CA2092357A1 - Process for the synthesis of 5-[(substituted)-amino]-8- [phenyl or substituted-phenyl]-3h, 6h-1, 4, 5a, 8a-tetraazaacenaphthylen-3-ones - Google Patents

Abstract

31,808-00 AN IMPROVED PROCESS FOR THE SYNTHESIS OF
5-[(SUBSTITUTED)AMINO]-8-[PHENYL OR
SUBSTITUTED-PHENYL]-3H,6H-1,4,5a,8a-ABSTRACT

A novel process for producing 5-[(substituted)amino]-8-[phenyl or substituted-phenyl]-3H,6H-1,4,5a,8a-tetraazaace-napthylen-3-ones of the formula:

Where R1, R2 and R3 are defined in the specification by reacting a 4,5-dihydro-7-[phenyl or substituted phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxaminde with carbon disulfide and a suitable base and a lower alkyl iodide to give a 5-(lower alkylthio)-8-[phenyl or substituted phenyl]-3H,6H-1,4,5a,8a-tetraazaacenphth-ylen-3-one which is further reacted with an amine of the formula:

Description

, 3l,808-00 AN I~PROVED_PROCESS FOR THE ~YN~ESIS OF
5~ UBSTITUTEDlANINO]-8-~PHENYL OR
SUB8TI~UTBD-PHENYL~-3H,6H-l,4,5a,8~-TETRA~ZA~CENAP~HYLEN-3-ONES

BACRGRO~ND OF TH~_INVENTION

1. FI~D OF THE INVENTION
The i~vention relate~ to a process for th~
synthe~is of 5 [~ubstituted)ami~o]-8-tphenyl or sub~
stituted-phenyl~-3H~6~ 4,5a~8a tetraazaacenaphth-ylen-3-one~ a~d to the ~ovel ~ wer al~yl-thio~-8-[phenyl or ~ub~titutea-phe~yl]-3H,6H,l,4,5a~8a-tetra-azaaaenaphthylen-3-o~e~ useful ~ i~termediate~ in the prooe3~.

2 7 DESC~IPTION OF ~H~ R~LATED ART
ThP S ~ubstitut~doamino)-8-(phe~yl or ~Ub-~titute~-phenyl~-3~,6~ ,5a,8a-tetraazaace~
~aphthylen3-one~ as di~olos~d in ~.~. Pate~t ~o~
4,916~137 po~se~s the ability to enhanoa neural fu~ct.ion in wax~-bloo~ed animal~ af~ected by behavioral neurological problems, including the coynitive de-terioration assoaiated ~ith decreased ~eural functio~ ~
which occur~ ~ith cerebral i~3ufficiency, agi~g, d~mentia, and ~imilar co~dition~. In additio~ syn-thetic procedures to prepare the 5-(sub~tituted-amino)-~- (phenyl or ~ub tituted-phenyl)-3~ r6~ r5 a-8a tetraazaacenaphthyleh-3-o~es ara also disclosed. A
~erie~ of reaction~ in whlah a 4,5-dihydro-7tphenyl or -2~

~ubstitute~ phenyl]-pyrazolo-~1,5-a]pyrimidine-3-carboxamide is reacted with 1,1~ -thio~arbonyl-diimidazole in the pre~ence of ~odium h~dride to pre-pare 4,5-dihydro-5-thioxo 8-tphe~yl or ~ub~tituted phenyl]3E,6H-1,4,5a,8a-t2traazaacenaphthylen-3~ones which are su~equently reacted with an amine i~ the presence of aqueous ~odium hydro~iae an~ hy~rogen pero~ide to give the 5-~substituted-~mino)-8-~phenyl or sub~tituted-phenyl3 3~,6H-1,4,5af8a-tetraazaace-naphthylen-3-one3 i~ di~closed~
It has b~en found that the S-(substituted-amino~ (phenyl or -~ub~titute~-phenyl)-3H,6H-1,4,~a, 8a tetraazaacenaphthylen-3-ones can be advantageously synthe~ized by reaction of 4,5-dihydro-7-rphe~yl or substituted-phenyl]pyrazolo[l~5-a]pyrimidine-3-~arboxa mide with carbo~ di~ul~ide i~ the pre~ence of a lower alkyl io~ide and suitable ba~e to give the 5-(lower alkylthio)-8-~phenyl or substituted-phenyl]-3H,6~ 1,-4,5a,8a tetxaazaacenaphthylen-3-ones ~hich re subseguently reacte~ with an ami~e to affora the S-[(substituted)amino~-8 [phenyl or ~ubstitute~-phenyl~ 3~,6H-1,4,5a,8a tetraazaace~aph$hyle~-3-cne~.
S~MMARY_OF THE INV~NTION
The i~vention provides a~ improved process for the preparation of 5-t(sub~tituted)amino]-8-tphenyl or substituted~phenyl~-3~,6~-1,4,5a,8a-tetraazaace-~aphthylen-3-ones which ca~ be represente~ by the following stru~tural formula:

\ 7J~N~

R2 ~,//~\
~R 3 ~ ` ? ~

~3-wherein R1 ~nd R~ are each indlvidually ~elected from the group con~l~ting of hy~rogen, br~nchea or un-branched al~yl(C1-C~ or benzyl, R3 i~ hyarogen, haloge~, alkyl3C1-C3), alkoxygCl C33 or S trifluoromethyl. For the purpo~e~ of thi~ i~vention, haloge~ may be fluorine, ¢hlori~e, ~romine or iodine.
The improved proce~ oompri~e~ reacting a 4,~-dihydro-7-Lphenyl or ~ubstituted phenyl~-pyrazolQtl,5 a]pyrimidine-3-c~rbo~amide havi~g the formula:

o H N N
~ R3 ~herei~ R3 i~ ~ defined above with c~rbon di~ulfi~e and a compound of the formula R4I~ ~herein R4 i~
defin~ a~ lower alkyl(C1-C3), to give a xanthate of the formula.

~

S~ N/~ N/

R4S ~ R3 ~

~hich oan be i~ol~ta~ or ~urther reacte~ in ~itu to a~ford a 5 (lower alkylthio~-8-[phenyl or ubstituted phe~yl]-3~,6~ ,5a,8a-tetraazaacenaphthyle~-3-o~s having th?~? formul~, Il ~ N
/r"N N
R4S ~

~ R3 wherein R3 i~ a~ defi~ed above, whiah i subsequently reac~ed wi~h an amine having the formulao R ~\ :
N H

wherein R1 and ~2 are defined abo~e an~ recovering the 5~ ub~titute~)~mino]-8-tphenyl o.r ~ubstituted-phenyl]-3H,6H,1,4,5a,8a-tetraazaa¢en phthylen-3-one so produced.

c.d ~ ~ 7 DESCRIPTION OF THE PllEFBP~RED l~MBODIM~Nr8 The proc:e~ zmd CO~pOUI!~ of the pre~e~t i:nve~tion ;llre de~cribed i~ t~e fs~llowi~g reactio ~cheme -S~x ~N
5~ ~?5 5~l ~ 11,5 ~_ R ~ :

2 0 ~R~

H--N'R 1 o ~ R 2 J~ "~
\NI N N
R 2 ~ i~k~

~ R 3 ' ' ` :

.

~ J~ ~ 3 In accoxaance wi~h th~ above reaction ~cheme,4,5-dihydro-7-~phenyl or sub~ti~uted-phenyl]pyrazolo-1,5-a]pyrimidine 3-carboxamide 1 where R3 i~ a~
de~cribed above, is reacted with carbon di~ulfide in the prese~ae of a ~uitable ba~e and R4I, where R4 i~ as de~cribed above to afford the xanthate 2. Thi~
reaction i~ pre~erably conducted at temperature~ from about -7C to about 6C for up to on~ hour. ho~ger reaction time~ of up to 18 houxs, ~ith the addition of lo exce~ ba~e, dilution ~rith ice and water and collection of the ~olid on a funnel gi~es the ~ully closed 5-~lower alkylthio~o8-[phenyl or sub tituted-phenyl3-3~,6X-1,4,5a,8a-tetraazaa~e~aphthyle~-3-one 3.
8uitahle ba~e3 in~lude qodium hy~ride, sodiu~ methoxide and pota~qiu~ t-butoxi~e b~. othex base~ ~ known i~
the art may be sub~tituted.
The 5-(lower alkylthio)-~-[phenyl or ~ub-~tituted-phenyl]-3~,6H-1,4,5a,8a-t:etraa~aacenaphthylen-3-one 3 i9 reacte~ with ~mine 4, ~here R1 and R2 are a~
de~cribed above, to yield the final compou~d~ 5. ~he reaction of 3 wit~ 4 i~ preferably conducted i~ a weak acid ~uch a~ acetic acid at about 80C to about 100C
for about ~8 hours. The solution i8 cooled to room tempera ure, diluted with ethanol, cooled to oC an~
the 5-~(substituted)amino]-8-[phe~yl or substi~uted-phenyl~-3~,6~,1,4,5a,8a-tetra~za-a4en~p~thylen-3-one 5 oollectea by filtration an~ ~rie~.
~ he above proce~ is an i~proveme~t over the procedures ~escribed i~ Patent No. ~,916,~37. ~
described herein above, the yields of each of the Yteps are higher and the wor~up o the reaotions are less labor and time inten~ive.
The $ollowing non-limiting example~ illus-trate the proaess o~ the pre~e~t inve~tion a3 well aq the prepaxation of the ~ovel ~o~pou~s.

2 0 q~ ~ r ~ ~; 7 Example 1 5-~Methylthio2~ (trifluoromethyl3phenyl~-3H,6H~ 5a,8a ~etraazaacenaphthylen-3-one A ~olution of 16~ g of 4,5-dihydro-7-~3-~trifluoromethylJphenyl]pyrazolo[1~5a~-pyrimidine~
3-carboxamide in lo 6~ L of warm tetrahydrofuran i~
dried wi h 40.3 g of anhydrous sodium ~ulfate, ~tirred for 3 hour~ and allowed to stand at room temperature for 1~ hours. ~he mixture i9 filtered a~d the ~ake lU wa~ed with 200 ml of tetr hydrofura~. ~he tetra-hydrofuran solution i~ cooled to ~3C under inert ga~.
While stirring, 28.~ g of ~odium methoxide i~ a~aed in ~mall portions over a 10 mi~llte period. ~he tem-perature i~ kept from -3C to g.5C. ~ ~olution of 45 ml o~ carbon di~ulfide in 45 ml of tetrahy~rofura~ i~
added dropwise while keeping th~ temperature ~rom -7C
to -4.5C. The temperatur~ rought to -1C and stirring ~o~tinue~ for 35 minute3. A ~olution of 96 ml of methyl io~ide in 96 ml o tetrahydrofuran i~ ~de~
dropwi~e over 20 minutes while m~intaining the tem-perature from -1C to ~4C. Follo~ing a~ a~itional 1 hour of stirring, 56.7 g of sodium metho~i~e i~ a~ded portionwise over 20 minute~ under inert ga~ ~hile keep-i~g the temperature from 8 C to 6 C. Follow~ng e~
portionwi~e a~dition the temperatuxe ro~e to 6C. The rea~tio~ mi~ture i~ ~tirrea at room temperature for 18 hour~. The reaotio~ ~i~ture i~ dilutea with 3.0 L o~
water and ~00 g o~ i¢e. ~e ~ol ~ is aolleatea o~ a filter an~ the ~aka ~a~he~ with 3 ~ 500 ml o~ ~t~r the~ ~ried to give ~60.5 g o the ~esire~ product. The collected solid i~ ~tirred with a ~olution o~ 700 ~1 of ~-hepta~e and 1~00 ml o~ ethyl acetate for 1 hour then collected by filtration. The cake is washe~ with 3 160 ml of ~2:1) ethyl acetate:~-heptane and drie~ to afford 105 g (5~.8%) of the ~e~ir2d pr~uat.

Example 2 ~-(MethYl~hio~-8~3-(~rifluoromethyl)phenyl~-3H,6~-1,4~a,~a-tetraa~aacena~hthylen-3-one A ~olution of 1~55 g of ~,5-~ihydro-7-t3-s ~trifluoromethyl)-phenyl]pyrazolo~1,5a~pyrimi~i~e-3-carbo~amide i~ 9L of tetrahydro~ura~ is stirred ~ith 263.~ g of ~oaium sulfate of 0.5 hours ana allo~ea to ~tand at room temperature overnight. ~he reactio~ mi~-ture i8 Pil~ered and the cakQ washea with tetr -~o hydrofuran (3 ~ 250 ml~. ~ho filtrate is coole~ to-3.5C and ~36~5 g of ~ 60% dispersio~ of sodium hydriae i~ mineral oil added oYer a 30 minute period ~hile mai~taini~g the temperature from -3.5C to 4C.
The solution is ~tirred ~bout 20 ~i~ute at 0C to ~4~C
and ~ ~olutio~ o~ 272.2 g o~ c~rbo~ di~ulfiae i~ 215 ml of tetrahy~rofur~ ~dded dxopwi~e over a 22 ~i~ute period while a~ orange 301;~ prea:ipitate~. The reaction mixture is ~tirred for 20 minutes 2t 2C to -3.5C followed by the a~ition o~ ~ ~o~ution o~ 1453 g of methyl iodiae in 637 ml o t~t.rahy~rofura~ ~ropwi~e over 40 mi~Ute3 while maintai~ing the temper~ture from -3.5C to 1C. ~he xe~ctio~ mi~ture i8 ~tirre~ 1.5 hour~ at -5C to -~C, while mai~tai~ing the te~-perature belo~ 2~C, 237 g of ~Oai~ hyari~e i~ addea portio~wise o~er 2.75 hours. The reaatio~ ~iæture i~
~tirre~ overnight whi~e warmi~g to room te~p~rature.
The rea~tio~ mixtur~ i~ dilute~ with 250 ml o~ ethanol, 16L of water, 3082 kg of i¢e ~ tirre~ ~or 1 hour.
~he re~ulti~g ~oli~ olle~tea b~-filtr~tiv~ a~ the~
~lurrie~ ~ith 9~ o~ ethyl acetate ~a 4.5~ o~ heptane for 1 hour. ~h~ oli~ i8 aollecte~ by filtration and washed with a 2-1 ethyl Aset~te-hepta~e ~3 ~ lL) ~olution, ~ried at 23mm~g at ~0C to afford 648 g (75%~
of the ~e~ire~ product.

E~ample 3 5-~Meth~lthio)~8-~3~trifluoromet~yl3~henyl1-3~,6~ ,5a,8~-tetraa~aacenaphthylen-3~one ~ ~olution of 3.~8 kg of 4,5-aihydro~7~
[3-(trifluoromethyl) phenyl]pyrazolo~l,5-a]pyrimidine--3 carboxamide in 30L oP tetrahydroftlran i~ cooled to 2~8C und~r nitrogen a~ ~tirred ~ile 1370 g of pota~ium tert butoxide is added portio~wi~e over 2S
minute~ ~hile mai~t~ini~g a temperature le8g than 4VC.
~he reaation mixture i~ ~tirred at -6.2C for ~5 ~i~ute~. ~o the reaation mixture is ~dded 850 g o carho~ di~ulfi~e through a ~ropping funnel over a 10 minute period ~hile maintaini~g the temperature below 2C. The :Eunnel i~ rin~ed ~ith 500 ml of tetra-~ydrofuran and the reaction ~ixture ~llowed to ~tir for4S minuteR~ ~hile maintaining the temperature from -0.8C to 3.2C, 1870 g of methyl io~ide i~ ndded dropwise through a dropping funnel. ~he fu~el i3 ri~se~ ~ith 500 ml of tetrahydrofura~ a~ the reactio~
mi~ture allowea to stir for 1 hour. An aa~itional 380 g of methyl iodi~e is addea. The reaation ~i~turQ i~
~tirre~ for 50 minute~ while ¢ooli~g to -23.1C. A~
additional 2530 g of pota~ium t~rt-buto~i~e i~ a~e~
over 2 hour~ while ~aintai~ing a temperature of -23.1~C
ZS to -10.0C. After hal~ of the pota~ium tert-buto~ide i~ ad~e~ another 300 ml o~ ~ethyl iOai~e i~ ad~ed. The rem~i~ing pot~ium tert-butoxi~e is a~de~ and the reac~ion mi~ture 3tirred ~hile ~a~i~g to roo~
temperature ov~r~ight. The re~ctio~ mi~tur~ iluted with 3 kg of ice an~ lOL of ~atex the~ ~aaed to ~OL of ~ater ~i h ~tirri~g. ~he re~Gtion fla~ iR rin~e~
with 26L of ~ater ~hich i~ aa~ed to the ice ~nd w4ter co~t~ini~g the original re2ction mi~ture~ 8tirring i~
oontinue~ ~or 40 minute~ an~ the ~oli~ oolle~te~ by ~iltration. Ths filter cake i~ ~q~e~ with 20L of water ~n~ arie~ ~t 30 mm ~gr 35C tc afford 3.4 ~g ~90%) of the de~ired pro~uct.

_~o_ ~ t,i~

~xa~ple 4 3-tAminvearbo~yl)-? r3-1tri~luor~meth~1)-phenyl]pyraæolo~l,5-~1pyrimidine-4t5~-~arbodithioic a~id methyl e~ter A s~lutio~ of 3O0 g of ~,5-dihydro-7-[3-~trifluoromethyl)phenyl]pyrazolo-[1,5a]pyrimidine-3-carboxamide in 30 ~1 of tetrahydrofuran i8 cooled to o9c. While ~tirring, 0.40 g of a 60% disper~io~ of sodium hydride is added and stirring continued at OC
for 30 minute~. While maintai~ing the temperature at OC, 1.11 g of carbon di~ulfide i~ ad~ed dropwi ~ at a rat~ tG maintain t~e temper~ture. Following 30 minutes of ~tirring the temperatur2 i~ lowered o -7C and 2.07 g o~ methyl iodide i~ a~ded at ~ rate to maintain the temperature at 7C to -4C, The reactio~ mi~ture i3 allowed to warm to room tempexatur~ ana ~tir overnight. While stirring, 66 g of ice w~ er is added with aontinued stirri~g over 20 minutes. The ~oli~ i~
collectedr wa~hed ~ith ~ater (3 ~ 25 ml), hexane (3 x 25 ml) and air drie~ to provide 3.5 g (90%) of the desired product.
ExamPl~ 5 5-~tPhenYlmeth~l~amino~;8- r 3~ rifluoromethyl~
phenyll-3~H-l~q,5a,8a-tetr~zaa~enaphthylen 3-one Ts a su~pe~ion of 5.0 g of 5-(methylthio)-8-~3-(trifluoromethyl)phenyl]-3~,6~-1,4~5a,8a-tetraz~-ace~aphthyle~ 3-o~e in ~5 ml of acetic ~ci~ i~ a~ed 4.~8 g of be~zylamine. ~he reactio~ mi~ture i~ heated on a teambath for 18 hour~. ~he ~olutio~ i8 cooled to room temperature and 17 ~1 of ethanol i~ ad~ed ~ollowed by ~ooling to 10C. ~ additional 35 ml o~ ethanol and 20 g of ice are a~ad a~d the re~ulting ~lurry stirred for 30 minute~ at 0C. The proauct i9 collecte~ by filtration, wa~hed ~ith ethanol ~2 x 20 ml) and ~ried at 40C/30~m ~g t~ gi~e 3.6 g ~62.1%) of the desired product.

~ ,2..3 Exam~le 6 5~[l1-Methylethyl)aminol 8 r3-~trifluoromethyl~
phe~yl]-3H,6~-1 4,5a,8a~tetraazaace~aPhthYle~-3-one To a ~u3pen~ion of 5. 0 g of 5- ~methylthio)-~ t~~ltrifluoromethyl3phenyl]-3~6~ 4i5a~8a tetraaza- :
acen p~thylen-3~one in 35 ml of acetic acid i~ added 2O64 g of i~oproyylamineO The reaction mi~ture is heated on a ~teambath ~or 18 hour~. The re3ulting solution i~ cooled to room ~e~perature and ~7 ~1 of ethanol added. The mi~ture i~ coolea to 10C and 35 ml of ethanol and 20 g of ice ~dded. The mixture i~
stirred for ~n a~ditional 30 minute~ at 109C. ~he product i~ collected by ~iltration, ~a~h~a with ethanol (2 ~ 20 ml) ~nd ~ir-dried to give 3.2 g (62.3%1 of the desired product.
ExamplQ 7 5-~2-~ethyl~roP~)amino]-n- r3-(trifluorometh~l~he~yl~3~,6~-1,~,5a,8a~tetraa~aacena~hthylen-3-one To 11.1 L of aaetic aci~ e~ 2.23 ~ o~
isobutylamine dropwi~e, under nitrogen over 0.75 hour at a ra~ such that the temperature ~oes not go above 45C. The temperatUre i eontrolled ~ith external cooli~g. Followi~g complete a~itio~, 2.78 kg of 5-2~ (methyl~io3-~-[3-~trifluorom~hyl)phenyl]-3E,6~-1,4-5a,8a-tetraaza~ce~aphthyle~-3-o~e i~ a~ed. ~he re-actio~ mi~ture i~ heated at 95C for 18 hours, The reactio~ mixture i~ cooled to ~5C ana tran~erre~ to a larger ves~el ~ith a~ ad~itio~al gl~ci~l a¢~tic acid ~a~h (2 ~ 500 ml). While 3tirri~g, 22.2 L of eth nol ~nd ~1.1 kg of crushed ice is adaed. ~tirri~g i~ con-tinued for 1 hourO the ~olid ~ollected and w~hed with (3 ~ 2L) o~ 2:1 etha~ol water to afford 2.82 kg (90.7%) of th~ ~e~ired pro~uct ~ riea solid.

Claims (6)

1. A process for producing a tetraazaacena-phthylen-3-one compound of the Formula I:

(I) wherein R1 and R2 are each individually selected from the group consisting of hydrogen, branched and unbranched alkyl(C1-C4) and benzyl and R3 is selected from the group consisting of hydrogen, halogen, alkyl(C1-C3), alkoxy(C1-C3) and trifluoromethyl; which comprises (a) reacting a 4,5-dihydro-7-[phenyl or substituted-phenyl]pyrazolo[1,5a]pyrimidine-3-carboxa=
mide having the Formula II:

(II) with carbon disulfide and a lower alkyl (C1-C3) iodide and recovering the 5-(lower alkyl thio)-8-[phenyl or substituted-phenyl]-3H,6H-1,4,5a, 8a-tetraazaacenaphth-ylen-3-one having the Formula III:

(III) wherein R4 is lower alkyl (C1-C3), and (b) reacting the compound of Formula III with an amine having the formula:

and recovering the tetraazaacenaphthylen-3-one compound of Formula (I).

2. A compound of the formula:

wherein R3 is selected from the group consisting of hydrogen, halogen, alkyl(C1-C3),alkoxy(C1-C3) or trifluoromethyl and R4 is lower alkyl(C1-C3).

3. A compound of the formula:

wherein R3 is selected from the group consisting of hydrogen, halogen, alkyl(C1-C3), alkoxy(C1-C3) or trifluoromethyl and R4 is lower alkyl (C1-C3).

4. A process according the claim 1 in which the reaction of step (a) is carried out in a suitable base selected from the group consisting of sodium hydride, sodium methoxide and potassium t-butoxide.

5. The compoun according to claim 2, 5-(methylthio)-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,-5a,8a-tetraazaacenaphthylen-3-one.

6. The compound according to claim 3, 3-(aminocarbonyl)-7-[3-(trifluoromethyl)phenyl]pyrazolo-[1,5-a]pyrimidine-4(5H)-carbodithionic acid methyl ester.