CA1290768C - Chloromethyl heterocyclics - Google Patents

Abstract

P.C. 7013 CHLOROMETHYL HETEROCYCLICS
Abstract Chloromethyl group substituted heterocyclic compounds of the formulae or I II
wherein X is O or S;
Y together with the two carbons to which Y is attached forms phenyl, pyridyl or pyrimidyl, each of which may be substituted by R;
R is one of iodo or trifluoromethylthio or one or two of fluoro, chloro, bromo, (C1-C4)alkyl, (C1-C4) alkoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl or trifluoromethyl; and R1 is hydrogen or R, are prepared by reacting a bifunctional compound of the formulae or

Description

7~

--1~

2~:. 7913 ~:~I~ROMET}~YI, NlXT~tOCYCL~CS
. ~9~
Thl~ lnv~ntion relates te~ ~ proc~s~ ~ox preparlng chloro~nethyl yroup Jul: ~titued he'c~roeycl~c s:ompound~ oP
use a~ in~er~e~iate~ ~n th~ ~anuf~3ctur~ of ph~r~a ;:eutlcally ~ctive compound~. The ~mrentiorl ~1BO
in~lude~ llov~l ~nt~ diate~ arld th~ prep~r~ on of 2-chloro~ t~i (Sl~C6~ al koxyethane ~tBrting materi~l~ o u~e ~n the ~bc~v~ proces~O
Prior ar method for th~ pr~par~tion of chloro-methyl group sub~t~tuted heteroeycl~e compous~d~ ~n~lu~e the reaction o~ ortho~ nophenol with chloroacetyl ~hlor~ae ~n ~ r~ J. Ch~m. ~o~., 1480 ~1956) resulting ~n a v~ry poor y$ela of 6~, ~nd the reaction o~ or~ho-aminothisphenol wit~ chlro~cety~ ~hlor~e in Japane~e patent p~licatlor ~Kokal~ 77 156531. Another method i8 disclosed ~n ~aito e~ ynthe~s, 102 (1979) wherein orthoaminoph~nol or orthoaminothiopb~nol ~
reacted with l-chloro-2 arnlno-2-ethoxyeth~JIe. Th~s react~on proceeds with ~s~ti8f8c1:0ry yi~ld~. ~owever,, on ~ub~itu~$on of the b@rlz~n~ rlng with ~-bro~o, ~h~
de~ired 5-bromo 2-chloro~ethylbensoghiazol~ ~ not ~or~ned~, Simildrlyt de~red prodluct3 ~re not o~taiI~ed on r~al:tion ~th the pyridlne co~pow~ds of th~ or~ula ~.~ X~ 2 Il ~ or ll J

A
where~n X i~ sxyge~ or ~ulph~r.

--2-- !

Accsx~lnq ~o ~h~ pxe~nt ~oce~$, ~ l~cto~y y~ld~ may ~e obts~n~d ln fo~lng ~ub~tltu~ an~
un~ub~tl~utæ~ ph~nyl, pyrl~yl ~r pyrl~yl ~hloro~ethyl hete~ocycllsl3, ~ cor~ng to the ln~rentlon, a proc~s $~ prvvld~
for prep~ring a ~hlorom~chyl qroup ~u~st~ut~d hetero-cy~lic cQml?ou~ad of the fon~ul~
Y ~~ C~2el c~r ~ 2 ~ 11 1 ~X~

~I
wh~rein X ~ O or 8~ Y toget~er with the two ~arDon~ to 10 wh~ch Y ~ att~hed fOriS18 phenyl, pyr~yl or pyrim~dyl, each of whlch Day be ~ubstitut~a by R5 R i~ one of iodo or tri~luorom~tbylthio OF one or two o~ fluoro, chloro, bro~o~ C")alkylO (C~ ) allcoxy9 ~C~-Cd,)alkylthio, (Cl-C4)alkyl~ulflnyl~ (Cl-C~alkyl~ulfonyl or 15 trifllAoromethyl~ and Rl i8 hydroge~ or ~0 ~y r~acting a blfun~lonal cs~ d of the fos~3nula~
`~ ~ ~2 0~ N~-~2 Y I ~ ~.
~ X~ 1~ ~X
R

III - IV
w~th a 2-~:hlo~o-1,1,1-tri(Cl C6~allcoxye~ne.
~ h~ inve~tion ~nclufle~ ~ovel ~nte~nedi~te~ of the for~nula ~N~ Q~ ~ C ~2C
5-~2~1 11 1 R

y VI
w~r~in X 1~ 0 or S~ Y tog~her w~ th~ ~wo c~r~s~ to which Y i~ attache~ for~ phe~yl ~ub~t~tute~ by R~
pyrldyl c~r pyri~i~yl9 ~ach o wh~l:h ~y b~ ~ub~t~kuted s ~y R~ ~nd R i~ one of lo~o or trlfluoro~thylthio or one or two o~ 1uo~o, chloro, ~romo, (~ 1kyl, Cl' ~4)~ylgh~oo ~ c4)~
Cl-C4)~1)cylsul~onyl, or trifluoromethyl,, ~ h~ ~Dvent~sn ~urthex ~clude~ a pro~s f~r prepar~ng a 2chloro-l,l,l-trllC~C~3~1~oxyetha~e ~y reac~g ~ ~orr~pon~ng tr~(Cl-C63~1koxyeth~e with N-chloro~uccinlmlde or wlth chlorine ln pyridine 2nd a ehlorohydrocarbcn $olv~nt.
The nitroqen ~tom 1~ Y w~e~ Y ~on~ pyrldyl togethor with the two carbo~ to wh~ch Y ~ t~hed ~ay ~ pre~nt ~n any ~ on ~n the ring. Co~
~enien~ly, the n~tr~gen ~tom 1~ locatea next ~o ~h~ ~o ~unc~ion~l group~ ~n c~m ~ ~d ~ for~ulae A ~n~
~ abov~

The pro~e~ for pr~parlng ~he c~pQsnds o~
formul~ I and IS ~ ~onvenl~ntly casr~d ou~ ~n a ~ol~ent. Suitable ~olv~t~ ~r~ r~a~tio~ ~nert ~u~h ~ha~ t~ey do ~ot ~nt~rfe~ wit~ the re~ction. Ex~pls~
2S of ~u~t~le ~olv~nt~ ar~ iC~-C4) alcohols such as ~ethanol~ ~th~nol or prop~nol, ~alocarbon~ ~u~h ~8 ~9~37~3 ~loro~Qna or ~ 14~0 ~o~ld~, ~n~ ¢th~r~ olv~nt~
-s~c~ a~ ~lglyme. ~he ~ ally p~ef~rr~d solvent i~
~thanol .
~he ~eac~on cemp~at~re r~nges ro~ ~out ro5:~
S tempera ur~ to a~ut ~e ~e~1l2x t~p~r~tu~ of th~
80~ n~ use~. ~ r~ct~oJI ti~ m~y raAge f~o~ about 15 ~inu~ o ~bout 2 h~urs or ~or~.
The lnt~ dliate~ of foranul~ I ~hen Y ~ogether wlth th~ ~wo c~rb~ to ~ h lt ~8 a~tach~d for~s ~enyl are di~clo~ ~ p~i~r art ~uch a~ c~ted ~oYe. ~he inter~e~iate~ nf for~ when Rl i8 hydrogeri are ~sclo~d la ~iainger ~t ~1~,, Berichte, 96, 104~ ~1963).
The start~ ter~al~ of fonaul~ III are coT~!mer-1.~ cl~lly ~vall~bl~ ~r ~ay ~e sll~de 3by pr~or ~r~ mel:hods.
~e~hod~ for prep~rln~ compo~2ds 6II~) ~re de~crlbed in J~. Am. Che~. Soc. 53, 309 ~19313 and J~ Org. ~he~. 29, 26~2 tl9643. In ge~al, the~e ~ethod~ ~ay be dep~cted ~s ~ollow~:
N2 ~ 2 2 ¦ Y III~
~ ~1 ~ `S--S ~
2~ re~n Y i~ ~ tlef~ed abov~ ~an~ ~al i~ fluoro or r~alo~o.
~referred ~ ct~T~l comE3ourlds ~ have tha ~o~ul~

~2~_ 11 where~ 2 i~ hyd~oge~O o~ sne ~r two of chloro, bro~o or ~riflll~ro~thylg sna X ~ ~xygen or ~ulfua:. P~r-- ti~ularly pr~ferr~h ~if~tlon~l compound~ are 2-~ino-4 ~roffloth~op~1 ~d 2-~ino-~-trifluoro~2$hyl-.

thlopheno~. Oth~r pr~gerrea blfw~$tlon~1 ~ompound~ ~re 2~thlol~3~ nopyr~d~ne ~n~ 2~ o-3~hy~roxypyrl~in~.
The~e pr~~xred an~ part~cul~rly p2e~r~s~ l~lfu~ctlonal ~anpoun~ lo~l to p~ferre~ ~n~ par1:1~ularly p~Qforre~, 5 resp~c~ v~ly, ~nterme~l~t~s ~I~. Thu~, pr~rred intsr~ t~ S~) ~a~e the fo~ul~

R2 ~ ~r C~2Cl whex~in R2 ~ hydrogen~ .ox on¢ or two of ~hloro, bro~no, or tr~fluoro~ethyl9 an~ X i~ oxy~n or sulfur. ~r ti~ularly preferr~d ~re ~-chloromethy~-5-1broDIobenzo-10 ~hiazole ~nâ 2-~hloro~ethyl 5-tr~1u~ro~ethylbenzo-th~a~ol~g Al~o preferrea ~re 2 t:hlos:o~thyloxa2010-1 4, Sob] pyr~ dine ~nd 2-~hloro~ethylthl~zslo- ~5 s 4 pyrid~ne .
~he pr~ferred and p~rt~eula~ preferr~ co~pounds (I) lea~ to preferxed and ~artl~ularly preferred phar~aceutic~l compounds descri~ed ln copendlng Canadian appli-cat~s-l Seri~ o.520,609 ~ca~e P.C~ 7006) ~led on October 16, 1986 by the ~ a~ignee ~ th¢ lpres~
~pplication. ~h~ pharmac~utl~al co~ ay be 20 ~a~e ~n gener~l by re~ctinq G~poun~s II) or ~II3 wi~
diaz~ne~ ~f the for~ula VII a~ ~ollow~:

. ~

C~ CO Rs ' CH CO R ' ~ ~2 2 ~ ~2 2 P~3 R3 ~:~2 Y~I YIII ~I ' wh~re~n ~ ' ana ~I ' ar~ th~ re~idues o co~poundn (I~
a~nd ~II) rema~ni~sg after re~t~e~n w~th co~poun~ (V~
~rh~ hy~r~z~ne~ of for~ula IV ~ay be ~ade by prior ~rt ~etho~ ~uch ~ d~s~6rtbed in ~e~lsen et ~1., Act~
S Che~ Scana. 15, 1û97 tl961) form~ng ~h~ohydrazi~e~ by :re~cti~g c~r~Ksxym~thyl dithioat~s ~nd hydraz~ne.
The pro~es~ for pr~par~ng ~ 2 chloroDl ~ tri-~Cl-C6)alkoxyetha~e proeeed~ by r~acting a~ corre-spor~ding tr~ (C~L-Cc~alkoxyethane with N-chloro~uc~in imld~, or with chlori~le ~n pyridin~ and a chlorohy~ro-~arbon ~olYent. ~rhe react~on Wit31 ~-EhlorosucciTIimide i~ gen~rally carrie~l out in ~ solYer~t~ 5uita~1e 80vlent8 are non-polar, arld re~ct~on-~Lnert ~ueh th~t tlsey do not int~r~E~re w~th the r~action. ~xa~apl~ of ~uitable ~olvents ~r~ haloc~r~ s ~uch as ~hloroorffl, ~ethyl~ne chlor~d~g c~rbont~t~ lor~de o~ t~ a-~ohloroethylene,. The r~act~o~a ~8 co~ve~ntly carr~ed out at about ~O~C to abc>~ the . reflux emp~ratur~ of ol~en'c~ T~e r~ct~or~ witl~ ehlorlna i~ py~di~e 2~ D~U~t be ~n th~ pre~nce o ~ chloxohydr~ar~on ~olov~n*
h~ving onç ~r more chloro atoms ~n~ one tc~ ~ix e~arbon al;om~, ~,.g. methylene chloride, chloroform, or gr~
chlo~oetha~e .
The ~nterrnediate~ nd (II~ dle~ribed a~ove ar~
of use in t1ne ~anufa~tur~ o colDpound~ haYing ~X~

phar~aceutical activity. Exampl~ of such active compounds are tho.Qe of above formula VIII.
The followlng examples illustrate the invention.
Examle 1 A mixtur~ 9f l,l,l-triethoxyethane ~97.3 g) and N-chloro-~uccinimide (88.1 g) in carbon tetrachloride ~600 ml) was warmed to 400C and then ~rradiated with an ultraviolet lamp. The reaction became exothermic and then subsided upon completion of the reaction. The precipitated succinimide byproduot wa~ filt~red off and the filtrate was concentrated to remove carbon tetrachloride. The residual liquid was distilled tG
obtain pure 2-chloro-1,1,1-trlethoxyethane (91.0 g;
b.p. 91C/25 mm).
ExamPle 2 A solution of 2-chloro-1,1,1-triethoxyethan~ (5.9 g) and 2-aminothiophenol (2.5 g) was heated at 800C for 15 minutes. ~fter cooling to room temp~rature, it was dissolved in methyleneohloride (30 ml) and the re5ultlng solution was washed with 3N HCl ~10 ml) and then with water (20 ml). The organic portion was evaporated and the residue chromato~raphed over silica gel to obtain 2-chloromethylbenzothiazole (3.35 g; 90 yield), m.p. 340C.
Exam~lg 3 2-ChloromethYl-5-bromobenzothiazole A mlxture of crude 2-amlno-4-bromothiophenol tin hydrochloride complex (71.~ g) prepared aceording to JACS 53, 209 (1931), 2-chloro-1,1,1-triethoxyethane 30 15B . 7 g) and ethanol (400 ml) was h~ated to gentle reflux ~or 30 mlnuteQ to ~btain a solution. To the warm solution wa~ added 3N HCl (10 ml) and the precipitated solid ~a colleoted, washed with water and then dried to obtain the title compound (35.5 g), m.p.
107C.

~X9(~7~8 ExamPle 4 2-Amino-4-tri~luoromethylthioPhenol. h~drochloride A. The commercially availabl~ 4-chloro-3-~itro-benzotrifluoride llO0 g) was dissolved in ethanol l400 ml). To this wa~ added portion wi3e a solution prepared ~y first adding ~odlum 8ul flde hydrate (80 g) to hot ethanol 5200 ml) and then ~ulfur t9.6 g). After the initial exothermic reaction had sub-sided, the reaction mixture wa~ re~luxed or an additional 30 minute~ and then cooled to roo~ temperature. The precipitated yellow solid was csllected, washed with cold ethanol and then dried to yield 4,4'-ditrifluoromethyl-2,2'-dinitrodiphenyldisulfide t63.0 g; m.p. 152-1540C). A mixture of this compound (6~ g), t~n metal (20 ~esh, 13Z.0 gl, ethanol 1500 ml) and concentrated HCl 1200 ml) wa~ gently refluxed at 800C
till a near ~olution was obtained. Then the reaction wa~ maintained at 700C for 30 minutes. The warm solution wa~ filtered and the filtrate concentrated under low pressure to a viscou~ l~quid. To this was ad~ed 6N HCl and the precipitat~d white solld was filtered to obtain the title compound (49.0 g; m.p.
208-2090C.).
2-ChloromethYl-5-trifluoromethylbenzQthiazole B. To a solution of 2-amino-4-trifluoromethyl-thiophenol hydrochloride (30.0 g) in ethanol l125 ml~
was added 2-chloro-1,1,1-triethoxyethane l31.0 g). The mixture was heated for 1 hour at 60~C. The solution was concentr ted to remove exce~s ethanol and the 3~ re~ulting material was extracted with ether 1500 ml ) .
The orga~ic extract wa~ washed successively with 10%
HCl t20 ml), water ~100 ml), 10% sodium bicarbonate solution and water llO0 ml~, and then Pvaporated to obta~n an amber colored oil, which cry~talli~ed upon 35 standing at room temperatur2 t28.9 g; m.p. 520C~.

7~3 ExamPle S
2-Chloromethvl-oxazolol4.5-b)~Yridine The commercially available 2-amino-3-hydroxy-pyridine (5.0 g) and diglyme 130 ml) were heated at 1250C to obtain a solution. To this solution was ~dded 2-chloro-1,1,1-trl~thoxyethane l9.9 g) and the mixture was held at 125 for 1 hour. The solution wa~ cooled to room temperature and then decanted to remove a black byproduct re~idue. The filtrate was dlluted with water (SO ml) and the re6ulting yellaw precipitate was collected ~1.5 ~). A ~mall sample was crystallized from l.~opropanol ~m.p. 115-118C) Exam~.le 6 2-ChloromethYl-5~7-dlchlorobenzoxazole To a solution of 2,4-diohloro-6-nitrophenol llO.O g) in water (450 ml) containing ~od~um bicarbonate ~4.8 g) was added sodium dithionate in a quantity sufficient to turn the original dar~ solution colorless. The hot reaction mixtur~ wa~ filter~d and the filtrate was cooled to room temp~rature and the crystallized product, 2-amino-4,6-dichlorophenol was coll~cted 11.6 g). Th~ 2-amino-4,6-dlchlorophenol (1.6 g) was dissolved in ethanol l5 ml) and 2-chloro-1,1,1-triethoxy~thane (1.9 g) wa~ added. The resulting solution wa~ warmed on ~ stea~bath for 1.5 hour, A~ter coolin~ to room temperature, cold water ~5 ml) was added. The precipitated solid wa~ coll~cted and then air dried to obtain the tltle compound ~1.12 g; m.p.
52-530C).
Example 7 2-Chloro~thYlthiazolo~5,4-bLpyridine A mixture of 3-amino-2-mercaptopyridine ~3.6 g~
prepared by the method o~ J. Org. Chem., 29, 2652 ~907~;8 (1963~, 2-chloro-1,1,1-triethoxyethane ~&.5 gJ and ethanol l60 ml) was heated at 600C for 4 hours. The crude solid resulting from evaporation of ethanol was chromatographed over silica gel to obtain the produot 12.94 g; m.p. 71-73~C).
Exam~le 8 2-Chlorometh~1~-5-bromobenzoxazole 2-Amino-4-bromophenol (1.6 g) prepared ~ccording to U.S. Patent 4,157,444 was di~olved in ethanol l5 ml) and 2-chloro-1,1,1-trlethoxyethane (1.9 g) was added.
The resulting solution was warmed on a ~teambath for 1.5 hour. After cooling the reaction mixture to room temperature, cold water (5 ml~ was added. The precipitated solid was collected and air-dried to ob~ain ~he product l1.12 g; m.p. 63-650C).
Exam~le 9 By a method similar to that of Example 2, 2-chloromethyl-5-chlorobenzoxazole, m.p. 53-560C., was prepared from co~mercially available 2-amino-4-chlorophenol using ethanol or chloroform as the solventinstead of ~ethylene chloride. Similarly, 2-chloro-methyl-5-methylthiobenzothiazole, m.p. 65-660C and 2-chloromethyl-5-fluorobenzothiazole, m.p. 73~C, were prepared from 2-amino-4-m2thylth~ophenol hydrochloride and 2-amino-4-fluoro-thiophenol hydrochloride, re~peotively, in ethanol solvent.
Example 10 5-Chloromethyl-2-~h~nYl-1,3~4-oxadiazole A mixture of 2-chloro-1,1,1-triethoxyethane 14.8 g), benzoyl hydrazlne (3.0 g) and ethanol (30 ~1) was ~9076~3 refluxed for 2 hours and the solution wa3 allowed to cool to room temperature. To the precipitated ~hite cry~talline 301 id was added water (10 ml) sontaining a ~ew drop~ of 10% HCl. The mixture was stirred for 10 ~inute~, and then ~iltered and the solid collected.
The mother llquor was evaporated to dryne~s, the residue triturated with wat~r and ~iltered to obtain a ~econd crop of white solid. The combined yield of the two crops amou~ted to 3.8 g l89%; 'HNMR identical to the product de~cribed ~n Che~. Ber. 96, 1049 (1969).

Claims

1. A process for preparing a 2-chloro-1,1,1-tri(C1-C6)alkoxyethane by reacting a corresponding tri(C1-C6)alkoxylethane with N-chlorosuccinimide or with chlorine in pyridine and a chlorohydrocarbon solvent.