CA1055497A

CA1055497A - Process for the preparation of 2,4-diamino-5-(2-methyl-4,5-dimethoxybenzyl) pyrimidine

Info

Publication number: CA1055497A
Application number: CA257,351A
Authority: CA
Inventors: Nedjeljko Kujundzic; Krunoslav Kovacevic; Berislav Gluncic
Original assignee: Individual
Current assignee: Pliva Farmaceutika dd
Priority date: 1976-07-20
Filing date: 1976-07-20
Publication date: 1979-05-29

Abstract

ABSTRACT OF THE DISCLOSURE
The process relates to the preparation of 2,4-diamino-5-(2-methyl-4,5-dimethoxybenzyl) pyrimidine, which displays synergetic activity with sulfonamides in the control of coccidiosis in poultry and is available under the name of ORMETOPRIM.

Description

~6~SS~97 P L I V A
Pharmaceutical and Chemical Works A PROCESS FOR THE PREPARATION OF 2,4-DIAMINO-5-(2-METHYL-4 r 5-DIMETHOXYBENZYL) PYRIMIDINE

The process relates to the preparation of 2,4-diamino-5-(2-methyl-4,5-dimethoxybenzyl) pyrimidine, which displays synergetic activity with sulfonamides in the control of coccidiosis in poultry and is available under the name of ORMETOPRIM.

It is already known to prepare 2,4-diamino-5-(2-methyl-4,5-dimethoxybenzyl) pyramidine by (a) condensing 2-methyl-4,5-dimethoxybenzaldehyde with beta-methoxypropionitrile in the presence of sodium methylate in methanol and converting the obtained alpha-(2-methyl-4,5-dimethoxybenzylidene)-beta-metho~xy-propio-nitrile by boiling in methanol with sodium methylate for 24 hours to alpha-(2-methyl-4,5-dimethoxybenzyl)-beta, beta-dimethoxy propionitrile, which gives ormetoprim (Dutch pat. 6 514 178) by the condensation with guanidine;
(b) converting acetylthymine by bromination with N-bromosuc cinimide in chloroform in the presence of benzylperoxide to 2,4-diacetoxy~5-bromomethyl pyrimidine which is con-densed with 4-methylveratrole in the presence of HgC12 ~i in nitrobenzene to 2,4-dihydroxy-5-(2-methyl-4,5-dymethoxybenzyl) pyrimidine. By the chlorination of the obtained compound with POC13 in the presence of N,N-dimethylaniline, the 2,4~dichloroderivative is prepared and converted to ormetoprim by the treatment with alcoholic ammonia (Dutch pat. 6 514 743).

-- 1 -- . , - ,,, , ... .. . . ., ~......... . ~ ' .
, : , , . . :
, , ",, , .,,, . . , . i. - , . ... . .

~55497 We have ~ound that by the co~de~atio~ o~ the (2-meth~l-4,5 dimethoxybenzgl) cy~nocetic acid ~th~l ester or (2-meth~l-4,5_dimethoxybenzyl) malonic acid diethyl e~tsr with guanidi~e or urea the compou~ds o~ general fo~mula I
are obtained:

C~

~3ao~C~2--~

`wherein ~ and Y ha~e the meanihg of OH and/or ~H~ Free amino group~ are protected b~ the treatme~t with a~etic ~-:
an~ydride and thus compound~ of ge~eral form~la I are ob-tained, wherei~ ~ and Y ha~e the meani~g of OH and~or ~XCOaH3, which compounds are the~ co~erted to the compounds o~ general formula II b~ chlori~atio~ with phosphorous o~chloride or phoæphorous ¢hlorides.

~3ao ~
X300~C~2 ~Z

C~3 Cl II

, .

) :. ... . - ~, . . . ~. ..

.... , , ~ , , ' ' ,'" . ' - ' ' .
;' ~ ' , , , , . - , l~SS~97 wherein Z ~nd W have the mea~ing of Cl, ~2 and/or ~HCOC~3.
~he obtai~ed co.mpounds are co~verted b~ the amination with a~mo~ia to 2,4-dia~ino-5-~2_meth~1-4,5-dimethoxybenzyl)-6-chloropyrimidine, which is converted by the h~dro~enolgtic dechlorination with hydroge~ in the prese~ce of Pd/C to 234-diami~o-5-(2-methyl-4,5-dimethox~be~z~l)p~rimidi~e.
~he ~ondensation of (2-meth~1-4,5-dimethoxy~enzyl) c~ano-acetic acid eth~l ester sr ~2-methyl-4,5-dimetho2ybe~zyl) malonic a¢id diethyl ester with guani~i~e or urea i~ brought about b~ boili~æ in a lower alcohol i~ the pre~ence of sodium alko~ide~
~he chlori~ation with pho~phorous oxyoh~oride or phosphorous chlorides i~ carried out i~ th0 pre~e~ce of ~ dimethyl-a~ili~e a cataly~t in a~ organic ~olvent, ~uch as be~ze~e, toluene or xylene a~ the boiling poi~t of the reactlon mi~ :
ture for a period of 2 to 4 hoursO After the completion of the reaction the ex¢es~ of pho~phorous oxychloride and the ~olvent are removed by di~tillatio~ u~der reduced pres~ure, water i~
added ~o the residue, a~d the precipitate of the co.mpounds of ~eneral formula II, wherein Z a~d W heve the meaning of Cl and/or ~2~ i~ sucked of~. ~he compound~ ~herei~ Z a~d W ha~e the ~ea~i~g o~ al æ~ECOCE~ ~re obtai~ed b~ the addition of water under cooling to 0 to 5 aPter the ~olve~ a~d POC13 have been remo~ed b~ di~tillation.
~he aminatio~ i8 carried out in co~ce~trated aqueo~ ammonia i~ an au~o¢la~e ~t a temperature betwee~ 100 and 150C. It ha~ boe~ ~ound tha~ the be~t ~ield i5 achieved i~ the pre~ence o~ a ~our~old molar ex¢es~ o~ a~mo~ia ~d b~ carryi~g out th~
reacbion ~or 5 to 7 hour~0 ~he de~ihloxi~ation i~ carried out with h~dro~en u~der the pre~isure betwee~ 1 and 5 a~mo~phere i~ th0 pre~ence o~ 5%
Pd o~ cih æcoal in diluted meth~nol or etha~ol i~ the prese~ce ~. .

.

......... . . . .
. ,-, .' - ' ' . , , ., , , ..
''; . ' , ~ .

~OS54~3 _ 4 _ of an acid scavenger for bindi~g the ~ormed h~drochlor~
acid, ~uch a~ sodium or potassium h~droxide or acetate~
~hereby practicall~ quantitatiYe yields o~ o~metoprim are achieved.
~he advantage~ of the presen~ process reside i~ ths ~act that the reactions are ver~ simplc a~d result in ver~ high ~ields, that the i~termediateæ are well cry~t~llized ~ub- :
stances a~d the overall yield amo~nts to about 65 ~ ~f the theory, calculated o~ (2_meth~l-415_d~methoxybe~z~1) c~no-aceti¢ acid ethyl e~ter.
~he proces~ i~ illu~trated but in no way limited by the fol_ lowing Example~.

mixture of 9~56 g. (0.0784 mole) of gua~idi~e ~tr~te, eth~nolic solutio~ of sodium eth~late (prepar~d by dissolvi~g 4.37 g. of sodium i~ 80 ml. of ethanol) and 16.70 g. (0.0602 mole) of 2-.methyl-4,5-dim~hoxy~e~z~l) c~anoa~etio a¢id eth~l ester was hea~ed to bdling for ~ hours, the solvent was re-mo~ed bg di~tillatio~ under re~uced pressure~ water wa~ added to the re~idu~ and a~idified with 10 % hydro¢hlorid acid to p~ 3. ~he ex~racted precipitate wa~ ~ucked o~f a~d washed with water. ~hu~ there wsre obtained 16.7 ~. (95.5 %) o~

2~4-diami~o~5 (2-methyl-4~5_dim~thoxyb~nzyl) 6-~ydroxyp~rimidi~e, m.p. 277-27~C (~tO~_D M ~)O
xample 2 A mix*ure o~ 16.7 g~ (0.0575 mole) o~ 2,4-diami~o-5-~2-meth~l-4~5_d~me~ho~ybe~yl)_6_h~drox~p~rimidine, 9 9 5 ml~ (0.118 mol~
of ~gridine and 72 ml. o~ acctic anhydride was heated to boil_ ing for t~o hour~. ~he ~olve~ wa~ evaporated and the re~idue wa~ ~u~pended i~ ~ater and acidi~ied with 10 X h~ro¢hloric a¢id to p~ 5. ~he resulting precipit~te wa~ ~ucked o~, wa~hed ., ' -, ' : ' : -~ ' , : ' , ,:
'' S5~L~7 ~ 5 ~

with water and dried. ~hus there were obtained 20050 g~
(g6.2 %) of 2,4-diacetamido_5_(2~-meth~1_4,5_dimethox~be~zyl) _6-hydro~pyrimidine, m.p~ 280-281C (EtO~I _ DMF).
E~ample ~
mixture of 20.5 ~. (0.0547 mole) of 2,4-diacetamido-5-(2-meth~1_4~5_dimetho~ybenzyl)_6_h~dro~ypyrimidine, 2 ml.
of ~ dimeth~lanili~e, 2095 ml. of POC13 R~d 145 ml. o~
be~zene wa~ hea*ed to the boiling te.mperature ~or t~o hour~.
The axee~ o~ POC13 a~d benze~ewe~ evaporated u~der reduced preesure, water was added to the re~idue, and the separated pre¢ipitate was sucked of~- Thu~ thare were obtained 15~25 gO
(90.1 %) of 2,4-diami~o-~5-(2_math~1-4,5-dimethox~be~zyl3-6 chloropyrimidine, m.p~ 228~ (Et~ _ DM~).
~a~ .
mi~ture of 10.37 g. (0.032 mole) of (2_math~1-4,5-d~methoxyben-~yl) malonic acid dieth~l ester, 4.27 g. (0.035 mole~ of gua- -nidi~e ~itrate ~nd 67 ml~ (00067 mole) o~ a 1 ~ sodium eth~la~e solution wa~ heated to boili~g for two hour~, eth~nol wa~ evap-orated, water ~as added to the residue (50 ml.) ~d acidified b~ addition of h~droehloric aeid~ ~he ~epara~ed c~ystals were ~ucked oP~ and wa3hed with water. ~hus there wera obtalned 7.57 g. (81.5 Yo) of 2-ami~o-4,6-di~drox~-5-(2-meth~1-475-dimethoxyben~yl) p~rimidine, m.p. 298 - 300C (~t~ _ DMF)~
~he (2-meth~1_4,5_dimetho~ybenzyl) malonic acid diethyl ester wa~ prepared b~ first he~king 7.2 g. (0.05 mole) of 2~methyl 4,5~dimetho~7benzaldehyde, 6.7~ g. (0.042 mole) o~ malo~ic a¢id dieth~l e~ter7 0.54 ml. o~ piperidi~e and 25 ml. of ethanol for 20 hour~ a~ the bdling te.mperature, evaporati~g th2 sol-ve~t, re~oving piperidi~e with h~dro~hloric acid and recry~tal~
lizi~ the re~idue ~rom 96 % ethanol to obtain 10.5 g. (82.0 %) of (2-meth~1~4,5-dimethoxy~enzylidine) malo~ic a~id dieth~1 e~ter, m.p. 85 - 86C. ~he obtained compou~d ~a~ di~sol~ed in 50 ml~

. . , . . . " .
. .. .
.,, ~. . , ~ , . ............ . ..... . .
.. . . . , . , . ,, ~ , , ,. . : . , 1~3559~7 _ 6 _ of 96 % etha~ol and hydroge~ated under pre~sure of 2 atmo ~pheres at the te.mperature o~ 50C i~ the prese~ce of 1 gD
of 5 % Pd on charcoal, until the equivalent amou~t of ~-drogen was co~sumed. ~hus there were obtained 10.37 g.
(9801 %) of (2-.~ethyl-4,5-dimethoxybenzyl) malonic acid diethyl e~ter, ~.p. 43 - 45 C (petroleum ether).

Example 5 A mi~ture o~ 7.57 gO ~0~026 mole) of 2-amino-4,6_d~hydro~y-5-(2-meth~1-4,5-dimetho~ybenzyl) pyrimidi~e, 7~95 g. (00078 mole) of acetic acid anhydride and 6.28 ml. (0.078 mole) of p~ridine wa~ heated to the boiling point of the reactio~ mix-ture for two hours. ~he resulti~æ ~u~pensio~ wa~ evaporated to drynes~, the residue ~as suspended in wa~er, the ~epara~ed GryStal~ were ~ucked off and washe~ with dilutsd h~drochloric acid. Thu~ there were obtained 7.85 g. t90.5 %) o~ 2-acetyl- :
ami~o-4,6~dihydroxy_5-(2~methyl ~,5-dimethox~benzyl) pyrimi-dine, m~p. 310 315 a (D~ _ H20).

E~ample 6 ~ mi~t~re of 7~85 g. (0002~6 mole) of 2-acetamido-4,6-di-hyd~oxy_5_(2_methyl-~75_dimethox~benzyl) pyrimidine, 12~6 g~
(0.0825 mole) of POC13, 3~92 ml~ (0~0306 mole) of ~ dimeth~l-anili~e and 118 ml. ~f banze~e wa6 heated to the boiling tem- -per~*urs of the rea¢tio~ mixture for two hour~ ~he u~reacted P0~1~ wa~ deco.mpo~d b~ the addition o~ ice, the benze~e layer was ~eparated a~d the agu~ou~ la~er wa~ twioe r~extra¢tsd b~
be~zene. The ¢ombined ex*ract~ were wa~hed with a 5 % ~odiu~
hydrox~de ~olutio~ and water, then th0 ~olvent wa~ evaporated.
~h~ there were obtai~ed 7.07 g. (91~5 %) of 2-amino-4~6-di chloro-5_(2-meth~1_4,5 dimethoxybe~zyl) pyrimidine, m.p. 238 -- 240 a (~tO~).

- , , - , .
t ' ' "'. ' ' " ', ', .

, ', ~ ''',, ',,' ',', ' ' ', ' 1~55497 ExamPle 7 ~ mixture of 5.0 g. (0.015 mole) of 2-acetamido_4,6-dihydro-xy_5-(2-methyl-4,5_dimethox~benzyl) pgrimidine, 8.02 g.
(0.0525 mole) of phosphorou~ oxychloride, 2.5 ml. (0.0196 mole) of ~_dimethylaniline and 75 ml. of benzene wa~ heated at the boiling temperature of the reaction mixture for 2 hours.
~he reaction mixture was then evaporated to dryness under reduced pre~sure, the residue ~was suspended in water while cooling, the ~eparated crystals were sucked off and washed with water. ~hus there were obtained 4.54 ~. (79.0 %) of 2-acetylamino-4,6-dichloro_5_(2-meth~1-4,5~dimethoxybenzyl) pyr; mi dine, m.p. 203 - 205 C (EtOH).

ExamPle 8 ~ odium eth~late solution prepared by dis~olvi~g 3.66 g. of ~odium in 72 ml. of ethanol was added dropwi~e at the boiling temperature within two hours to a ~olution of 20.0 g. (0.0722 molé) of (2-methyl_4,5_dimethoxybenzyl) cyanocetic acid eth~l ester and 6.48 g. (0.108 mole) of urea i~ ~4 ml. of ab~olute ethanol a~d then heating wa~ continued for another period of 6 hour~. ~he al¢ohol wa~ evaporatod, water wa~ added to the r0~idue and a¢idified by adding diluted h~drochlori¢
acid. ~he separated pre¢ipitate wa~ su¢ked off, wa~hed with water and dried. ~hu~ there were obtained 20.67 g. (98.5 ~) of 4-amino-2,6-dihydrox~-5-(2-methyl_4,5-dimethoxyben~yl) ~rimidine, m.p. 289 _290 C (EtO~ _ DMF).

Ex~m~le 9 mixture of 20.67 g. (0.071 mole) of 4-amino-2,6-d~hydroxy-5-(2-methyl-4,5-dimethoxybenzyl) pyrimidine, 22.2 ~1. (0.235 mole) o~ aceti¢ acid anhydride and 85 ml~ ~1.055 mols) o~ pyridine was heated at the boiling temperature for 7. hour~.~fter evaporation to dr~-. , .. . .. . - , . - - .. . . . ~

1~35S4~37 _ 8 _ n~ under reduced pre~ure the re~idue wa~ ~uspended in diluted h~drochloric acid, the resulti~g precipitate was sucked off, washed with water and dried. Thu~ there were obtained 23,15 g. (97.9 %~ of 4_acetylami~o_2j6-dihydroxy-5_(2_meth~1_4,5_dimethoxybenz~1) pyrimidine, m.p. 268 -_ 269 C (~tOH _ DMF).
~a~
Analogou~ly to the procedure de~ribed i~ ~xample 6 ther~
wa~ obtained with a ~ield of 71~1 % 4-amino-2,6-dichloro-5-(2-meth~1~4,5_dimethoxybenzyl) pyrimidi~e, m.p~ 195 - 197 C ~EtO~ _ D~F) from 4-acetamido 2~6-dih~droxy-5-(2-meth~1-4,5-dimethoxy~enzyl) pyrimidine.

Example 11 A mi~ture of 20~0 g~ (0.0615 mols) ~f (2-methy1_4,5_dimethox~-be~zgl) malonic acid dieth~l e~ter, 4~05 ~. (0.0671 mole) of urea and 67.1 ml.(O.0761 mole) of a 1 ~ ethanolic ~olu~ion o~
~odium ethyla~ were hea~ed to boili~g for ~wo hour~, ethanol was e~aporated~ the ra~idue wa~ di~olved in 60 ml. o~ w~er and acidi~ied b~ the additio~ o~ hydro~hloric a¢id. The ~ep-arated cry~tals ~ere ~uGked of~ and wa~hed with water. ~hus there wer~ obtained ~3.6 ~. (75~9 %) of 5_(2_meth~1_4,5_di-methox~b~nz~l) barbituri¢ acidg m.p. 185 - 187 C (~tO~).

Example 12 ~nalogousl~ to the proce~ure de~cribed ln Ex~mple 6 there was obtained with a ~ield o~ 61~2 % 2~-trichloro-5-(2-meth~1-4.5-dimethox~be~zyl) p~rimidi~, m.p. 159 _ 16~ a (EtOH) ~rom 5-(2-methyl~4,5-dimethoxybenz~l) barbituric acid.

. ,: . , - . . . .. . . . . . . . .

, .: .,, , ~ ~, ... ... . ..
, . . . . . . .. . . . .
., , ~ ~ . -.,, , ~ , , ~ -; , ,"" , ,, ~ ,: ' "., ', . . . .
,. . . . . .
"
, . . . . . . .

~ss~

A mixture of 7.07 g. (0.0215 mole) of 2-am~no~4,6-dichloro-5-(2 methyl-4,5_dimetho~ybe~2yl) p~rimidin~ and 50 ml. of a 25 % aqueous ammonium h~droxyde solutio~ were heated with ætirring in an autocla~e at the tempera~ure of 130 C for 6 hour~. After cooli~g to O C~ the ~eparated product wa~
~ucked of~ and wa~hed with w~or~ ~hu~ there were obtained 6.0 gO (9004 %) o~ 214-diamino-5_(2_meth~1_4,5_dimethoxy- -benzyl)-6_chlorop~rimidine, m.p. 228 ¢ (80 % Et~

Example 14 Analogou~1~ to the pxocedure de~cri~ed in Exampl~ 13 there wa~ obtained, with a ~ield o~ 89 %, 2,4-diami~o 5-(2-methyl-4,5-dimethoxybenz~ 6_chloropgrimidine, mOp~ 228 C (80 % E
EtOH)9 from 2-acet~lamino-4,6-di~hloro-5-(2-meth~1-4,5-di-methoxy~ez~l) p~rimidi~e~
~ ,-~nalogouæly to the procedure described i~ Example 1~ there : -was obtained with a ~ eld o~ 79.1 % 2,4-diami~o_5_(2_methyl- :
4,5_dimetho~be~z~1)-6_¢hloropyrimidine, m~p~ 228 QG (EtOE _ DMF) from 4-~mi~o-2,6-di¢hloro-5_(2-meth~1-495-dimetho~ybenæ~l) -p~rimidine~

Exam~le 16 ~nalogou~l~ to the procedure described in Example 13 there wa~ obtained with a ~ield of 82.4 % 2,4-diamino~5~(2-meth~
4,5_dimethox~e~z~ 6_chloropyrimidine; m.p. ~28 C (EtOH - -DMF), from 2,4,6-trichloro-5_(2-methgl-4,5-dimetho~enz~l) pgTimidine.

.

, ~ ,, . . . , , ., . " .
,, ". : - ,. . .
, . ~ - ~ , . , . . , , :, . ...
,. . .. .. . .. . ..
, ~ , , . , , : , . . . .. . . .
, , .
" :' ,, ,' ' ', . ,, ' , ,, ,' ', ' '' ' , ' ':, ', ,' ,,, " ' " , ' , ; ' " ' ' .', '' , . ', , , . ' , . . .
~ , . .. . . . .
: , . . . .

1~554 - 10 _ Example 1 7 A mixture of 5.0 g. (0.0162 mole) o~ 2,4-diami~o_5-(2-methyl-4,5-dimethox~benzyl)_6-chlorop~rimidine, 300 mlO of 80 % ethanol, 103 g. ~0~0325 mole) o~ sodium hydrox~de and 1.0 g. of 5 % palladium o~ activated charcoal was hydrogerlat;ed for three hours under the pre~slLre of 4 a~mospheres at the te.~-perature oî 7O C. l~ter cooli:ag, the cai;al~st was sucked off ~ d the filtrate wa~ e~Taporated to dry~ess b;sr the distillation under reduced press~re. The residue wa~ ~u~pe~ded in water and the precipita~e of 2,4-diamino-5-(2_methyl-4,5_dimethoxy-banz~l) pgri~idine was sucked off~ ~here were obtai~ed 400 g.
(90.0 %) of the product~ m.p. 234 C (80 % ~tOE).
~a~
Analogou~1~ to the procedure de~eribed i~ Example 7 there was obtained from 2,4-dia¢etamido-5-(2-meth~1-4,5-dimetho~y-benæ71)-6_h~droxypgrimidine the corresponding 6.chloro deriv-a~ive.

Analo~ou~l~ to the procedure d~scribed in ~xample 7 there was o~tain~d ~rom 4-a¢atamido-276-dihydrogy_5-(2_meth~1_4,5 dimetho~y~enzyl) pyrimidine the correspo~di~g 2,6-dichloro de-rivative.

, .-...... : :. .... ,: , ~ : :
~, . . . .... . . . .
, :, , ., . ' : , , .. . .

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of 2,4-diamino-5-(2-methyl-4,5-dimethoxybenzyl) pyrimidine which comprises condensing (2-methyl-4, 5-dimethoxybenzyl) cyanocetic acid ethyl ester or (2-methyl-4,5-dimethoxy-benzyl) malonic acid diethyl ester with guanidine or urea to give a compound of general formula I:

I¦

wherein X and Y are the same or different and are selected from the group consisting of -OH and -NH2, protecting therein the free amino groups by acetylation with acetic anhydride whereby these groups are converted to -NH COCH3, and converting said compound to a compound of general formula II by chlorination with phosphorous oxychloride or a phosphorous chloride II

wherein Z and W are the same or different and are selected from the group consisting of -C1, -NH2 and -NHCOCH3; and converting said compound of formula II by amination with ammonia to 2,4-diamino-5-(2-methyl-4,5-dimethoxybenzyl)-6-chloropyrimidine, and catalytically dehalogenating said 2,4-diamino-5-(2-methyl-4,5-di-methoxybenzyl)-6-chloropyrimidine.

2. A process according to claim 1, wherein the condensation is carried out in a lower alcohol in the presence of a sodium alcoholate at the boiling temperature of the reaction mixture for 2 to 6 hours, the solvent is evaporated, and the residue is treated with dilute hydrochloric acid to give the compound of formula I.

3. A process according to claim 1, wherein the acetylation is carried out in the presence of pyridine by heating the reaction mixture at boiling temperature for 2 to 7 hours, the reaction mixture is evaporated to dryness under reduced pressure to leave a residue, and the residue is treated with diluted hydrochloric acid.

4. A process according to claim 1, wherein the chlorination is carried out with phosphorous oxychloride, phosphorous trichloride or phosphorous pentachloride in benzene, toluene or xylene in the presence of N,N-dimethylaniline as catalyst by heating the reaction mixture at boiling temperature for 2 hours.

5. A process according to claim 1 or claim 4, wherein, upon completion of the chlorination reaction, the excess of the chlorination agent is decomposed by addition of ice, the organic solvent layer is washed with a diluted sodium hydroxide solution, and the solvent evapora-ted to give 2,4,6-trichloro-5-(2-methyl-4,5-dimethoxybenzyl) pyrimidine or 2-amino-4,6-dichloro-5-(2-methyl-4,5-dimethoxybenzyl) pyrimidine.

6. A process according to claim 1 or claim 4, wherein, upon completion of the chlorination reaction, unreacted phosphorous oxychloride and organic solvent are evaporated to leave a residue, which is taken up with water and sucked off to give 2,4-diamino-5-(2-methyl-4,5-dimethoxy-benzyl)-6-chloropyrimidine or 4-amino-2,6-dichloro-5-(2-methyl-4,5-dimethoxybenzyl) pyrimidine.

7. A process according to claim 1 or claim 4, wherein, upon completion of the chlorination reaction the reaction mixture is evaporated to dryness under reduced pressure to form a residue, ice is added to the residue to form crystals, the temperature of the reaction mixture being kept below 0° C, and the separated crystals are sucked off to give 2-acetamido-4,6-dichloro-5-(2-methyl-4)5-dimethoxybenzyl) pyrimidine, 2,4-diacetamido-5-(2-methyl-4,5-dimethoxybenzyl)-6-chloropyrimidine or 4-acetamido-2,6-dichloro-5-(2-methyl-4,5-dimethoxybenzyl) pyrimidine.

8. A process according to claim 1, 3 or 4 wherein said compound of formula II is aminated with a concentrated aqueous ammonia solution in an autoclave at a temperature from 100°C to 150°C for 6 hours in the presence of a fourfold molar excess of ammonia.

9. A process according to claim 1, wherein 2,4-diamino-5-(2-methyl-4,5-dimethoxybenzyl)-6-chloropyrimidine is dehalogenated with hydrogen in the presence of 5% palladium on charcoal at a temperature between 20°C and 80°C under a pressure of from 1 to 5 atmospheres in diluted methanol, ethanol or propanol in the presence of an agent, such as sodium or potassium hydroxyde or acetate, for removing the formed hydrochloric acid.