Note: Descriptions are shown in the official language in which they were submitted.
7~ ~
The present invention relates to benzylpyrimidine
derivatives. More particularly, the invention is concerned
with benzylpyrimidine derivatives, a process for the manufact-
ure thereof and antibacterial compositions containing same.
~he benzylpyrimidine derivati~es provided by the present
invention are compounds of the general formula
~1 An
Z ~ C H2 ~ \ ~ NH2 (I)
R H2N
, wherein Rl and R2 each independently represent
a Cl 3 alkyl, Cl_3 alkoxy, C2_3 alkenyl or
C2 3 alkenyloxy group9 Z repreæents a nitro,
amino, pgrrolo, p~rrolidino, piperidino,
-NHR4 -NtR4) -N~R5 -N(R4)(R5), -NR4CooR 9
-NHCooR4, -~HCoNHR3, -NHCSNHR3, -N3, -N=N-N(R4)2,
~N(No)R4 or ~R3-NH2 group, R4 represents a
lS 1 3 Y r C2_3 alkenyl group, R5 repre t
an acyl group, R3 represents a hydrogen atom or
a Cl 3 alkyl or C2 3 alkenyl group, A represents
an oxygen atom bonded to one of the cyc~ nitrogen
atoms and n stands for zero or 1,
and salts thereof~
~he terms "Cl 3" and "C2 3'~ used in thi9 description
Grn/31.7.1974 - 2 - ~
L7~
and in the claims appended hereto denote that the groups
prefixed therewith contain 1 3 or 2-3 carbon atoms. The alkyl,
- alkoxy, alkenyl and alkenylox~ groups can be straight-chain
or branched chain~ Examples of such groups are methyl, ethyl,
propyl and isopropyl, methoxy, ethoxy, propoxy and isopropoxy,
vinyl and allyl and vinyloxy and allyloxy. ~he acyl groups can
be derived from aliphatic, araliphatic, aromatic or hetero-
aromatic carboxylic acids or thiocarboxylic acids or from
aliphatic or aromatic sulphonic acids. ~he preferred acyl
groups are derived from Cl 4 aliphatic monocarboxylic acids
(e.g. formyl, acetyl, propionyl, butyryl and ethoxyacetyl),
monocyclic aromatic and aromatic sulphonic acids (e.g. benzoyl,
toluoyl and tosyl) and aliphatic sulphonic acids (e.g. mesyl).
Examples of hereroaromatic acids are pyridinecarboxylic acids
(eOg. nicotinic acid) and thiophenecarboxylic acids. Examples
of thiocarboxylic acids are thioacetic acid ~ld thiopropionic
acid.
A pre~erred class of compou~ds of formula I hereinbefore
compri~es those in which Z represents a nitro9 amino, pyrrolo,
pgrrolidino, piperidino, -~HR4, -N(R4)2~ -~HR5, -N~R4)(R5),
--NR4cooR49 -NXCooR4~ - NHCoNHR3 or ~N~CSNHR3 group.
Especially preferred compounds of formula I are those in
which Z represents a nitro, amino, -N~4~ -N(R4)2, -NHR5,
-NR4CooR4, ~HCooR4 or -N3 Kroup.
Of the preferred compounds mentioned hereinbe~ore~ those
in which Rl and R2 each represent a Cl 3 alkoxy ~roup, especially
a methoxy or ethoxy group, are preferred. Also preferred are
:~3~'~1L7~
those compounds in which ~ represents an amino group and n
stands for zero.
,:
According to the process provided by the present invention,
the benzylpyrimidine derivatives aforesaid (i.e. the compounds
of formula I and their salts) are manufactured by
a) reacting a compound of the general formula
~;' Rl
CN (IIB)
\o~6
or
~1
C N
Z ~ ~ C~l2- C ~ (IIb)
,~=/ ~ CHY
R~
~wherein zl represents a nitro, amino~ pyrrolo,
. pyrrolidino, piperidino, -NHR4, -N(R4~2, -NHR5,
-N(R4)(R5), -NR4CooR4, -NHCooR4, -NHCoNHR3, -NHCSNHR3
or -NR3NH2 group, the ymbol R6 represents a lower
alk~l group or the two R~ symbols together represent
a lower alkylene group, Y represents a leavin~ group
and Rl, R2, R3, R4 and R5 have the si~nificance given
earlier,
with guanidine, or
-- 4 --
7~
c) reductively removing the subs~ituent denoted by X
in a compound of the general formula
R NH~
~ N :~.
zl ~ ~ N > (IV)
R xl
, wherein Xl rcpresents a chlorine or brom:ino
atonl or a hydroxy group and Rl, R and Z
have the significance given earlier,
or
d) diazotising a compound of formula I in which Z
represents an amino group and subsequently reacting the
lo product with sodium azide, with an amine of the formula
NH~R4~2 or with an alkali sulphi~e, or
-- 5 --
.. . . .. . .. . . . .
3'79~7~ .
e) treating a compound of formula I in which ~ represents
~ B a NHR4 group with ~ acid, or
~) converting the group z2 in a compound of -the general
formula
Z~CH2~ NH2 (Va)
R2 H2N
R
z ~ C H2 ~ ~\ ~ z2 (~b
)= N
R2 z2
or
R~
Z~3CH2~ \~Z (v~)
R2 z
, wherein ~1 and R2 ha~e the significance
given earlier and z2, which can ba the same
or different in formulae Vb and Vc~ represents
a group convertible by reduction or hydrolysis
into an amino group or a -N~4 group,
into an amino group or a -NHR4 group, or
-- 6 --
~3~ 76
g) alkylating or a]kenylating the group denoted by Z3 in a com-
pound of the general Eormula
R \
3 ~ N
~2 2 ,.
, wherein Z3 repreC~ents a -N~1R5 or -N11COOR4 group and Rl, R2,
R4 and R5 have thc signlficanco givon carlior,
and when recluired converting a compound oE Eormula I obtained
into a pharmaceutically acceptable salt thereof.
According to embodiment (a) of the present process, a com-
pound of formula IIa or IIb is reacted with guanidine. The symbol Y
in a compound of Eormula IIb represents a leaving group. Examples of
suitable leaving groups are ether groups ~e.g. lower alkoxy groups
such as methoxy and ethoxy), thioether groups (e.g. alkylthio groups)
or amino groups derived from primary or secondary amines. Examples ~;
of such amino groups are i) groups derived from primary aliphatic,
aryl-aliphatic or aromatic amines such as lower alkylamino, ben~yl-
amino, and arylamino ~e.g. naphthylamino), but especially phenylamino
(anilino) which may carry in the phenyl ring one or more
"ll ~
-- 7 --
.: , . . : . : .
7~
:: halogent lower alkyl or lower alkoxy substituents, or ii)
groups derived from secondary aliphatic~ aromatic or he~ero-
cyclic amines such as N,N-di(lower alkyl)amino, N-(lower alkyl)-
-N-arylamino [e.~0 N-methyl-N-phenylamino (N-methylanilino)
which may carry in the phenyl ring one or more halogen, lower
alkyl or lower alkoxy substituents~, pyrrolidino, piperidino,
piperazino and morpholino. An especially preferred amino lea~-
ing group i8 the anilino group.
The reaction of a compound of formula IIa or IIb with
guanidine can be carried out according to methods known per se;
for example, as desc.ribed in Belgian Patent Spec.if`ications Nos
594,131, 671,982 and 746,846. For exampIe, the reaction can be
carried out in a solvent such as an alkanol (e.g. methanol or
ethanol), dimethylformamide, dimethyl sulphoxide or N-methyl-
-pyrazolone at a temperature in the approximate range of from
25C to 200C, preferably at a temperature of from 50C to 170C.
The compounds of formula IIb can be formed in situ under
the conditions of the reaction from the tautomeric compounds
of the ~eneral formula
R~
~_ CN
Z~ CH=(: \ (IIc)
~=/ CH.2Y
R~
, wherein Rl, R2, zl and Y have the
significance gi~en earlier.
I`he compounds of formulaeIIb and IIc can occur as the cis or
trans isomers or as mixtures thereof.
, ' ' , : , , ~.
Embodiment (a) of the present process leads to compounds
of formula I in which n stands for zero, Z has ~ny of the values
accorded to ~1 hereinbefore and Rl, R2 and ~1 have the signifi-
cance given earlier.
In accordance with embodiment (b) of the present proces~
a compound of formula III is reacted with ammonia, the bromine
or chlorine atom or the alkylmercapto or alkylsulphonyl group
present in the pyrimidine nucleus being replaced by an amino
group. This reaction is conveniently carried out in an alkanolic
solution, e~pecially a methanolic solution. In a pre~erred
a~pect, the r0action i~ carried out using meth~nolic ~mmonia~
The reaction i~ con~eniently carried out at a temperature between
about 80C ~nd 200C, e~pecially at a temperature ~etween about
100C and 150C. Since the~e temperatures lie above the boiling
point of methanol, the reaction is then carried out in a closed
sy~tem (e.g. in an autocla~e).
E~bodiment (b) of the proces~ lead3 to compounds of
~ormula I in which n st~ndq for zero9 Z ha~ any o~ the values
accorded to zl hareinbefore and Rl Rnd R2 have the signific~nce
~ive~ ~arli~r~
~he removal o~ a bromine or chlorine atom rrom a compound
of formula IV in accordance with embodiment (c) Or the present
procee~ ¢an be c~rried out by treatment with a reducing agent
such as hydro~en iodide or catalytic~lly activated hydrogen
(e.~. pall~dium in alcohol) or with zinc and glacial acetic acid
or amal~mated zinc and sodium hydroxide When Xl represents a
hydroxy group, the compound o~ ~ormula IV i~ reacted with 1-
-phenyl-5-chlorotetrazole and the resulting 1-phenyltetrazol-5-
... . .
,................................................ . . .
7~
~yl eth~r is hydrogenated over palladium on carbon. Alternat-
ively, the compound of formula IV is first reacted with cyanogen
bromide in the presence of triethylamine and the reaction product
hydrogenated over palladium on carbon.
Embodiment (c) provides compounds of formula I in which
n stands for zero, Z represents an amino, pyrrolo, pyrrolidino,
piperidino, -NHR4, -N(R4)2, -NHR5, -NR4CooR4, -N(R4)(R5)~
-NHCooR4~ NHCoNHR3, -NHCSNHR3 or -NR3NH2 group and Rl, R27 R3,
R4 and R5 have the significance Kiven earlier.
The di~zotisation of a compound of formuJ~ I in which Z
repre~ents ~n amino grou~ in accordance with embodiment (d) of
the present process can be carried out in a manner known per se
n i t~o~,$
using ni~;P~-acid or a nitrite and acid. Aqueous hydrochloric
acid can be used as the solvent for this diazotisationO ~he
resulting diazo~ium salt is then reacted, expediently without
isolation, with sodium azide to give a compound of formula I
in which Z represents a -N3 group~ or with an amine of the
~ormula NE(R4)2 to give a compound Or formula I in which Z
.
represents a ~N=N-N(R4)2 group, or with an alkali sulphite to
give a compound of formula I in which Z represents a -N~I NH2
group.
Embodiment (e) of the present process can be carried out
in a manner analogous to that described in the preceding para-
graph for the diazotisation and ylelds compounds of rormula I
in which Z rapresentq a -N(No)R4 group.
-- 10 --
~37~
Examples of groups d~noted by ~2 which are convertible
b~ reduction into an amino group in accordance with embodiment
(f) of the process are nitro~ carbobenzoxyamino, -NH-NH-aryl
and -N=N-~ryl. The reductive conversion of the aforementioned
groups into an amino group can be carried out b~ catalytic
hydrogenation; for example~ by means of hydrog~n and palladium
on carbon in an alcohol (e.gl me-thanol) at 10-50C, preferably
at room temperature.
Groups denoted by Z which are convertible by hydrolysis
into an amino group or a -NHR4 group are, ~or example, the
-NHR5, -N=C~7, -N=C(R7)2, -N=CHoR4, -NHCoo~4, -NR4Coo~4 ~lnd
-N(R4)(R5) groups (~7 representing an alkyl, alken~l or aryl
group) and the phthalimido group. ~he hydrolysis of the afore-
mentioned groups i9 expediently carried out in an acidic medium
(e.g. with a~ueous or aqeuous~alcoholic m neral acids such as
hydrochloric acid)~ Groups denoted by Z which can be hydro-
lysed under alkaline conditions are the -NR4CooR4, -NH~CooR4
and -NHCH0 groups. ~he alkaline hydrolysis can be carried out
u~ing aqueous or aqueous alcoholic (methanolic) alkali. The
phthalimido group can preferably be converted into an amino
group by hydrazinolysis.
l'he groups denoted by Z which are present in the pyrim-
idine nucleus are expedien-tly hydrolysable groups such as -the
acetylamino or formylamino groups, the phthalimido group or
the carbobenzoxyamino group.
Embodiment (f) yields compounds of formula I in which n
stands for zero, Z represents an amino or NHR4 group and Rl,
R2 and R4 have the significance given earlier.
~3s7~
The alkylation or alkenylation of a compound of formula
la in accordance with embodiment (g) o the present process can be
carried out using an alkyl halide (e.g. methyl iodide) or an alkenyl
halide (e.g. allyl bromide) in the presence of a base (e.g. sodium
methylate or sodium hydride). As the solvent there can be used, for
example dimethylormamide or dimethyl sulphoxide.
Embodiment (g) yields compounds of formulcl [ in w}licll n
stands for ~ero, Z ropresents a -N(R4)(RS) or -NR4CooR4 group and
Rl, R2, R4 and R5 have the signific~mco gLvell ourLior.
The starting materials used ln the present process, inso-
far as they are not known or insoar as they are not described here-
inater, can be prepared in a manner analgous to that described in
the Examples hereinafter or according to the methods outlined in the
following Table in which Rl, R2, Y and zl have the significance given
earlier:
~; '
'
-12 -
. .
~;~3~4~;
. .~
,. ~o; o
a) ~g
h ~ rl ~1 ~D o o
~ ~ ~ ~ ~ ~ ,1 ~I ~0
.~ ~ 0 ~a~ p~ 00 U~
h ~ rl ;;t ~D C~ ^ N`
rl Ir\ o
rl ~ 0 ~1 ~ O
. r~ rl Lr~
a~
--~ ~~ -- ~-~- ~ ~ w w
S ~ ,~ h ~1 ~1 0 ~ ~ rl
~-~ ~ 4 E3
~ ~ rl ~ h ~17 ,~
O ~ ~d O, l r r~ ~ 7 w
t~ ~ rO ~ S g ~7 ~ ~d El w ~ 0 ~
~; 1~l h ,~4 0 c) 1~ ~d ~ w .~ C) .~1 0
O ~) a1 r-l rl ' ~ P~ a ~ P,~c~ p
C.) ~7 El ~ ~$ r F I ~ ~ ~r ~ d O
r-l OJ
__ ,__ .
E~ . ~
r
0~
~ \ ~ r ~ ~ O
rc~ ~ r \ /
0 P T ~ ~
~ H ~ ?J
1~
r-l
C~i N ~;i
.. ._~
rl
rl H H H H
.
0h
~ _. .__ .. _ .. __
., /~
The compounds of formula I can be converted into acid
addition salts, especially those which are customary in pharma-
ceutical preparations~ by treatment with inorganic acids (eig.
hydrochloric acid7 sulphuric acidl phosphoric acid etc) or
organic acids (e.~. formic acid, acetic acid, succinic acid,
lactic acid~ citric acid, maleic acid, fumaric acid, tartaric
~cid, methanesulphonic acid, p-toluenesulphonic acid etc).
~ he benzylpyrimidine derivatives provided by the present
invention (i.e. the compounds of formula I hereinbefore and
their acid addition salts) possess antibacterial acitivity.
They inhibit the bacterial dihydrofolate reductase and potent-
iate the ~ntibacterial acitivity of ~ul~phonamides such as, for
example, sulphisoxazole, sulphadimethoxine, sulphamethoxazole,
4-sulphanilamido-5,6-dimethoxy-pyrimidine, 2 sulphanilamido-
-4~ 5-dimethyl-pyrimidine, sulphaquinoxaline, sulphadiazine,
sulphamonomethoxine, 2-sulphanilamido-4,5-dimethyl-isoxazole
and other inhibitors for enzymes which are involved in the
folic acid bios~nthesis such as, for example, pteridine deriv-
atives.
A combination of one or more of the benzylpyrimidine
derivatives aforesaid with sulphonamides can be used in human
medicire in a form adapted for oral, rectal or parenteral
administration. The ratio of a compound of formula I to a
sulphonamide can vary within a wide range; for example, between
1:40 (parts by weight) and 5:1 (parts by weight), the preferred
ratio bein~ between 1:1 and 1:5.
? ~ ~
~3~
Thus, for example, a tablet can contain 80 mg of a
compound of formula I and 400 mg of sulphamethoxazole, a tablet
for children can contain 20 mg of a compound of formula I and
100 mg of sulphamethoxazole and a syrup (per 5 ml) can contain
400 mg of a compound of formula I and 200 mg of sulphamethoxazole.
The compounds of formula I possess a high antibacterial
acitivity or a pronounced synergistic effect in combination with
sulphonamides. They also have a good compatibility.
. I s
~L~3~'7~ ~
~he ~ollowing Examples illustrate the process provided
by the invention:
Example 1
A solution o~ 1~16 g of sodium in 300 ml of absolute
ethanol was treated with 9.1 g Or guanidine carbonate and 5.9 g
of 4'-(3-anilino-2-cyano-allyl)-2',6'-dimethoxy-acetanilide and
boiled under relfux ~or 18 hours. The mixture was diluted with
100 ml of water and the alcohol removed in vacuo. The precip-
itated ~-(2,1~-diamino-5-pyrimidinyl)-2',6'~dimethoxy~p-~ce-to-
toluidide was filtered of~ under ~uction, washed w.ith water and
recry~talli.sed ~rom methanol/ethyl acetate; melting point 278-
~279~-
~he starting material was prepared as follows:
A solution of 3105 g o~ 4-acet~mido-~,5-dimethoxy-toluene
in 2 litres of pyridine/water (1:1) was tre~ted portionwise with
142 g of pota~sium permanganate during 30 minutes while stirring
at 80Co ~he mixture was boiled under reflux ~or 1.5 hours.
The manganese dioxide was filtered of~ under suction and washed
with 500 ml of hot water. ~e filtrate was evaporated to dry-
ness in vacuo at 60C and the residue was dissolved in 200 ml
of water. The resulting solution was treated with 2-N sodium
hydroxide up to a strongly alkaline reaction and then ext;racted
with two 500 ml portions of ethyl acetate. The ethyl acetate
extracts were rejected and the aqueous solution was ad~usted to
pH 1 with concentrated hydrochloric acidO The precipitated
4-acetamido-3~5-dimethoxy-benzoic acid was ~iltered off under
. ............. . .
1L7~
suction, washed with water and recrystallised from methanol~
ethyl acetate; melting point 237-238C~
A solution of 20.4 g of 4-acetamido-3,5-dimethoxy-benzoic
acid in 500 ml of abaolute methanol was saturated with dry
hydrogen chlorida. After standing ~or 18 hours at room temp-
erature, the ~olvent was removed in vacuo. ~he residue was
treated with ice-water ~nd with 2-N sodium hydroxide up to a
strongly alkaline reaction. The resulting emulsion was extracted
with two 500 ml portions of ethyl acetate. ~he ethyl acetate
extracts were washed with two 200 ml portions Or water, combined,
dried over magnesium sulphate and evaporated to dryness in vacuo.
The residue was dissolved in ~00 ml of absolute tetrahydrofuran.
'rhe solution was treated with 40 ml o~ absolute pyridine and
40 ml of acetic anhydride, stirred for 20 hours at room -temper-
ature and subsequently evaporated to dryness in vacuo. The
residue was tre~ted with 300 ml of water and extracted with two
600 ml portio~s of ethyl acetate. The ethyl acetate extracts
were washed with two 200 ml portions of water, combined, dried
over magnesium sulphate and evaporated to dryness in vacuo.
The remaining 4-acet~ido-3~5-dimethoxy-benzoic acid methyl ester
was recry tallised from ethyl acetate; melting point 183-184~C.
A suspe~sion of 30.1 g of dimethylsulphone and 11.5 g of
sodium hydride (5~/o dispersion in oil) in ~0 ml of dimethyl
sulphoxide w~s stirred at 50C for 3 hours with the exclusion
f moisture. ~hen, 20.3 g of 4-acetamido-3,5-dimethoxy-benzoic
acid methyl ester were added and the mixture was stirred at
room temperature for 20 hours. The solution was diluted wi-th
1 litre of water and extracted with three 1 litre portions of
'i '~. ?~
", . . .
~37~
eth~l acetate~ The ethyl acetate extracts were wa~hed with
two 300 ml portions of water, combined~ dried over magnesium
sulphate ~nd evaporated to dryness in vacuo~ Recrystallisation
of the residue from ethyl acetate gave 2',6'-dimethoxy-4'-
5 -(methylsulphonyl-acetyl)-acetanilide of melting point 206-
-207C.
A suspension of 10.1 g of 2',6'-dimethoxy-4'-(methyl-
sulphonyl-acetyl)-acetanilide and 4.85 g of sodium borohydride
in 400 ml of ethanol was stirred at room temperature for 18
hours. The solution was treated with 100 ml of water and the
alcohol was removed in vacuo. The precipitated 4'~ hydro.xy-
-2-methylsulphonyl-ethyl)-2',6'-dimethoxy~ace-tan.i.lide was filt-
ered off under suction and recrystallised ~rom methano:L/ethyl
acetate; melting point 193-195C.
A mixture Or ~.78 g of sodium methylate, 5.1 g of ~-
-anilino-propionitrile and 9.8 g of 4'-(1-hydroxy-2-methyl-
sulphonyl-ethyl)-2',6'-dimethoxy-acetanilide in 40 ml of dime-thyl
sulphoxide was stirred at 50C for 4 hours with the exclusion of
moisture~ The mixture was poured into 400 ml of water and the
resulting emulsion was extracted with three 500 ml portions of
ethyl acetateO The ethyl acetate extracts were washed with two
200 ml portions of water, combined, dried over magnesium sulpha-te
and evaporated in vacuo. Recrystallisation of -the residue from
ethyl acetate gave 4'-(3-anilino-2-cyano-allyl)-2',6'-dime~hoxy-
-acetanilide of melting poi.nt 165-167C.
1~ .
~, ....
~ E ~mple 2
.
A solution of 10~1 g of ~ (2~4-diamino-5-pyrimidinyl)-
-2'~6'-dimethoxy-p acetotoluidide in 600 ml of l-N hydrochloric
acid was boiled under reflux for 5 hours and subsequently evap-
orated to drynes~ in vacuo. The residue was recrystallised frommethanol/ethanol and yielded 2,4-diAmino-5-(4-amino-3,5-
-dimethoxy-benzyl)-pyrimidine dihydrochloride of melting point
286C (decomposition)~
Example ~
A solution of 1.3~ g of sodium in 300 ml of absoLllte
ethanol was treated with 10~8 K Of Kuanidine carbonate ~md
7.5 g of 4'-(3-anilino-2-cyano-allyl)-2',6'-dimethoxy-N-methyl-
-acetanilide and boiled under reflux for 20 hours. The alcohol
was removed in vacuo and the residue taken up in a mixture of
100 ml of water and 20 ml of ethyl acetate. After stirring at
room temperature for 1 hour1 the precipitated ~-(294-diamino-
-5-pyrimidinyl)-2',6'-dimethoxy-N-methyl-p-acetotoluidide was
filtered off under suction, washed with water, dried and recry-
stallised from methanol/ethyl acetate; melting point 262-264C.
The starting material was prepared as follows:
A suspension Or 12.0 g of sodium hydride (5~/o dispersLon
in oil) in 50 ml of absolute dimethylformamide was treated with
a solution of 46.0 g of 4-acetamido-3,5-dimethoxy--toluene in
200 ml of absolu-te dimethylformamide during 30 minutes Imder
stirring and exclusion of moisture. After stirrin~ at room
. ~ .
~g93747~ f
temperature for 4 hours, 31.2 ml of methyl iodide were added
dropwise during 20 minutes under stirring and ice-coolingO The
mixture was stirred at room temperature for 70 hours and
subsequently evaporated to dryness in vacuo9 ~he residue was
treated with 300 ml of water and the resulting suspension was
with
extracted/two 500 ml portions of ethyl acetate. The combined
ethyl acetate extracts were washed with 300 ml of water, dried
over magne~ium sulphate, filtered and evaporated in vacuo.
Recrystallisatior. of the residue from ethyl acet~te gave 3,5
-dimethoxy-4-(N-methyl-acetamido)-toluene of melting ~oint
160-161Co
A solution of ~20l~ g of 3,5 dimetho~y~ (N-mei;hyl-ncel;arn~do)-
-toluene in 2 litres of pyridine/w~ter (1:1) W~lS treated portion-
wise with L80 g of potassium permanganate during 1 hour while
stirring at 80C. ~he mixture was boiled under reflux for 1
hour. ~he manganese dioxide was filtered off ~der suc-tion and
washed with 1 litre of hot water. ~he filtrate was evaporated
to dryness in vacuo. ~he residue was dissolved in 500 ml of
water and the resulting solution was extracted with 250 ml of
ethyl acetate. ~he ethyl acetate extract was rejected and the
aqueous phase treated with concentrated hydrochloric acid up to
a strongly acidic reaction~ The precipitated 3,5-dimethoxy-4-
-(N-methyl-acetamido)-benzoic acid was filtered off under suction,
washed with water and recrystallised from methanol; melting
point 293~-295C.
suspension of 35.8 g of 3,5-dimethoxy-L~-(N-methyl-
~cetamido)-benzoic acid in 500 ml o~ absolute methanol was
saturated with dry hydrogen chloride, a solution gradually
: 1 , . . .
.
7~7~i
occurring~ ~fter standing at room temperature for 20 hours,
the solution was evaporated to dryness in vacuo. The residue
was treated with 200 ml of ice-water and with a concentrated
sodium hydroxide solution up to a strongly alk~line reaction
and the resulting emulsion was extracted with two 500 ml portions
of eth~l acetate. The ethyl scetate extracts were washed with
two 100 ml portions of water, combined, dried over magnesium
sulphate, filtered and evaporated in vacuoO After recrystal-
lisation from ethyl acetate/cyclohexane, the residue yielded
3~5-dimethoxy-4-(N-methyl-acetamido)-benzoic acld methyl ester
of melting point 115-116C.
A suspension Or 35.7 K Of dlmethylsulphone and 1,?.0 ~ Or
sodium hydride (5~/o disperc3ion in oil) in 100 ~1 of` abc;oLIlt;e
dimethyl sulphoxide wa~ stirred at 50C for 3 hours with the
exclusion of moisture and subsequently treated with 34-0 g of
3,5-dimethoxy-4-(N-methyl-acetamido)-benzoic acid methyl ester.
After stirring at room temperature for 2.25 hours, the mixture
was diluted with 1 litre of water ~he resulting solution was
made acidic with 3-N hydrochloric acid and extracted with two
1 litre portions of ethyl acetate. The ethyl acetate extracts
were washed with ~wo 200 ml portions of water, combined, dried
over magnesium sulphate and evaporated in vacuo. Recrystallisa-
tion of the residue from ethyl acetate gave 2't6'-dimethoxy-N-
-methyl-4'-(methylsulphonyl-acetyl~-acetanilide of melting
point 141-142C.
A suspension of 20.9 g of 2',6'-dimethoxy-N-methyl-~'-
-(methylsulphonyl-acetyl)-acetanilide and 9.5 g of sodium boro-
hydride in 300 ml of ethanol was stirred at room temperature
..
7~
for 20 noursO The solution was diluted with 300 ml of water
and the alcohol removed i~ vacuoa ~he resulting suspension
was extracted with two 1 litre portions of ethyl acetate. ~he
ethyl acetate extracts were washed with two 200 ml portions of
water, combined, dried o~er magnesium ~ulphate and evaporated
in vacuo. Recry~tAllisation of the residue from ethyl acetate
gave 4'-(1-hydroxy-2-methylsulphonyl-eth~1)-2',6'-dimethoxy-
-N-methyl-acetanilide of melting poi~t 175-177C.
A mixture of 302L~ g of sodium methylate, 8~75 g of ~-
-~nilino-propionitrile and 14c9 g o~ 4'~ hgdroxy-2-methyl-
sulphonyl-ethyl)-2',6'-dlmethoxy-N-methyl-acetE~ilide in 60 ml
of absolute dimethyl sulpho~ide was stirred at 50C for 4 hours
with the exclu~ion of moisture. ~he solution was poured into
600 ml of water ~nd the resulting emulsion was extracted with
two 400 ml portions of ethyl acetate. ~he ethyl acetate extracts
were washed with kwo 150 ml portions of water, combined, dried
over magnesium sulphate and evaporated in vacuo. Xecrystallisa-
tion of the residue from ethyl acetate gave 4'-(3-anilino-2-
-cyano-allyl~-2'~6'-dimethoxy-N-methyl-acetanilide of melting
poi~t 202-2~4C.
Example 4
A solution of 6.9 g of qodium in 1 litre of absolute
ethanol was treated with 54 K Of guanldine carbonate and ~1.0 g
of 4-amino-x~ ilino-methylene)-3,5-dimethoxy-hydrocinnamic
acid nitrile and boiled under re~lux for 20 hoursO 500 ml of
water were added and the alcohol was removed in vacuo. ~fter
standing at room temperature ~or 2 hours, the crystallised 2,4-
-diamino-5-(4-amino-3,5-dimethoxy-benzyl)-pyrimidine was
t~
:
~3~47~i
filtered off under suction~ washed wi-th water and recrystal-
lised from methanol; melting point 215 216C~
The starting material was prepared as follows:
13.8 g of sodium were dissolved in 900 ml of methanol.
To this solution were added 46.8 g of 3-hydroxy-5-keto-3-
-cyclohexene-carboxylic acid. This mixture was stirred, held
between -4~C and -8C by means of a cooling bath and treated
during 30 minutes with a phenyl-diazonium chloride solution
[prepared from 27.9 g of aniline, 450 ml o~ water, 72 ml of
concentrated hy~rochloric acid and 2100 g of sodium nitrlte
in 90 ml of water~. The resulting mixture wa~ stirr~d ~or a
further 1 hour at -5C to -10C. ~he deposited, red reaction
product was filtered o~ under vacuum and washed with ca 1000 ml
of water. There was obtained 3-hydroxy-5-keto-4-phenylazo-3-
-cyclohexene-carboxylic acid o~ melting point 218C.
60 g of 3-hydroxy-5-keto-4-phenylazo-3-cyclohexene-
-carboxylic acid, 200 ml of methanol, 1200 ml of benzene and
5 g o~ p-tolue~esulphonic acid were boiled together under reflux
on a wat~r separator ~or 18 hours. After cooling~ the solution
was washed with 500 ml of a 5% sodium bicarbonate solution9
then washed with water, dried and e~aporated. The residue was
dissolved in ethyl acetate and purified on an aluminium oxide
column [500 g; activity stage I~o After evaporation o~ the
ethyl acetate and recr~stallisation o~ the residue ~rom benzene/
petroleum ether, there was obtained 3-hydrox~-5-keto-~-phen
azo-3-cyclohexene-carboxylic acid methyl ester as a solid of
melting point 1l~C~
~ 3
~3~
54~8 g o~ 3-hydroxy-5~keto-4~phenylazo-3-cyclohexene-
-carboxylic acid methyl ester~ 12~0 g of acetamide and 2.0 ~
of bromosuccinimid~ were stirred in 600 ml of chloro~orm ~nd
treated dropwise with 32.0 g of bromine in 400 ml of chloroform
[the reaction temperature being held below 35C~. The separa-
tion of acetamide hydrobromide 800n beganO ~he mixture wa5
stirred for a further 30 minutes at room temperature9 the
acetamide hydrobromide filtered off and the filtrate evaporated
to dryness. The residue was taken up in a small amount of
eth~ol, filtered off under vacuum and washed with ethanol.
There was obtained 3,5-dihydroxy~4~phenylazo benzoic acid meth~l
es-ter of melting point 216-218C.
A mixture of 27~2 g of 3,5-dihydroxy~ phenylazo-benzoic
acid methyl ester, 150 ml of methanol and 64 g of dimethyl
sulphate w~s treated during 45 minutes with a solution of 23 K
of sodium hydroxide in 50 ml of water while stirring. Care was
taken that the temperature did not exceed 55C by means of a
cooling bath. The mixture was stirred at room temperature for
a further 1 hour9 cooled with ice-watert filtered off under
vacuum and recrystallised from 400 ml of ethanol. Red crystals
of 3 9 5-dimetho~y-4-phenylazo~benzoic acid methyl ester were
obtained; melting point 130-132C.
12 g of 3~5-dimethoxy-4-phen~lazo-benzoic acid methyl
ester were dissol~ed in 400 ml of ethanol and, after the addi~
tion of 0080 g of palladium on carbon, hydrogenated under
atmospheric pressure and at room temperature. With slight
warming, 2 moles of hydrogen were taken up durin~ 1.5 hour-.
~he catalyst was filtered off and the filtrate concentrated
- 26'_
.
. .
in vacuo. ~he resulting aniline was dis-tilled off with steam~
After cooling, the 4~amino-395-dimethoxy-benzoic acid methyl
ester which remained as an aqueous suspension9 was filtered off
under vacuum, dried and recrystallised from cyclohexane; melting
point 115-116C.
A suspension of 214 g of dimethylsulphone and 78.2 g of
sodium hydride (5~/o dispersion in oil) in 400 ml Or absolute
dimethyl sulphoxide was stirred at 50C under nitrogen and with
exclusion of moisture for 3 hours~ ~he mixture was cooled to
30C, whereu.po~ 137 g of 4-~mino-3,5-dimethoxy-benzoic acid
methyl ester were added~ the temperature risin6 to 50C. After
stirring under nitrogen and at room temperature for ca 1 hour,
the resulting mixture wa~ left to stand for 3 hou~s an~l the
dissolved in 2 litre~ of water under addition of ice. q1he
solution was ad,justed to pH 6-7 with glacial acetic acid. ~fter
stirring under ice-cooling for 1 hour9 the crystallised ~'-~nino-
-3'~5'-dimethoxy-2-methylsulphonyl-acetophenone was filtered off
under suction, washed with wa-ter, dried and recrystallised from
ethyl acetate; melting point 166-167C.
~ suspension of 123 g of 4'-amino-3',5'-dimethoxy-2-
-methylsulphonyl-acetophenone and 68 g of sodium borohydride
in 1J5 litres of alcohol was sti`rred at room temperature for
20 hours. The suspension was diluted with 1.5 litres of water.
~he alcohol was evaporated in vacuo and the resulting 4-amino-
-3,5-dimethoxy-~-(methylsulphonyl-methyl)-benzyl alcohol was
filtered off under suction, washed with water and dried; meltin~
point 178-179C.
_,~_
~;33~9~7~
A mixturs of 8.64 g o~ sodium methylate, 1406 g of B-
-anilino-propionitrile ~nd 22.0 g of 4-amino-395-dimethoxy-~-
-(methylsulphonyl-methyl)-benzyl alcohol in 50 ml of absolute
dimethyl sulphoxid~ was stirred at 50C for 1 hour under nitro~en
and with the exclusion of moisture. ~he solution was poured into
500 ml Or ice-water and the resulting emulsion was extracted with
two 50~ ml portions of ethyl acetate. The ethyl acetate extracts
were washed with two 250 ml portions of water, drled over mag-
nesium sulphate and evaporated in vacuo. The residue was
dissolved in 60 ml of ethyl acetate. After standing at room
temperature for 20 hours, the crystallised 4-amino-a-(anilino-
-methylene)-3,5-dimethoxy-hydrocinnamic acid nitrile was filt-
ered of~ under suction, washed with a small amount Or ethyl
acetate and dried; melting point 150-151
A solution of 360 mg of sodium in 100 ml of absolute
ethanol was treated with 2.8 g of guanidine carbonate and 2.0 g
of 4-(3 anilino-2-cyano-allyl)-2,6-dimethoxy-carbanilic acid
ethyl ester and boiled under reflux ~or 20 hours. The solution
was diluted with 100 ml of water and the alcohol removed in
vacuo. After standing at room temperature ~or 1 hour, the
precipitate was filtered off under suction, washed with water
and dissolved in ca 2U0 ml of boiling ethanol. The solution
was chromatographed on 100 g Or silica gel (Merck~ usin~
ethanol/ethyl acetate (1:1). There was obtained 4-[(2,4-diamino-
-5-pyrimidinyl)-methylJ-2,6-dimethoxy-carbanilic acid ethyl
ester which, a~ter recrystallisation from ethanol, had a melt-
ing point of 228C (decomposition).
'
: ' '. ' ',...................... '
~3~7~
~he starting material was prepared as follows:
'
A solution (cooled to 0C) of 12~0 g of 4'-amino-3'95'-
-dimethoxy~2-methylsulpho~yl-acetophenone in 100 ml of absolute
pyridine was treated with 5.06 ml of chloroformic acid ethyl
ester while stirrirlg. After stirring at room temperature for
20 hours7 the p~ridine wa~ removed in vacuo and the residue
t~ken up in 100 ml of water. ~he precipitated 2,6-dimethox~-4-
~methylsulphonyl-acetyl)-carbanilic acid ethyl ester was filtered
off under suction, washed with water and recrystallised from
ethanol; melting point 192 193C.
A su~penslon of 1201 g Or 2,6-dilllethO~-~-(meth;y.lSUlphOn,yl-
-acetyl)-carbanilic acid eth~l e~ter ~nd 5.~ g of sodium boro-
hydride in 150 ml of ethanol was stirred at room temperature for
70 hours. The alcohol was evaporated in vacuo and the residue
treated with 150 ml of waterO After standing at room temperature
for 1 hour, the cry~tallised 4-(1-hydroxy-2-methylsulphonyl-
-ethyl) 2~6-dimethoxy-carbanilic acid eth~l ester was filtered
off under suction~ washed with ~ter and recrystallised from
ethanol; melting point 168-170C.
A mixture of 4042 g of sodium ethylate, 5.1 g of ~-anilino-
-propionitrile and 10.0 g of 4-(1-hydroxy-2-methylsulPhonyl-
-ethyl)-2,6-dimethoxy-carbanilic acid ethyl ester in 150 ml of
dimethyl sulphoxide was stirred at 50C for 2 hol~s with the
exclusion of moisture. The solution was poured into 1.5 litres
of water and the resulting emulsion extracted with two 1 litre
portions of ethyl acetate. 'rhe ethyl ace-tate extracts were
washed with two 500 ml portions of water, combined, dried over
magnesium sulphate and evaporated in vacuo~ 'rhe residue was
c~ ~ .
g~3~
chromatographed on 800 g of silica gel (Merck~ using methylene
chloride/ethyl acetate (3:1). There was obtained 4 (3-anilino-
-2-cyano-allyl)-2,6 dimethoxy-c~rbanilic acid ethyl ester of
melting point 150-151C (recrystallisatlon from alcohol).
., .
~
,, .
A suspension of 1.04 g of 4-[(2~4-diamino-5-pyrimidinyl)-
-me-thyl]-2,6-dimethoxy-carbanilic acid ethyl ester in a mixture
- of 50 ml of 4-N sodium hydroxide and 50 ml of ethanol was boiled
under reflux for 18 hours, a solution gradually resulting. ~he
alcohol was removed in vacuo. After stand~n~ at rourn temperatllre
for 1 hour, the crystalli~ed 2,4-diamino-5-(4-amino-~,5-
-dimethoxy-benzyl)-pyrimidine w~s filtered of`f under suction~
washed with water and recrystallised from methanol; melting
point 215 216C.
~ E~ Z
A solution of 0.1 g of mercury (II) chloride in 2 ml of
water and 1.5 g Or zinc powder was added to a solution of 1.5 g
of 2~4-diamino-5-(4-amino-3,5-dimethoxy-benzyl)-6-chlorop~yrimidine
in 15.5 ml of glacial acetic acid and the mixture was boiled
under reflux with stirring overnight. ~'hen, the mixture was
filtered while hot, the zinc powder washed with 5 ml of acetic
acid and the combined fll-trates added dropwise with stirring at
a temperature below 20C, to 1~0 ml of concentrated ammoniaO ~he
mixture was stirred at 20C for a further hour and the solid
material was filtered off under vacuum, washed with water, dried
and recrystallised from methanol. ~here was obtained 2,4-
.. . .
~7~L7~i
-diamino-5-(4-amino 3 9 5-dimethoxy-benzyl)-pyrimidine of mel-ting
point 214C~
.,
~he starting material was prepared as follows:
.
138 g of 4-amino-3,~-dimethoxy-~-(methylsulphonyl-methyl)-
-benzyl alcohol in 250 ml of dimethyl sulphoxide were treated
with 9~75 g of sodium amide. The mixture was stirred at room
temperature for 1~25 hours and then poured into 2 litres of
water. The resulting precipitate was extracted with 2 litres
of ethyl acetate and the aqueous phase was extracted with 2
litres of ethyl acetate. ~he combined ethyl acetate phases
were washed with two 1 litrc portions O:e deionised wa~er, dried
over magnesium sulphate, filtered and evaporated to dryness in
vacuo at 40C. ~he crystalline residue was dissolved in 250 ml
of hot methanol and the solution treated with 150 ml of water
and left to stand at 4C for 18 hours. The crystallised 4-
-amino-3,5-dimethoxy-benzaldehyde was filtered off under suction9
washed with a mixture of 40 ml of methanol and 20 ml of deionised
water and dried in vacuo at 50C; melting point 90-93C.
A mixture of 18~1 g of 4-amino-3,5-dimethoxy-benzaldehyde~
11.3 g of cyanoacetic acid ethyl ester and 3 drops of piperidine
was heated at 120C for 1 hour in an open vessel, by which means
the resulting water escaped. ~he residue was recrystallised
~rom ethyl acetate/pet~oleum ether. ~here was obtained l~-amino-
-a-cyano-3,5-dimethoxy-cinnamic acid ethyl ester of melting
point 134-136C.
" ' - .:
13 a8 g of 4-amino-a cyano-3,5-dimethoxy-cinnamic acid
ethyl ester were hydrogenated in 500 ml of ethanol in the
presence of 3 g of palladium on carbon at room temperature and
a pressure of 1 atmosphere. After the uptake of the theoretical
amount of hydrogen, the reaction was stopped~ The catalyst was
separated, the ~iltrate evaporated in vacuo and the residue
purified by chromatographyO There were obtained 10.8 g of
4-amino-~-cyano-3,5-dimethoxy-hydrocinnamic acid ethyl ester of
melting point 77-78C (recrystallisation from ethyl acetate/
petroleum ether).
13.9 g of 4~amino-~-cyano-3,5-dimethox~ hydrocinnamic acid
ethyl ester and a ~uanidine ~olution (pr~p~red from 1.15 g of
30dium in 50 ml of ethanol and 5 g of guanidine hydrochloride)
were added to a solution of 1015 g of sodium in 50 ml of ethanol.
The mixture was stirred under reflux for 1 hour and evaporated
to dryness. The residue was dissolved in a small amount of
water and the solution was filtered, made slightly acidic with
acetic acid and then made alkaline with sodium bicarbonate. The
precipitat0d 256-diamino-5-(4-amino-3,5-dimethoxy-benzyl)-4-
-pyrimidinol was filtered off under vacuum and recrystallised
from ethanol/water; melting point 267-269C.
2.5 g of dime-thylaniline were added dropwise to a suspension
of 2.9 g of 2,6-diamino-5-(4-amino-3,5-dimethoxy-benzyl)-4-
-pyrimidinol in 15 ml of phosphorus oxychloride while stirring.
The mixture was then brought to boiling during 1 hour and boiled
under reflux for 4 hours. 8 to 9 ml of phosphorus oxychloride
were distilled off under reduced pressure and the residue was
poured on to 80 g of ice while stirring. The mixture was left
to st~nd at room temperature for 6 days and then 35 ml of conc-
~ ~ 3 ~
entrated ammonia were added portionwise. After standin~ for 2
k hours, the solid material was filtered off lmder vacuum, dried
and recrystallised from dimethylform~nide/ether. r~here WRS
obtained 2,4-diamino-5-(4-amino-3 9 5-dimethoxy-benzyl)-6-chloro-
pyrimidine of melting point 222-224Co
ample 8
A solution of 0.53 g of sodium in 36 ml of absolute
ethanol was treated with 2.16 g of guanidine hydrochloride and
3.4 g of ~-(anilino-methylene)-3,5-dimethoxy l~-(pyrrol-l-yl)-
-hydrocinnamic acid nitrile and boiled for 20 hourt3 Imder nit-
rogen while stirring. '~he ethanol W~fi re~moved under re(lllc(!d
pressure and the residue taken up in wate~rl ~illered off under
v8CUUm~ washed with water and recrystallised from ethanol. There
was obtained 2~4-diamino-5-[3~5-dimethoxy-4-(pyrrol-l-yl)-beny~;
-pyrimidine Or melting point 220C.
'rhe starting material was prepared as follows:
A mixture of 9 g of diethoxy-tetrahydrofuran and 5 ml of
glacial acetic acid was added dropwise at room temperature to a
solution of lOo 5 g of 4-amino-3j5-dimethoxy-benzoic acid methyl
ester in 50 ml of glacial acetic acid while stirring. The
mixture was stirred at 100C for a further 30 minutes, cooled
with ice, filtered off undex vacullm, drled and recrystaLlic;ed
from cyclohexane. r1'here was ob-tained ~rj-dimethoxy-~-(pyrrol 1-
-yl)-benzoic acid methyl ester of mel-ting point 1~5-146C.
A suspension of 2.9 g of sodium hydride (5~o dispersion in
oil) and ~o8 g of dimethylsulphone in 20 rnl of absolute dimethyl
`' ~3 _ ~ _
. .~
~, , . . ~ , , ,
~L~37~
sulphoxide was stirred at 50C for 2 hours under nitrogen and
with the exclusion of moisture~ ~hen, the heating was stopped
and 5.2 g of 3,5-dimethoxy~4-(pyrrol-1-yl)-benzoic acid methyl
cster wero added, the temperature rising to 67C~ ~he mixture
was stirred ~or a ~urther 2 hours and dilut~d with 200 ml of
ice-water. ~hc a~ueou~ solution w~s sh~ken out with 50 ml of
ethyl acetate, filtered over carbon, made acidic with glacial
acetic acid and left to ~tand overnight in a refrigerator. The
precipitated 3',5'-dimethoxy-2-methylsulphonyl-4'-(pyrrol-1-yl3-
-acetoph0none was recrystallised from ethyl acetate/petroleum
ether; melting point 180C.
A suapension o~ 1.54 g of 3',5'-dimethoxy-2-methylsulphonyl-
-4'-(pyrrol-1-yl)-acetophenone in 20 ml of ethanol and 20 mL of
water wa~ treated with a ~olution of 0./~ g o~ ~odiurn borohydri(3e
in 5 ml of water with addition of 0~1 g o~ sodium hydroxide. The
mixture was stirred at room temperature for a further 3 hours,
cooled with ice, diluted with 50 ml of water and filtered off
under vacuum. A~ter recrystallisa-tion from ethanol, there was
obtained 3,5-dimethoxy-~-(methylsulphonyl-methyl)-4-(pyrrol-1-
-yl)-benzyl alcohol of melting point 192C~
A mixture of 2045 g of sodium methylate, 9.75 g of 3,5-
-dimethoxy-x-(methylsulphonyl-methyl)-4-(pyrrol-1-yl)-ben%yl
alcohol and 6.6 g of ~-anilino-propionitrlle in 75 ml of absolute
dimethyl sulphoxide was stirred at room temperature for 1 hour
under nitrogen and with the exclusion of mois-ture. Then, the
mixture was poured into 250 ml of ice-cold water and extracted
with three 200 ml portions of ethyl acetate. The ethyl acetate
extract was washed with water, dried and evaporated. After
chromatography on aluminium oxide and recrystallisation from
i ~. ~ . .
, .
7~
ethanol, there was obtained a-(anilino-methylene)-3,5-dimethoxy-
-4-(pyrrol-1-yl)-hydrocinnamic acid nitrile of melting point
182~184C~
A solution of 0.53 g of sodium in 36 ml of ethanol was
treated with 2016 g of guanidine hydrochloride and 3~2 g of
4-amino-~-(anilino-methylene)-3,5-diethoxy-hydrocinnamic acid
nitrile and the mixture boiled for 20 hours under nitrogen while
stirring. 'rhe ethanol was removed under reduced pressure and the
residue taken up in water, fil-tered o.~f under vacuum, washed with
wat0r and recrystallised ~rom methanol '~h~re wa~ ob~a:i.rled 2,~-
-diamino-5~ ~mino-3,5-d:Letho.~-benY.;yl)~pyr;.m:idlne of`ln~lkir
point 200-202C.
q'he starting material was prepared as ~ollows:
A solution of 50 g of sodium hydroxide in 200 ml of water
was added dropwise to a mixture of 5494 g of 3,5-dihydroxy-4-
-phenylazo~benæoic acid methyl ester, 400 ml of methanol and
86 g of diethyl sulphate, while maintaining the temperature
between 40C and 45C. ~he mixture was then stirred for 2 hours
at room te~perature and e~aporated to dr~nessr The residue was
shaken with water and ethyl acetate and the organic phase was
separated, washed with a sodium carbonate solution and then with
water, dried and evaporated. By chromatographic separation a:nd
crystallisation from me-tha.nol, there was obtained 3~5-dieth
-4-phenylazo-benzoic aci.d methyl ester of meltin~ point 92(,.
,
~L~3~
6.56 g of ~,5-diethoxy-4-phenylazo-benzoic acid methyl
ester were dissolved in 100 ml of ethanol and, after the addi-
tion of 0.4 g of palladium on carbon, hydrogenated at atmospheric
pressure and at room temperature. With slight warming, 2 moles
of hydrogen were t~ken up. ~he catalyst was filtered off and
the filtra-t~ concentrated in VACUO- ~he aniline formed was
di~tilled off with steAm~ After cooling, the 4-amino~3,5-
-diethoxy-benzoic acid methyl ester which remained as an agueous
suspension was filtered off u~der vacuum, dried and recrystal-
lised from cyclohexane; melting point 90-92C.
~ suspension of 3.76 ~ of dimethylsulphone and 2 ~ g of
sodium hydride (5~/o dispersion in oil) i.n 20 ml of absol.ute
dimethyl sulphoxide wa~ stirred at 50C for 2 hour~ der
nitrogen and with the exclusion of moisture. 'rhe heating was
stopped and ~78 g of 4-ami.no-3~5-diethoxy-benæoic acid methyl
ester were added. ~he mixture was heated to 90C for 1 minute,
then stirred at room temperature for 1.5 hours and dilu-ted with
100 ml o~ ice-water The aqueous solution was shaken with 50 ml
of ethyl acetate, filtered over carbon, made acidic with glacial
acetic acid, filtered o~f under vacuum and the resulting 4'-
-amino-3',5'-diethoxy-2-methylsulphonyl-acetophenone was recry-
stallised from ethyl acetate; melting point 161-163C.
A suspension of 26 g of 4'-amino-3',5'-diethoxy-2-methyl-
sulphonyl-acetophenone in 350 ml of ethanol and 350 ml Or wate.r
was treated with ~ solution of 7.0 g of sodium borohydride in
90 ml of water, with the addition of` 0.5 g of sodium hydroxideO
The mixture was stirred for 17 hou.rs at room temperatule, cooled
with ice, diluted with 500 ml of water and filtered off under
vacuum~ After recrystallisation from methanol~ -there was
' ~ -,3~-
. . ~ . . .
. ' ' , ' , ;,
~7~
obtained 4-amino-3,5-diethoxy-~-(methylsulphonyl-methyl)-benzyl
alcohol of melting point 166-168C.
A mixture of 0~82 g of sodium methylate, 300 g of 4-amino-
-3,5-diethoxy-x-(methylsulphonyl-methyl)-benzyl alcohol and
2.2 g of ~-anilino-propionitrile in 1205 ml of absolute dimethyl
sulphoxide was stirred at 55C u~der nitrogen and with -the
exclusion of moisture for 5 hours, poured into 100 ml of water
and extracted with three 100 ml portions of ethyl acetateO ~he
ethyl acetate extract was washed with water, dried and evaporated.
After chromatography on aluminium oxide and recryst~llisation
from ethyl acetate/petroleum ether, there was obtained ~-a~nino
~a-(anilino-methylene)-3,5-diethoxy-hydrocinnamic acid nitrile
of melting point 179-181C.
Exam~le 1~0
A solution of 0~26 g of ~odium in 20 ml o~ ethanol was
treated with 1.08 g of guanidine hydrochloride and 1~9 g of
2'76'-diallyloxy-4'-(3-anilino-2-cyano-allyl)-acetanilide and
boiled under ~itrogen while stirring for 20 hours. The ethanol
was removed under reduced pressure and the residue taken up in
water9 filt@red off under vacuum, washed with wa-ter and recrystal-
lised from methanol/water~ ~here was obtained 2,6-di-allyloxy-
-~-(2,4-diamino-5-pyrimidinyl)-p-acetotoluidide of melting point
176-177C.
~he starting material was prepared as follows:
~35
!'~ '.' _ ,~-
.. ..
A mixture of 27 g of 395-dihydroxy-4-phenylazo-benzoic
acid methyl ester, 250 ml of ~lacial acetic acid and 21 g of
acetic anhydride was ~tirred at 100C for ~ hours, complete
solution occurring. This solution was evaporated to dryness
under reduced pressure, the residue taken up in methanol, again
~vaporated to drynes~ and the re~idue recrystallised from
dimethylformamide/methanol. There was obtained 3-acetoxy-5-
-hydroxy-4-phen~l~zo-benzoic acid methyl ester of melting point
162G.
30 g of 3-acetoxy-5-hydroxy-4~phenylazo-benzoic acid
methyl e~ter were di~sol~ed in 500 ml of metha~ol and, after
the addition o~ 3 g of palladium on carbont hydrogenated at
atmospheric pressure and at room temperature. With slight
warming, 2 moles of hydrogen were taken up. The catalyst was
filtered off and the filtrate concentrated in vacuo. The
aniline formed was distilled off with steamr After cooling, the
4-acetamido-3,5-dihydroxy~benzoic acid methyl ester which
remained as an aqueous suspension was filtered off under vacuum,
dried and recrys-tallised from ethyl acetate/petroleum ether;
melting point 202-20~C~
A mixture of 11.25 g of 4-acetamido-3,5-dihydroxy-benzoic
acid methyl ester, 12.1 g of allyl bromide, 15 g of dry potassium
carbonate and 100 ml of acetone was boiled and stirred on a
reflux condenser for 17 hours. The acetone was removed by
distillation, the residue taken up in water/ethyl acetate cmd
the organic phase separated, washed with water, dried and evap-
orated. After recrystallisation from ethyl acetate/petroleum
ether~ there was obtained 4-acetamido-3,5-diallyloxy-benzoic
3~
,` `., ,~
,~ . .
acid methyl ester o~ melting point 135-137C.
A suspension of 3076 g of dimethylsulphone and 2.9 g of
sodium hydrid~ (5~/o dispersion in oil) in 20 ml o~ absolute
dimethyl sulphoxide was stirred at 50C under nitrogen and with
the exclusion of moisture for 2 hours. The heating was stopped
and 3.0 g of 4-acetamido-3,5-di~llyloxy-benzoic acid methyl
ester were added, the temperature rising to 58C. The mixture
was then stirred at room temperature ~or 2 hours and diluted
with 200 ml of ice-water. The aqueous solution was extracted
: 10 with 50 ml of eth~l acetate, filtered over carbon, made acidic
with glacial acetic acid and le~t to stand in a refri~erator
for 2 hours~ Th~ precipitated 2',6'-bis(~llyloxy)~ (methyl-
sulphonyl-acetyl)-acetanilide was r~crystalli~ed from methanol;
melting point 196-197C.
; 15 A Ruspension of 1.7 g of 2',6'-bis(allyloxy)-4'-(methyl-
sulphonyl-acetyl)-acetanilide in 20 ml of ethanol and 20 ml of
water waq treated with a solution of 0.40 g of sodium borohydride
in 5 ml of water, with addition of 0.1 g of sodium hydroxideO
; The mixture was stirred for ~ hours at room temperature and
evaporated to dryness~ The residue was taken up in water~
filtered off under vacuum, dried and recrystallised from ethyl
acetat~/petroleum ether. There was obtained 2',6'-bis(allyloxy)-
-4'~ hydroxy-2-methylsulphonyl-ethyl)-acetanillde o.f melting
point 162C.
A mixture of 1.4 g of sodium methylate, 3.75 g of ~-
-anilino-propionitrile and 6.3 g of 2',6'-bis(allyloxy)-4'-
-(l-hydroxy-2-methylsulphonyl-ethyl)-acetanilide in 43 ml o~
absolute dimethyl sulphoxid~ was stirred at room temperature
~ ,~7
, .. : ' :
~ 379~
under nitrogen and with the exclusion of moisture for 3 hours,
poured into 200 ml of water and extracted with ethyl acetate.
~he sthyl acetate extract was washed with water, dried and evap-
oratedr After chromato~raphy on aluminium oxide and recrystal-
lisation from ethanol, there was obt~ined 2',6'-bis(allyloxy)-
-4'-(3-anilino-2-cyano-sllyl)-acetanilide of melting point
176-178C~
Example 11
'
A mixture of ~.5 g of sodium methylate, 21.6 g of guanldine
carbonate and 12.~ g of a-(4-amino 3,5-dimethoxy-benzyl)-4-
-morpholino-acrylonitrile in 120 ml of ab~olute dim0thyl
suiphoxide was ~tirred at 120C ror 60 hours. Subsequently,
the mixture was diluted with 1.2 litre~ of water and extracted
with two 2 litre portions of ethyl acetate~ ~he ethyl acetate
extract wa~ washed with two 1 litre portions of water, dried
over m~gnesium sulphate and evaporated in vacuo. After recrystal-
lisation of the residue from methanol9 there was obtained 2,4-
-diamino-5-(4-amino-3,5-dimethoxy-benzyl)-pyrimidine of melting
point 215-216C.
The starting material w~s prepared as follows:
A mixture of 8.1 g (0.15 mol) of sodium ~ethylate and
2100 g (0.15 mol) of ~-morpholino-propionitrile in 100 ml of
ab~olute dimethyl sulphoxide was treated during 10 minutes with
a solution of 18.1 g (0.1 mol) of 4-amino-3,5-dimethoxy-benz-
aldehyde in 50 ml of absolute dimethyl sulphoxide while stirrin~at 60C. A~ter stirring at 60C for 30 minutes, the mixture
was poured into 1.5 litres of water and the precipitate was
.
~.~3~t7~
extracted with two 1 litre portions of ethyl acetate. The
ethyl acetate extract was washed with two 500 ml portions of
water~ dried over ma~nasium sulphate and evaporated in vacuo.
~here wer~ obtained 35 g of crystalline residue which were
triturated with 40 ml of alcohol and, after standing for 2 houris
at 4C, filtered o~f under suction, washed with a small amount
of ice-cold alcohol and driedD ~here was obtained a-(4-amino-
-3,5-dimethoxy-benzyl)-4-morpholino-acrylonitrile of melting
point 128-129C.
_ ample~ 12
A isolution of 1.~ g of sodium in 200 ml of absolute
alcohol was treated with 10~3 g of ~uanidine carbonate and 5 g
of 4-amino-3,5-dimethoxy-a-(ethoxy-methyl)-cinnamic acid nitrile
and boiled under reflux for 48 hours. After the addition of
200 ml Or water, the alcohol was removed in vacuo and the
mixture wa~ then extracted with two 500 ml portions of ethyl
acetate. The insoluble material was separated and rejected.
The eth~l acetate extract was washed with 200 ml of water, dried
over magnesium sulphate and evaporated in vacuo. ~he residue
was chromatographed on 90 g of silica gel (Merck) using ethyl
acetate/methanol (3:13. There was obtained 2,4-diamino-5-
(4-amino-3t5-dime-thoxy-benzyl)-pyrimidine of melting point
215-216C (recrystallisation from methanol).
~he starting material was prepared as follows:
A solution of 4~6 ~ o~ sodium in 400 ml of absolute
alcohol wa~ treated with 18.1 g of 4~amino-3,5-dimethoxy-benz-
aldehyde and 1908 g of ~ethoxy-propionitrile and boiled under
.: ~ . :
7~i
reflux for 20 hours~ The mixture was then evaporated to dr~fness
in vacuo and the residue dissolved in a mixture of 1.2 litres
of ethyl acetate and 300 ml of water with shaking~ After sep-
araticn of the phases, the ethyl acetate extract was washed with
300 ml of water9 dried over magnesium sulphate and evaporated to
dryness in vacuo. The residue was chromatographed on 1 kg of
silica ~el (Merck) using ethyl acetate/methylene chloride (1:9).
There was obtained 4-amino-3~5-dimethoxy-~-(ethoxy-methyl)-
-cinnamic acid nitrile of melting point 54-55C (recrystallisa-
lQ tion from alcohol/water).
A solution of 1.~4 g o~ sodium in 200 ml of absolute
alcohol was treated with 14.4 g of guanidine carbonate and 8.9 g
of 4'-(3 anilino-2-cyano-allyl)-2',6'-dimethoxy-formanilide and
boiled under reflux for 20 hours. Then, 200 ml of water were
added and the alcohol was removed in vacuo. After standing at
room temperature for 2 hours, the crystals formed were filtered
off under suction, washed with water and recrystallised from
methanol. ~here was obtained 2,4-diamino-5-(4-amino-3,5-
-dimetho~y-benzyl)-pyrimidine of melting point 215-216C.
The starting material was prepared as follows:
~ solution (cooled to 10C) of 18.1 ~ (0.1 mol) of 4-amino-
-3,5-dimethoxy-benzaldehyde in 210 ml of 98~' ~ormic acid was
treated dropwise with 70 ml of acetic anhydride while stirring
and maintaining the temperature below 15C~ The solution wa5
then stirred for 2 hours at room temperature, treated with 80 ml
of water and evaporated to dryness in vacuo7 The residue was
0
7~i
washed with water and recrysta.llised from alcohol. There was
obtained 2'96'-dimethoxy-4'-formyl-formani.lide of meltin~ point
159-160C.
A mixture of 2~7 g of sodium methylate, 3.. 65 g of ~-anilino-
-propionitrile and 1~ o 2 g of 2',6'-dimethoxy-LL'-formyl-formanilide
in 30 ml of absolute dimethyl sulphoxide was stirred at 50C for
30 minutes. 'rhe solution was poured into 500 ml of water and
the resulting emulsion extracted with two 500 ml portions of
ethyl acetate. The ethyl acetate extract was washed wi.th two
300 ml portions of water, dried over magne~ium sulphate and evap-
orated in vacuo. ~he residue wa~ recrystall:~s~d from ethyl
acetate.. ~here was o'bta.ined l~'-(3-ani:Lillo-2-cy~no-all~yl)-2',6'-
-dimethoxy-formanilide of meltin~ point 186-187C~
Exemple 14
A solutioIl of 2~75 ~ of 2,4-diamino-5-(4-amino-395-
-dimethoxy-benzyl)-pyrimidine in 50 ml of methanol was treated
with 10 ml o~ l-N hydrochloric acid. The resulting precipitate
was dissolved by warming and the solution evaporated at 60C in
vacuo to ca 20 mlO After standing at room temperature for 2 hours.
the precipitate was filtered off under suction9 washed with
methanol and dried. 'rhere was obtained 2,4-diamino-5-(4-amino-
-3,5-dimethoxy-benzyl)-pyrlmidi.ne hydrochlor.ide of meltin~; point
296C (decomposition).
A solution of 7 g of 2,4-diamino-5-(4-amino-3,5-dimethoxy-
-benzyl)-pyrimidine dihydrochloride in 60 ml o:E l-N hydrochlori.c
~/
7~
acid and 40 ml of water was treated durin~ 5 minutes with
- stirring and ice-cooling with a solution of 1~52 g of sodium
nitrite in 10 ml of water. After stirring at 0C for 30 minutes9
a solution of 1~43 g of sodium azide in 20 ml of water was added~
The solution was stirred at 0C for 2 hours and then treated with
soda up to an alkaline reaction. After stirring at 0C for 1
hour, the precipitate was filtered off under suction, washed with
water and recrystallised from methanol. There was obtained 2,4-
-diamino-5-(4-azido-3,5-dimethoxy-benzyl)-pyrimidine of melting
point 152C (decomposition).
Example 16
A solutio~ Of 7 K Of 2t~-diamino-5-(4-amino-3,5-dimethoxy-
-benzyl)-pyrimidine dih~drochloride in 60 ml of l-N hydrochloric
acid and 40 ml of water was treated during 5 minutes with stirring
and ice-cooling with a solution of 1.52 g of sodium nitrite in
10 ml of water. ~he solution was stirred at 0C ~or 30 minutes
and 14.6 g of diethylamine were then addedO After stirrin~ with
ice-cooli~g for 2 hours, the precipitate was filtered off under
suction, washed with water and recrystallised from methanol.
There was obtained 2,4-diamino-5-[4-(3,3-dieth~ triazino)-
-3,5-dimethoxy-benæyl]-pyrimidine of melting point 196-197C
(decomposition)0
Example=17
A mixture of 807 g of 4-~(2,4-diamino-5-pyrimidinyl)-
-methyl~-2,6-dimethoxy-carbanilic acid ethyl ester and 1-L~4 g
of sodium hydride (50% dispersion in oil) in 75 ml of absolute
dimethylformamide was stirred at room temperature for 1 ho~r
- ~ _ ,~ _
7~
and then treated with 4.26 g of methyl iodide. After stirring
at room temperature for 3 hours7 the dimethylformamide was
removed at 60C in vacuo and the re~sidue dissolved in a mixture
of 500 ml of ethyl acetate and 150 ml of water. After separa-
- 5 tion of the phases, the aqueous phase was extracted with 500 ml
of ethyl acetate. ~he cornbined ethyl acetate extracts were
washed with 300 ml of water, dried over maKnesium sulphate and
evaporated in vacuo. After recrystallisation of the residue
from alcohol, there was obtained 4-[(2,4-diamino-5-pyrimidinyl)-
-methyl]-2~6-dimethoxy-N-methyl-carbanilic acid ethyl ester of
melting point 187-188C.
A mixture of 12 g of 4-C(2,4-diamino-5-pyrimidinyl)-methyl~-
-2,6-dimethoxy-carbanilic acid ethyl ester and 2 g of sodium
hydride (5~/o dispersion in oil) in 100 ml of absolute dimethyl-
formamide was stirred at room temperature for 4 hours and then
treated with 6.5 g of ethyl iodide. After stirring at room
temperature for 30 minutes, the dimethylformamide was removed
at 60C in vacuoO rrhe residue was taken up in 250 ml of water
and the precipitated product extracted with two 600 ml portions
o~ ethyl acetate. rrhe ethyl acetate extract was washed with two
300 ml portions of water, dried over magnesium sulphate and
evaporated in vacuo. rrhe re5idue was chromato~raphed on ~50 g
o~ silica gel (Merck) using ethyl acetate/alcohol (3:1). r~here
was obtained N-ethyl-4~[(2,4-diamino-5-pyrimidinyl)-methyl~-
-2~6~dimethoxy-carbanilic acid ethyl ester of melting point
165-167C (recrystallisation from ethyl acetate)O
' _~_ .
3~
~e~
.
A solution of 414 mg of sodium in 100 ml of absolute
alcohol was treated with 3.24 g of guanidine carbonate and 2 g
of ~-(anilino-methylene)-4-dimethylamino-3,5-dimethoxy-hydro-
cinnamlc acid nitrile and boiled under reflux for 20 hours.
After the addition of 50 ml of water, the alcohol was removed
in vacuo. rrhe precipitate was filtered off under suction,
washed with water and recrystallised from methanol. There was
obtained 2,4-diamino-5-(4-dimethylamino-3,5-dimethoxy-benzyl)
-pyrimidine of melting point 218-219C.
'rhe starting material was prepared as follows:
.~
48 g of dimethyl sulphate were added dropwise durin~ 30
minutes while stirring at room temperature to a suspension of
40 g of 4-amino-3,5-dimethoxy-benzoic acid methyl ester and
130 g of anhydrous potassium carbonate in 1.7 litres of anhydrous
tetrahydrofuran. The mixture was boiled under reflux for 18
hours while stirring. r~he tetrahydrofuran was evaporated in
vacuo and the residue treated with 600 ml of water. The prec-
ipitated product was extracted with two 600 ml portions of ethyl
acetate and the extract was washed with two 300 ml portions of
water, dried over magnesium sulphate and evaporated in vacuo.
rrhe residue was chromatographed on 1.5 kg of silica gel (Merck)
usin~ methylene chloride/ethyl acetate (9:1). rrhere was obtained
4-dimethylamino-3,5-dimethoxy-benzoic acid methyl ester of
~5 melting point 71-72C (recrystallisation from cyclohexane).
A suspension of 21.6 g of dime-thylsulphone and 7.7 g of
sodium hydride (50Yo dispersion in oil) in 80 ml of absolute
, ~ --~
~g~3~
dimethyl sulphoxide was stirred at 50C for 3 hours under
nitrogen and with the exclusion of moisture~ The mixture was
cooled to 30C and 15.6 g of 4-dimethylamino-3,5-dimethoxy-
-benzoic acid methyl ester were added. hfter stirring at room
temperature for 4 hours, 500 ml of water were added and -the
solution was made neutral wi-th glacial acetic acid. ~he prec-
ipitate was filtered off under suction, washed with water, dried
and recrystallised from ethyl acetate/cyclohexane. ~here was
obtained 4'-dimethylamino-3l,5'-dimethoxy-2-methylsulphonyl-
-acetophenone of melting point 111-112Co
A suspension of 24 g of ~'-dimethylam:ino-~',5'-dimethoxy-
-2-methylsulphonyl-acetophenone and 12~1 ~ of ~odium borohydride
in 260 ml of alcohol was stirred at room temperature for 16 hours,
a solution resultin~. After the addition of 260 ml of water,
the alcohol was evaporated in vacuo. The precipitate was filt-
ered oXf under suction, washed with water and recrystallised from
ethyl acetate. There was obtained 4-dimethylamino-3,5-dimethoxy-
-~-(methylsulphonyl-methyl)-benzyl alcohol of melting point
~47~148Co
A mixture of 3.3 g of sodium methylate, 8.9 g of ~-anilino-
-propionitrile and 15.7 g of 4-dimethylamino-3,5-dimethoxy-~-
-(me-thylsulphonyl-methyl)-benzyl alcohol in 40 ml of absolute
dimethyl sulphoxide was stirred at 50C under nitrogen for 2
hours~ ~he mixture was poured into 400 ml of water and the
resulting emulsion was extracted with two 400 ml portions of
ethyl acetate. 'rhe ethyl acetate extract was washed with two
200 ml portions of water, dried over magnesium sulphate and
evaporated in vacuo. AXter recrystallisation of the residue
from ethyl acetate, there was obtained ~-(anilino-methylene)-
~ .
,~ _.~ _
-4-dimethylamino-3,5-dimethoxy-hydrocinn~nic acid nitrile of
melting point 130-1~2C~
A solution of 1.29 g (56 mmol) of sodium in 200 ml o~
absolute alcohol was treated with 10 ~ (56 mmol) of guanidine
carbonate and 6 g (18.6 mmol) of a-(anilino-methylene)-3,5-
-dimethoxy-4-methylamino-hydrocinnamic acid nitr:i.le and boilQd
under re~lux ~or 20 hours. Subsequently, 200 ml of water were
added and the alcohol was evaporated in vacuo~ .~fter standing
at room temperature for 2 hours, the preci.pitat~ was ~:i.l-tered
off under suction, washed with water and .recrystallised ~rom
alcohol. I`here was obtained 2,4-diamino-5-(3,5-dimethoxy-4-
-methylamino-benzyl)-pyrimidine of mel-ting poin-t 204C.
~he startin~ material was prepared as follows:
A solution of 5006 g of ~-amino-3,5-dimethoxy-benzoic acid
methyl ester in 1 litre of absolute pyridi~e was treated during
30 minutes with 82 g o~ carbobenzoxy chloride while stirring
a~d/~ce-coolingO q'he mixture was stirred at room temperature
for 20 hours. The pyridine was evaporated in vacuo and the
residue treated with 1 litre of water and 3-N hydrochloric acid
up to a strongly acidic reaction. q1he result:ing emulsio.n was
extracted with two 1.5 litre portions of ethyl aceta-te. I`he
ethyl acetate extract was washed with two 800 ml por-tions of
water, dried over magnesium sulphate and evaporated in vacuoO
Arter recrystallisation Or the residue rrom ethyl acetate 9 there
was obtained 2,6-dimethoxy-4-(methoxy-carbonyl)~carbanilic acid
~03~
benzyl ester of melting point 132-133C,
A suspension of 3402 g of 2~6-dimethoxy-4-(methoxy-
-carbonyl)-carbanilic acid benzyl ester and 5.8 g of sodium
hydride ( 5~/a dispersion in oil) in 300 ml of absolute dimethyl-
formamide was stirred at room temperature for 4 hours. Theresulting solution was treated with 17 g of methyl iodide while
stirring and with ice-cooling. After stirring at room temper-
ature for 1 hour, the dimethylformamide was removed in vacuo
at 60C. Then, 1 litre Or water was added to t;he residue and
the emulsion was extracted with two 2 litre portions Or ethyl
acetate. 'rhe organic phaseR were washed with two 1 Litr~e ~ortions
of water, dried over magn~sium suLphate and evaporate~d ln VaCllO-
After recrystallisation of the residue from alcohol, -there was
obtained 2,6-dimethoxy-4-(methoxy-carbonyl)-N-methyl-carbclnilic
acid benzyl ester of melting point 1~0 1~1C.
A suspension of 3305 g of 2,6-dimethoxy-4-(methoxy-carbonyl)-
-N-methyl-carbanilic acid benzyl ester in 1 litre of methanol
was hydrogenated in the presence of 105 g of palladium on carbon
(5C/o) until the hydrogen uptake stopped. The suspension was
heated to boiling and filtered. The filtrate was evaporated in
vacuo and the residue recrystallised from cyclohexaneO There
was obtained 3,5-dimethoxy-4 methylamino-benzoic acid methyl
ester of melting point ~9-51~C.
~ suspension of 44.2 g of dimethylsulphone and 16 g of
sodium hydride (5~Yo dispersion in oil) in 150 ml Or absolute
dlmethyl sulphoxide was stirred at 50C for 4 hours under
nitrogen and with the exclusion of mois-ture. 30.4 g of 3,5-
~}`` ~7
7g~
-dimethoxy-4-methyl~mino-benzoic acid methyl ester were added
and the mixture was stirred at 80C for 10 minutes and at 25C
for 30 minutes. '~he mixture was then dissolved in 600 ml of
water and the solution was made neutral by the addition of
glacial acetic acidO The precipitate was filtered off under
suction, washed with water, dried and recrystallised from ethyl
acetate. ~here was obtained 3',5'-dimethoxy~4'-methylamino-2-
-methylsulphonyl-acetophenone of melting point 98-99C.
A suspension of 31 g of 3',5'-dimethoxy-L~'-methylamino-2-
-methylsulphonyl-acetophenone and 16.3 g Or sodium borohydride
in 600 ml of ethanol was stirred at room temperature for 16 hoursO
'~he ~olutlon was diluted with 600 ml O.r water and the ~lcohol
distilled off in VACUO. ~he crystals formed w~re filtered off
under suction, washed with water and dried. ~here was obtained
3,5-dimethoxy-4-methylamino-~~(methylsulphonyl-methyl)-benzyl
alcohol of melting point 141-142C.
A mixture of 2.7 g of sodium methylate, 7.3 g of ~-anilino-
-propionitrile and 12 g of 3,5-dimethoxy-4 methylamino-~-(methyl-
sulphonyl-methyl)-benzyl alcohol in 100 ml of absolute dimethyl
sulphoxide was stirred at 50C under nitrogen for 30 minutes and
then poured into 1 litre of water. The resulting emulsion was
extracted with two 1 litre portions of ethyl acetate. The ethyl
acetate extract was w~shed with two 500 ml portions of water,
dried over magnesium sulphate and evaporated in vacuo. After
recrystallisation of the residue from ethyl acetate, there was
obtained a-(anilino-methylene)-3~5-dimethoxy-4-methylamino-
-hydrocinnamic acid nitrile of melting point 150-152C.
~37
. ~
. A solution of 2~9 g of 2,4~diamino-5-(3~5-dimethoxy-4-
-methylamino-benzyl)-pyrimidine in 40 ml of l-N hydrochloric
acid was treated dropwise with a solution of 830 mg of sodium
nitrite in 10 ml of water while stirring and with ice-cooling.
The mixture was stirred for 3 hours at room temperature and then
sodium carbonate was added up to an alkaline reaction. ~he .. .
precipitate was filtered off under suc-tion, washed with water
and recrystallised from methanol. There was obtained 2,4~
-di~mino-5-~3,5-dimethoxy-4-(methyl-nitro~oamino)-benzyll
pyrimidine of meltin~ point 249-250C (decomposition)~
Example 22
A solution of 4.3 g of sodium in 1 litre of absolute
alcohol was treated with 33.6 g of guanidine carbonate and 21 g
f a-(anilino-methylene)-4-ethylamino-3 5-dimethoxy-hydrocinnamic
acid nitrile and boiled under reflux for 20 hours. After cooling,
1 litre of water was added and the alcohol was removed in vacuo.
The precipitate was filtered off under suction, washed with
water and recrystallised from alcohol. ~here was obtained 2,4-
- 20 -diamino-5-(4-ethylamino-3~5-dimethoxy-benzyl)-pyrimidine of
melting point 186-188C.
~he starting material was prepared as follows:
A suspension of 103 ~ of 2,6-dimetho~y-4-(methoxy-carbonyl)-
-carbanilic acid benzyl ester and 17.3 g of sodium hydride (50Yo
dispersion in oil) in 1 litre of absolute dimethylformamide was
stirred at room temperature for 4 hours and subsequentl~ treated
~3~
.. ~
with 56.2 g of ethyl iodide while stirring and with ice-cooling.
After stirring at room tempera-ture for 30 minutes t the dimethyl-
formamide wa~ removed at 60C in vacuo. ~hen, 1 li-tre of water
was added to the residue and the mixture was extracted with two
1.5 litre portions of ethyl acetate. The ethyl acetate extract
was washed with two 700 ml portions of water, ~ried over magnesium
sulphate and evaporated in vacuo. After recrystallisation of
the residue from alcohol, there was obtained N-ethyl-2,6-
-dimethoxy-4-(methoxy-carbonyl)-carbanilic acid benzyl ester of
melting polnt 85-86C~
A suspension of 77.5 g of N-ethyl-2,6-dimethoxy-~l-(methoxy-
-carbonyl)-carbanilic acid benz~l e~ter in 1 litre of methnnol
was hydrogenated in the presence Or 2 g of palladium on carbon
(5%) until the hydrogen uptake stopped. The suspension was
heated to boiling and filtered. '~he filtrate was evaporated in
vacuo. After recrystallisation of the residue from cyclohexane,
there was obtained 4-ethylamino-3,5-dimethox~-benzoic acid methyl
ester of melting point 50-51CD
A suspension of 58~4 g of dimethylsulphone and 21~2 g of
sodium hydride (5~/o dispersion in oil) in 200 ml of absolute
dimethyl sulphoxide was stirred at 50C under nitrogen and with
the exclusion of moisture for l~ hours. 'rhen, 4206 g of 4-
-ethylamino-3,5-dimethoxy-benzoic acid methyl ester were adcled
and the mixture was stirred at 80~C for 10 minutes and subsequent-
ly dissolved in 1 litre of water~ 'rhe solution was made neutralwith glacial acetic acid. '~he precipitate was filtered off
under suction, wa~hed with water, dried and recrystallised from
ethyl acetate. 'rhere was obtained 4'-ethylamino-3',5'-dimethoxy-
-2-methylsulphonyl-acetophenone of melting ooint 129-130C.
5~
3 -~
t,
A suspension Or 48 g of 4' ethylamino-3'95'-dimethoxy-
-2-methylsulphonyl-acetophenone and 23.8 g of sodium borohydride
i in 1 litre of alcohol was stirred at rocm temperature for 20
hours9 a solution resulting. After the addition of 1 litre of
water, the alcohol was evaporated in vacuo. ~he crystals formed
were filtered off under suction~ washed with water and dried.
There was obtained 4-ethylamino-3,5-dimethoxy~-(methylsulphon~1-
-methyl)-benzyl alcohol of melting point 121-122C.
A mixture of ~9 g of sodium methylate, 24.1 g of ~-
-anilino-propionitrile and 41.5 g Or 4-ethylamino-3,5-(iimethoxy-
-~-(methylsulphonyl-methyl)-benz~l alcohol in 200 ml of' a'bsolute
dimethyl sulphoxide was stirred uncler nitro~e~ at 50C for 20
minutes. ~he mixture was poured into 2 litres of water and the
resulting emulsion was washed with two 1 litre portions of water9
dried over magnesium sulphate and evaporated in vacuo. After
recrystallisation of the residue from ethyl acetate, there was
obtained ~-(anilino~methylene)-4-ethylamino-3,5-dimethoxy-hydro-
cinnamic acid nitrile of melting point 128-130C.
Example 2~
A solution of 1~95 g of sodium in 500 ml of absolute
alcohol was treated with 15.3 g of guanidine carbonate and 9.~ g
of 4 amino-~-(anilino-methylene)~3~5-dimethyl-h~drocinnamic acid
nitrile and boiled under reflux for 40 hours. 500 ml of water
were added and the alcohol was removed in vacuo. The precip-
itate was filtered off under suction, washed with water and
recrystallised ~rom methanol. ~here was obtained 2,4-diamino-
-5-(4-amino-395-dimethyl-benzyl)-pyrimidine of melting point
258~260C.
\, ~/
; ~3~76
~he starting material was prepared as fo]lows:
A suspension of 33 g of dimethylsulphone and 11 g of
sodium hydride (5~/o dispersion in oil) in 160 ml of absolute
dimethyl sulphoxide was stirred at 50C under nitrogen and with
the exclusion of moisture for 3 hoursO '~hen, 18 g of ~-amino-
~3,5-dimethyl-benzoic acid methyl ester were added. ~he mixture
was stirred at 80C for 30 minutes and at room tempera-ture for
1 hour and then dissolved in 400 ml of water. ~he solution was
made neutral with glacial acetic acid and the precipitate fil-
tered off under ~uction, washed with water, dried and recrystal-
lised from ethyl acetate~ ~here was obtained 4'-~mino-3',5'-
-dimethyl-2-methylsulphonyl-acetophenone of melting point
179-180C.
A suspension of 16~5 g of 4'-amino-3',5'-dimethyl-2-
-methylsulphonyl-acetophenone and 10.6 g of sodium borohydride
in 500 ml of alcohol was stirred at room temperature for 20
hours~ a solution resulting. After the addition of 500 ml of
water~ th~ alcohol was evaporated in vacuo and the mixture
extracted with two 1 litre portions of ethyl acetate. The
ethyl acetate extract was washed with two 500 ml portions of
water, dried over magnesium sulphate and evaporated in ~acuoO
After crystallisation of the residue from ether, there was
obtained 4-amino-3,5-dimethyl-~(methylslllphonyl-methyl)-benzyl
alcohol of meltin~ point 1~6-148C.
A solution of 14.6 g of 4-amino-3~5-dimethyl-~-(methyl-
sulphonyl-methyl)-benzyl alcohol in 50 ml of absolu-te dimethyl
sulphoxide was treated with 1.17 g of sodium amide, stirred for
,. . . : . . ,,., , - . .: . . .
~3
2 hours at room temperature, diluted wi-th 500 ml of water and
extracted with two 500 ml portions of ethyl acetate. The ethyl
acetate extract was washed with two 200 ml portions of water
and evaporated in vacuoq After recrystallisation of the residue
from cyclohexane, there was obtained 4-amino-3,5-dimethyl-benz-
aldehyde of melting point 75-76Cv
A mixture of 1.38 g of sodium methylate and 3.8 g of
4-amino~3,5-dimethyl-benzaldehyde in 30 ml of absolute dimethyl
sulphoxide was treated under nitrogen during 10 minutes with a
solution of 3.72 g of ~-anilino propionitrile in 30 ml of
absolute dimethyl sulphoxide while stirring a-t 55C and th~n
~tirred for 1 hour at 700a~ The solution was pollred into 1
litre of water and the resulting emulsion extracted with -two
500 ml portions of ethyl acetateO The ethyl acetate extract
was washed with two 300 ml por-tions of water, dried over ma~-
nesium sulphate and evaporated to dryness in vacuo. After
recrystallisation o~ -the residue from ethyl acetate, there was
obtained 4-amino-~-(anilino methylene~-3,5-dimethyl-hydro-
cinnamic acid nitrile of melting point 165-167C-
~
A solution of 0.69 g of sodium in 100 ml of absolutealcohol was treated with 504 g of guanidine carbona-te and 3 g
of ~-(anilino-methylene)-4-dimethylamino-3,5-dimethyl-hydro-
cinnamic acid nitrile and boiled under reflux for 20 hours.
200 ml of water were added and the alcohol was evaporated in
vacuo. ~he crystals formed were filtered off under suction,
washed with water and recrystallised from alcohol. ~here was
.,
~r 5e~
.
~D3~
obtained 2,4-diamino-5-(4-dimethylamino-3,5-dimethyl-benzyl)~
-pyrimidine of melting point 162-163C.
The starting material was prepared as follows:
50.4 g (0.4 mol) of dimethyl sulphate were added dropwise
during 20 minutes to a suspension of 18 g of 4-amino-3,5-
-dimethyl-benzoic acid methyl ester and 69 g of potassium
carbonate in 1 litre of absolute tetrahydrofuran while stirring
at room temperature. The mixture was boiled at reflux for 18
hours while stirring and then filteredO The filtrate was evap-
orated to dryness in vacuo. The residue was treated with 500 ml
of water and then extracted with two 300 ml portions Or et;hyl
acetate. The ethyl ac~tate e~tract was washed with two 150 ml
portions of water, dried over magnesium sulphate and evaporated
in vacuo. r~he residue was chromatographed on 500 g of silica
gel (Merck) using methylene chloride. ~here was obtained 4-
-dimethylamino-3,5-dimethyl-benzoic acid methyl ester as a
colourle2s oilO
A suspension of 240 5 g of dimethylsulphone and 9 1 g of
sodium hydride (5~/o dispersion in oil) in 5Q ml of absolute
dimeth~l sulphoxide was stirred at 50C under nitrogen and with
the exclusion of moisture for 3 hours and then treated with 16 g
of 4-dimathylamino~3,5-dimethyl-benzoic acid methyl ester. The
mixture WAS stirred at 80C for 45 mi~utes, cooled and dissolved
in 300 ml of water. ~he solution was made neutral with ~lacial
acetic acid. The precipitate was filtered off under suction,
washed with water and recrystallised from alcohol~ ~here was
obtained 4'-dimethylamino-3' 9 5'-dimethyl-2-methylsulphonyl-
~acetophenone of melting point 132-133C.
A suspension of 12 g of 4'-dimethylamino-3' 9 5'-dimethyl-
-2-methylsulphonyl-acetophenone and 6.6 g of sodium borohydride
in 300 ml of alcohol was stirred at room temperature for 20
hours, a solution resulting. After the addition of 300 ml of
water, the alcohol was removed in vacuo. ~he crystal~ formed
were filtered off under suction, washed with water and dried.
~here was obtained 4-d.imethylamino-3,5-dimethyl-~-(methyl-
sulphonyl-methyl)-benzyl alcohol of melting point 133-134Co
A mixture of 1.3 g of sodium methylate, 3.5 g of ~-anilino-
-propionitrile and 4~8 ~ of 4-dimeth~lamino-3,5~dimeth~1-a-
-(methylsulphonyl-methyl)-benzyl alcohol iXl 30 ml of a~solute
dimethyl sulphoxide was stirred R~ 50C f`or ~0 minutes. ~he
solution w~s poured into 1 litre of water and extracted with two
500 ml portions of eth~l acetate. ~he ethyl acetate extract was
washed with two 300 ml portions of water, dried over magnesium
sulphate and evaporated in vacuo. After recrystallisation of
the.re~idue from ethyl acetate, there was obtained ~-(anilino-
-methylene)-4~dimethylamino-3,5-dlmethyl-hydrocinnamic acid
nitrile o~ meltin~ point 195-196C~
S~
- . . ..
~ ~ 3~
Exam~le 25
Tablet ~ormulation:
2,4 diamino-5-(4-amino-~,5~dimethoxy~
benzyl)-pyrimidine-dihydrochloride 101.2 mg
SulYamethoxazol~ . 400 mg
Corn Starch 142 mg
r~alc 5 mg
Magne~ium Steara-te 1.8 mg
. rl'otal ~ lght650 mg
~ :"
s6~
~~ ~,
.. . . . .
