 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 | ||
| PCT/US1993/006177 WO1994000433A1 (en) | 1992-06-30 | 1993-06-30 | Process for making phenylthiomethylpyridinylalkenoates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2138955A1 true CA2138955A1 (en) | 1994-01-06 |
Family
ID=26699426
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002138955A Abandoned CA2138955A1 (en) | 1992-06-30 | 1993-06-30 | Process for making phenylthiomethylpyridinylalkenoates |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0649408A4 (en) |
| JP (1) | JP3181917B2 (en) |
| KR (1) | KR950702184A (en) |
| CN (1) | CN1095713A (en) |
| AU (1) | AU678979B2 (en) |
| CA (1) | CA2138955A1 (en) |
| MX (1) | MX9303972A (en) |
| NZ (1) | NZ254473A (en) |
| TW (1) | TW247907B (en) |
| WO (1) | WO1994000433A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09506367A (en) * | 1993-12-08 | 1997-06-24 | スミスクライン・ビーチャム・コーポレイション | Compound |
| GB9508137D0 (en) * | 1995-04-21 | 1995-06-07 | Smithkline Beecham Plc | Formulation |
| CN1314666C (en) * | 2005-12-19 | 2007-05-09 | 华中师范大学 | Method for synthesizing thioether compound by aid of microwave |
| KR200481393Y1 (en) * | 2014-08-06 | 2016-09-27 | 김상열 | Smart slim stand |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3810379A1 (en) * | 1988-03-26 | 1989-10-12 | Hoechst Ag | AZANEOPHYL AND SILAZANEOPHYL SULFIDES, METHOD FOR THE PRODUCTION THEREOF, CONTAINERS THEREOF AND THEIR USE AS A PEST CONTROL |
| KR930700102A (en) * | 1990-06-07 | 1993-03-13 | 원본미기재 | Benzoic acid derivatives |
| JPH06501019A (en) * | 1990-09-13 | 1994-01-27 | スミスクライン・ビーチャム・コーポレイション | Pyridylthio or pyridyloxyalkanoic acid |
| AU2573592A (en) * | 1991-09-19 | 1993-04-27 | Smithkline Beecham Corporation | Pyridine compounds for treating leukotriene-related diseases |
-
1993
- 1993-06-30 WO PCT/US1993/006177 patent/WO1994000433A1/en not_active Application Discontinuation
- 1993-06-30 CA CA002138955A patent/CA2138955A1/en not_active Abandoned
- 1993-06-30 EP EP93916841A patent/EP0649408A4/en not_active Withdrawn
- 1993-06-30 NZ NZ254473A patent/NZ254473A/en unknown
- 1993-06-30 AU AU46557/93A patent/AU678979B2/en not_active Ceased
- 1993-06-30 CN CN93109433A patent/CN1095713A/en active Pending
- 1993-06-30 MX MX9303972A patent/MX9303972A/en unknown
- 1993-06-30 JP JP50263894A patent/JP3181917B2/en not_active Expired - Lifetime
- 1993-07-27 TW TW082105973A patent/TW247907B/zh active
-
1994
- 1994-12-24 KR KR1019940704738A patent/KR950702184A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU678979B2 (en) | 1997-06-19 |
| EP0649408A1 (en) | 1995-04-26 |
| WO1994000433A1 (en) | 1994-01-06 |
| CN1095713A (en) | 1994-11-30 |
| TW247907B (en) | 1995-05-21 |
| MX9303972A (en) | 1994-04-29 |
| AU4655793A (en) | 1994-01-24 |
| JPH07508283A (en) | 1995-09-14 |
| NZ254473A (en) | 1996-11-26 |
| EP0649408A4 (en) | 1995-06-21 |
| KR950702184A (en) | 1995-06-19 |
| JP3181917B2 (en) | 2001-07-03 |
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