PROCEDE INDUSTRIEL D'OBTENTION D'ESTERS D'ACIDE 3-ACYLAZO-PROPIONIQUE ET ISOMERES AINSI OBTENUS

PROCESS FOR THE MANUFACTURE OF 3-ACYLAZO-PROPIONIC ACID ESTERS AND ISOMERS THEREOF

Abrégé anglais

3-Acylazo-propionic acid esters of the general formula
I
<IMG> (I)
and isomers thereof (in which R1 represents C1-C6-alkyl and
R2 represents alkoxy or amino), suitable as starting
materials for the manufacture of 1,2,3-thiadiazole-5-car-
boxylic acid derivatives, are prepared by a process which
comprises reacting an acrylic acid ester of the general
formula H2C = CH - COOR1 with a hydrazine derivative of the
general formula H2N - NH - CO -R2 to form a 3-acylhydra-
zino-propionic acid ester of the general formula
<IMG>
and oxidizing this ester in an inert solvent with an
oxidizing agent.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WMICH AN EXCLU-
SIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of a compound se-
lected from a 3-acylazo-propionic acid ester of the general
formula I
<IMG> (I),
in which R1 represents a C1-C6-alkyl group and R2 represents
an alkoxy group or an amino group, and isomers thereof of
the general formula V
<IMG> (V),
in which R1 and R2 have the meanings given above, and of
the general formula VI
<IMG> (VI),
in which R1 and R2 have the meanings given above, which com-
prises reacting an acrylic acid ester of the general formula
II
<IMG> (II),
in which R1 has the meaning given above, with a hydrazine
derivative of the general formula III
H2N - NH - CO - R2 (III),
in which R2 has the meaning given above, to form a 3-acyl-
hydrazino-propionic acid ester of the general formula IV
<IMG> (IV),
. 25 .

in which R1 and R2 have the meanings given above, and oxi-
dizing this compound of the general formula IV in an inert
solvent with an oxidizing agent.
2. A process as claimed in claim 1, wherein R2
represents a C1-C4-alkoxy group.
3. A process as claimed in claim 1 or 2, wherein
the reaction of the acrylic acid ester of the general formula
II with the hydrazine derivative of the general formula III
is carried out in an inert solvent.
4. A process as claimed in claim 1, wherein the
reaction of the acrylic acid ester of the general formula
II with the hydrazine derivative of the general formula III
is carried out in the presence of a catalyst.
5. A process as claimed in claim 4, wherein the cata-
lyst is a basic or an acidic catalyst.
6. A process as claimed in claim 1, wherein the
reaction of the acrylic acid ester of the general formula II
with the hydrazine derivative of the general formula III
is carried out at a temperature within the range of from
-20°C to 150°C.
7. A process as claimed in claim 6, wherein the
temperature is within the range of from 0°C to 50°C.
8. A process as claimed in claim 1, wherein the reac-
tion of the acrylic acid ester of the general formula II
with the hydrazine derivative of the general formula III is
carried out at a pressure within the range of from 1 to 10
atmospheres.
9. A process as claimed in claim 8, wherein the
. 26 .

pressure is 1 atmosphere.
10. A process as claimed in claim 1 or 2, wherein
approximately equimolar amounts of the acrylic acid ester of
the general formula II and of the hydrazine derivative of
of the general formula III are used.
11. A process as claimed in claim 1, wherein the
oxidation of the 3-acylhydrazino-propionic acid ester of
the general formula IV is carried out with a conventional
oxidizing agent at a temperature within the range of from
-20°C to 100°C.
12. A process as claimed in claim 11, wherein the
temperature is within the range of from -5°C to 50°C.
13. A process as claimed in claim 1 or 2, wherein
the 3-acylhydrazino-propionic acid ester of the general
formula IV is not isolated from the reaction mixture in which
it is formed, and the formation of this ester and the oxi-
dation thereof is a continuous process.
14. A process as claimed in claim 1, wherein a
resulting compound of the general formula I is rearranged
to form a compound of the general formula V and/or a com-
pound of the general formula VI by treatment with a
catalyst.
15. A process as claimed in claim 14, wherein the
catalyst is an acid or a Lewis acid.
16. A process as claimed in claim 14, wherein the
catalyst is a base.
17. A process as claimed in claim 14, 15 or 16,
wherein the rearrangement is carried out in a solvent.
.27.

18. A process as claimed in claim 14, wherein the
rearrangement is carried out at a temperature within the
range of from -20°C to 50°C to form a compound of the general
formula V and a compound of the general formula VI.
19. A process as claimed in claim 18, wherein the
temperature is within the range of frorn 0°C to 30°C.
20. A process as claimed in claim 1, wherein a
resulting compound of the general formula I is reacted with
thionyl chloride of the formula SOCl2 to form a 1,2,3-thia-
diazole-5-carboxylic acid derivative of the general formula
VII
(VII),
<IMG>
in which R1 represents a C1-C6-alkyl group.
21. A process as claimed in claim 20, wherein the
reaction is carried out at a temperature within the range
of from -20°C to 100°C.
22. A proeess as claimed in claim 21, wherein the
temperature is within the range of from -5°C to 50°C.
23. A process as claimed in any one of claims 20,
21 or 22, wherein the molar ratio of the compound of the
general formula I to the thionyl chloride used for the re-
action is 1 : 3.
24. A process as claimed in claim 1, wherein a re-
sulting compound of the general formula V and/or a resulting
. 28 .

compound of the general formula VI is/are reacted with
thionyl chloride of the formula SOCl2 to form a 1,2,3-
thiadiazole 5-carboxylic acid derivative of the general
formula VII
(VII),
<IMG>
in which R1 represents a C1-C6-alkyl group.
. 29.

Description

~ ~62~
Process for -the manufacture of 3--acylazo-propionic
acid esters and isomer~ thereof
_ .
The present invention 18 co~cerned with a ~ proces~
~or the manufacture o~ ~-ac~lazo-propionic acid e~ters and
also isomers thereof including the i~omeric ~ormylacetic
ac~d e~ter acylh~d~azone~ ther~o~
Proces~es ~or the manu~acture o~ formylacetic acid
ethyl e~ter ~emicarbazone ~W. Wi~licenus, H.W. Bywaters,
~iebig~ ~n~ Chem. ~56, 50 (1907)] and formylacetic acid
ethyl ester ethoxycarbonylhydrazone ~R. Raap, Ro~ Nicetich,
CanO J. of Chem. 46,1057 (1968)] are already kno~n~ ~he~e
compound~ can be ma~u~actured by reacting the ~odium sal~
of the ~o~myl~cetic acid ester in questio~ with the corres~
ponding h~drazine derivative, which proce6s require~ the
synthe~is and i~olation oi the formylacetic acid e~ter
~odium salt. The latter can, howe~er~ be manufactured
only b~ u~ing oomplicated ~nd le~thy ~orking proceduree
~ and, mor~over, only ~ un~atls~actory ~ield~ (Germa~
Patent ~pecificatio~ ~o, 708,51~; Britiah Patent Speci-
.- ~icatio~ No. 568,~12)~
The problem upon ~hich the present inve~tion i~ based
ha~ therefore bee~ to pro~ide a proces~ thst permit~ the
manufacture o~ 3-acylazo-propionic acid e~ter~ a~d als~
the isomer~ ther~oi in a technicall~ ~imple manner and
- ~n high ylelds~
Thi~ problem is now ~olved according to the proce~s
o~ the prese~t inventio~.
~he pre~ent inventio~ accordingly provide~ ~ proce~8
~or the manu~acture o~ a compou~d selected ~ro~ a ~-acylazo-
Y ~

~ 29
r 3 ~
propionic acid e~t0r of the general :~ormula I
~2 ~ C~ ~ C~l
(I~ g
CO - R;2
in ~hich
~1 repres~lts a ~1-C6-alkyl group arLd
5 ~2 repre~ents ~ alko~:y group, preferably a Cl-C4-alko2~r
group, or a~l amino group~
and i~omer~ thereo~ o~ the general ~ormu:La V
~E - OH2 - COOR
11 (Y),
11 ;~ ~ - CO - R~
in which R~ d ~2 1~ the mear~ g~ giY~n above9
1(:) alld o~ the gen~ o~n~la VI
0
'- I (VI)., ,
CO -- ~2
i~ ~hich ~tl and :a2 have the m~anin~gs given abo~e"
which comprises reacting an aeryli~ acid ester o~ the
general f ormula II
/ c = a - ~OORl ( II 3

~ ~62
-- 4 ~
i~ which Rl ~BS the meaning given aboYe~ with a hgdrazine
deri~atlv~ o~ th~ ge~ral formula III
~2~ ~ NH - CO ~ R2 (III~,
in which R2 has ~he meanin~ given abo~e, i* deæir~d with
the uae of an i~ert ~ol~ent and/or i n the presence op a
cataly~t, to form a 3-acy-hydra~ino-proplonic acid ester
of the general formula I~
~2 ~ COO~
- CO -- R2
in whlch Rl and R2 ha~e the meaning~ given above, and
og~dizin~ thi~ compound o* the gelleral ~ormula IV in a~
inert 801vent with an o:cidi~ snt.
As alkyl group~ there mag b~ mentloned,~or e:2tampls,
methyl, eth~l, prop~ oprop~l, n-but~ ec~-but~l,
n-pentyl and n~heæyl grOUpB.
A~ alko~ group~ there ~ be ment~o~ed, ~or egamp~,
metho~y, etho~y, propo~y and buto~y group~.
The proce~ 4~ th~ pre e~t in~e~t~o~ thu~ make~ use
o~ readil~ aYaila~le ~tarting ~aterials and make~ po~sibl~
a technically slmpl0 and ~a~e manu~actur~ oY the desir~d
proGes~ product~ ~n hTgh yi91d~.
Particular em~odiment~ o~ th~ proce~ o~ the pre~ent

9 '~ ~
invention consists in that, the reaction of the acrylic acid
ester of the general formula II with the hydrazine derivative
of the general formula III is carried out at a temperature
within the range of from -20C to 150Ct preferably within
the range of from 0C to 50C, and a-t a pressure within the
range of from 1 to 10 atmospheres, preferably at 1 atmosphere,
if desired as a base- or acid-catalysed reaction and that
approximately equimolar amounts of the acrylic acid ester
of the general formula II and of the hydrazine derivative
of the general formula III are used, and that the oxidation
of the 3-acylhydrazino-propionic acid ester of the general
formula IV is carried out wi-th an oxidizing agent, for exam-
ple a conventional oxidizing agent, at a temperature within
the range of from -20C to 100C preferably from -5C to
50C, and that a 3-acylhydrazino-propionic acid ester of
the general formula IV is used which is not isolated from
the reaction mixture in which it is formed, so that the
formation of this ester and the oxidation thereof may be a
continuous process.
The process of the present invention is carried out
in a technically simple and elegant manner.
The synthesis of the 3-acylhydrazino-propionic acid
~5 esters of the general formula IV may be carried out according
to the process of the present invention starting with an
acrylic acid ester of the general formula II and reacting
it with an approximately equimolar amount of a hydrazine

~ 6
derivative o~ the general formula III i~ an aqueou~
medium, in an i~ert organic ~olvent, pre~Eerably i~ an
aqueou~ or alcoholi¢ medium, or9 i~ de~irea, e~en u9ing
no solvent at all. Advantageou31ys the acrylic acid
e~ter i~ added, in portion~ or diluted with a ~olvent,
*or esa~ple a Cl-C4-alcohol~ to a ~olutio~ o~ the hydra-
zine component which i~ diluted with wa~er or a Cl~C4--
alcohol~ In ~o doing~ ~he mixing ra~io o~ alcohol/water
can var~y within wide limi~ ince both alcohol on it3
own and water on its 4Wn Ca~ be uaed. ~he ratio b~ weight
o~ alcohol/water can preferably be l lo The reactanto
may al~o be added 1~ the reverse oraer~
~ he reaction takes place at temperatureo o~ ~ro~
-20~ to 150~C, preferably from 0C to 50C. ~he pres~urc
can be ~rom 1 to 10 atmosphere~, preferably~ howe~r~ 1
~ atmo~phere~ Solvent~ that are in.ert with re~pect to the
reacta~t~ are, for e~ ~ ple, al~C4-alcohol~ ~or e~ample
m~thanol9 ~hanol, propanol9 l~opropanol, butanol, sec,-
butanol and tert.-butanol~ halogenatoa hydrocarbons 9
~or e~ample meth~len~ chloride, c~ oro~orm and carbon
tetrachlorlde, aliphatic and aro~at~c hydrocarbon~, for
e~ample petroleum ether~ pentane, c~clohe~ane~ benz~ne,
toluene a~d ~yle~e~ ethers, ~or a~ampl~ diethyl eth~rv
tetrahydro~ur~n, dio~an and ethylene glycol diethyl ether7
27 carbo~ylio acid nitriles, for e~ample acetonitrile, and
carbox~lic acid ~m~de~, for e~ample dime~thylformamldeO
The reaction may be carried out advan~ageou~l~ u~ing
.
... .. .. .. ... . .. . .. . ..

a ba~ic or alternativelg an acidic catalyst. ~8 ba~i~
cataly3t~ there are mo~t ~requently used alkali hydro~ide~,
alkali alcoholates, tertlary am~ne~ for ~xample triethyl-
ami~e and ~gN-dimethylaniline~ benz~ltr~.alkyl ammonium
5 hydroxide~9 for example be~zyltrimethyl ammonium hydro~ide~
and dialkylcarbox;ylic acld amides, for example dimethgl
~ormamide and dimethylacetamide. ~or the acidic catalyeis
there ~a~ be u~ed sulph~ric acid, phosphoric acid, acetic
acid~ lactic acid and boroll trifluorlde~
10After the reactio~ ha~ taken place the reaction mix-
ture i~ worked up, i~ desired in a manner ~now~ ~r se~
~ter an~ solvent ha~ been removed~ the re~idue iB either
fractionally di~tiiled under reduced pres~ur~ or recry-
stallized ~rom uitable ~ol~ent~, ~or e~ample ~etone~,
alcohols, nitrile~, e~ter~, ether~ a~d chlorinated ~ydro-
carbons, ~or example acetone, met~ ol, ethanol~ aceto~ -
nitrile; ethgl acetat~, dii~oprop~l ether an~ chloro~orm~
The reaction product8 are obtai~ed i~ the ~orm o~ eolour- -
le~s cr~tals or a~ ~olo~rle~s liqu:Lds that are stabl~ at
-~ . 20 room temperat~re~
~ hen~ howe~er~ a continuou~ proces~ i~ choseD~ ths
r~ac~ion product of the ~neral ~ormula IV doe~ not ~eed
to be ~olated, but oan be ~urther processed direc~ly.
~ he ~-acylazo-propionic acld esters o~ the ge~eral
~ormula I ma~ then be produGed aocording to the process o~
the present invention by reacting the ~-acylhydrazino-
propion~c acid e~ter~ o~ the general ~ormula IV with
.. . .... .

3 1g~29
co~entional o~idizing agents in an aqueou~ medium, or in
organic ~ol~ent~ that are inert with respect to the reac-
tant~, the o~idizi~g agent~ being u~ed either in ~toichio-
metric amount~ or in e~cess.
Advantageou~ly, the oxidizing agent i~ added~ i~
portion~ aa an aqueou~ ~olution or alternati~ely diluted
with a solvent~ to a 801utlon of the 3-acylhydrazino-
propionic acid ester which i8 ailuted with water or a
801vent. ~he reactantY may a1YO be added in the rever~e
~ O order~ ~his reactios step -take~ place at temperature~
withi~ the ran~e o~ from -20a to 100C, preferably ~rom
-5C to 50C. ~he reaction time ca~ be betwee~ 0~5 hour ~nd
: 5 hour~ depending o~ the reaction temperature.
The ~ollowing may be mentioned a~ solvent~ that ar~
inert with re~pect to the reacta~tis: aliphatiio a~d aro-
matic h~drocarbon~, for ~xample cyclohe~ane, heptane,
ligroin, benzene, toluene and ~ylene, and halogenat~d
~ hydrocarbons, ~or example chlorobe~zene, meth~lene chloride~ ~
chloro~orm, carbon tetrachloride ~nd 1,2-dichloroethane.
- 20 In the pre~ence o~ these 901~ent~, ~urther proce~ing
can be carried out even with the crude ~olutions~ ~ince
the~e ~ol~en~s al~o behavc i~ an inert manner in the
following opt~onal steps.
The ~ollowing may be mentioned as eæamples o~ conven-
tional oxidizing agent~ which corre3pondingl~ determi~
the choice o~ solvent : nitric aoid, potassium dichromate~
potassium permangana~e~ mercury o~do~ ammonium nitrate and

~ 39~
_ g _
~odium ~itrate~ sodium chlorate~ chlorine, alkall metal
hypochlorite~ and alkall~e earth metal hypochlorite~
ammonlacal hydrogen pero~id~g iron(III) chlorida, dinitro-
gen trio~ide and lead(IV) o~idaO
S ~ter the reactio~ ha8 taken place,the reac-tion
mixture may be worked up i~ a manner known ~r ~ , ~or
e~ample by distilli~g o~f the ~ol~nt used at a reduoed
or normal pressure or by e~tractio~, it being possible to
us~ th0 org~c 801vent~ employed in the cour~e o~ the
reac~ion also a~ agent~ for e~tracting the 3-acylazv~
propio~ic acid ester~. The e~tract~ may the~ be worked
up in a known man~er9 ~or e~ample a~ter ~uitable drying
by di~tilli~g o~f the 301vent ~3ed at normal or a reduced
pre3sur~ In thi~ manner the 3-acylazo-propionic acid
ester~ are obtained in the form o~ ~lightly yellow
coloured cry~tal~ or oils in an e:~tremely pur~ for~`a~d in
very high yields9 80 that they c~ be rea~ted ~ithou~
~urther puri~cation. ..
~y the o~idatio~ o* the ~-acylhydrazino-propionic-- 20 acid e~ter~ of the general ~ormula IV, primary compound~ o~
the ~tructural general ~ormula I are ~ormed a~ can be ~ee~
by e~amining th~ nuclear magnetic resonanc~ speotra~
In ~olution the~e compounds have the tendency to
rearrang~ to ~orm ~orm~laoetic acid ester acylhydrazones
of the genaral ~ormula V

1 16~9.~6
~H -` CE2 - C~l
Il (V~,
ao - ~2
which accordillgly repre~ent i~omere o~ the compound~ o~
thc general ~ormula L
The manafacture oi the compound~ o~ the general
~ormula V9 that i~ the iormylacetlc acid e~ter ac;ylhydra
zo:aesll is there~ore 2180 included within the scope o~ the
prese~t i~ventio~.
The compound~ o~ the general Iormula V areg on the
o~her ha~d, in an isomeric equilibriun with compound~ o~
the general formula VI
C~I = C:~ - COO~
", I ~VI),
~ ~ CO -- ~2
the manu~acture o~ which is there~ore also i~cluded wi~hin
-- the scope of the preserlt invent~on.
I~ desired 9 an irreversible rearrangement o~ the com-
pounds oi the structural general f ormula I int~ the i~o-
meric form(s) o~ the ~tructural ~o~mula(e) V and/or VI c~n
be carried out irl a controlled manner7 which rearrangeme~t
~ ~ al~o included wi~hin the ~cope QI` the proce~ o~ the
pre~e~t in~ention.
Accord~g to this optio~al step oi the proc.e 8 o:i~ the
.. , . _. ... .~ . .. , . . . . . ... . . ... ..... . . . .. . . (

1 ~;2~
~ 11 ~
present invention, the 3-acylazo-propionic acid e~ters
o~ the ge~cral formula I are treated with cataly~t~,
optio~ally usi~g an inert ~ol~e~t, ~ and R2 havi~g the
mea~ings given aboveO
One particular embodiment o~ thi8 proces~ ~ature
con~i~t~ i~ that a 3-acylazo-propionic acid ester o~ th~
general ~ormula I i~ rearranged, at a temperature within
the range of irom -20C to 50~a, preferably at a temperature
within the range oY irom 0C to 30C, to ~orm the acyl-
hydrazonc of the ~ormylacetic acid e~ter of the g~naral
for~ula V and to form the enhydrazine o~ the general
~ormula VI.
Thi~ react~on may be carri~d ou~ u~ing both acicl or
~ewi~ acid cataly~t~ and al~o ba~ic catalystc. The follo~-
ing may b~ mentioned a8 e~ample~ o~ acid catalyst~ :
hydrochloric acld, ~ulphurlc acid a~d nitric acid,
HgCl (NE ) ~04, N~4Cl~ NH4~r~ r2~ 3 2 3
SnCl~ BF3, E-toluenesulphonic acld hydrate, acetic acid
and tri~luoroace~ic acid~
-s--- 20 The iDllowing ma~ be mentio~ed a~ ba3i~ cataly~ts 0
o~ide~ hydro~ide~, alooholate~ and carbonates o~ th~
al~aline earth met l~ and alkali metals, a~monia~ tertiary
~mine6, ~or e~ample triethylamine and ~ dimethyla~ ne,
and p~ridine bases~ ~he isome~ization reaction advan~ageou~-
ly take~ place ~ an aqueous medium and/or in orga~ic
~ol~ents.
The ~ollow~ng may be me~tioned a~ inert solvents
.... ... .

~ ~2
_ 12
halogenated hydrocarbon~, ~or e~ample methylene chlorid~
chloroform~ 1,2-dichloroethane, carbon -tetrachloride and
chlorobenzene, aliphatlc and aromatic hydrocarbon~, for
eæample petroleum ether9 pentane~ ~eptaneg cyclohexane,
5 benzene, toluene and xylene 9 ether~, for e~ample dieth~l
ether, ~etrahydro~uran, dioxan and dii~opropyl ether, and
alcohol~ for example methanol and ethanol.
The reaction may take place at a temperature within
the ra~ge of irom -20C to 50C, pre~erably at a tempera-
10 ture withi~ the range of from 0C to ~0C.
In pract~ce the proce~s i3 carr~ed ou~ in such amanner that an appropriate catalyst i~ added to the crude
solution oi the 3-acylazo-propionic acid ester and the~
the react~on products, which are normally ~ol~d~ ar~ i~o~
15 lated in the form of colourle~s cr~stal~ b~ iiltration~ bg
~reezi~g-out or b~ removing the solventJ ~hese can be
readily recry~talli~d ~rom suitable organic ~olYents~
.. for e~ample ketone~ alcohol~, nitrile~, e~ter~9 ether~
and chlori~ated h~drocarbon~9 for e~ample acetone, met~anol,
.- ~0 ethanol, acetonitrile, ethyl acetate, dii30propyl ether
and chloro~orm7 2nd are stable at room temperature. ~he
compound~ are general~9 however, produced i~ such a highly
pure ~orm that they ca~ be ~rther re~cted ~n the un-re-
crystQllized ~tateO
2~ The product~ manufactured according to the process of
the prese~t invention repre~e~t important starting material~
for the man~factur~ o~ 1,293-thi~diazole-5-carbo~ylic acid
.. _ . . .. .. ........... _ . . . . _ . , .. _.. __ . . ., .. . _ .

- 13 -
deri~ative~ from which valuable plant protecting agent~
and pe~t-controlling agentæ and alBO pharmaceutical
product~ can be manufactured.
Thi~ manu~acture o~ 1,2,3-thiadia~ole-5-carboxylio
acid derivatives of the general formula VII
~ (VII),
3~ c - ~OOR L
\S/
in which Rl ha~ the meani~g give~ above, can be carried
out, ~or example, ~n a m~nner kno~n Per ~e b~ react~ng the
proce~o product~ oi the genaral ~ormula(e~ ~ and/or VI
with thion~l chlorid~.
Th~ proce~ o~ the pre~ent i~entio~ o~er~,.iu
addition~ a ~ew ad~antageous method o~ manufacture ~or
the compounds o~ the ge~ral iormula VII~ by directiy
react~g the primaril~ formed proces~ product~ o~ the
gen~ral formula I with thio~yl chloride o~ the ~orm~ls
--- . SOal2 to ~orm the de~ired product~ o~ the general ~ormula
VII, a~ a ~esult of which one ~tep o~ the proces~ ie avoided-
(a~ compared with the rsaction-o~ thionyl chlorlde with com-
pou~da o~ the gen~ral ~ormula(e) Y and/or VI). This pro-
ceæ~ feature i~ also included within the scope of the
process c~ the pre~ent invention.
The ~ynthe~i~ o~ the 1,2~-thiadiazole-5-carboxylic
acid e~ters o~ the general iormula VII 1B ¢arried out in
.. , ....... . .,.: ... . .. ...... . . .

- 14 -
thi~ case by ~tart~ng from 3-acyla~o-propionic acid eater~
of the general *ormula I and reacting them with thionyl
chlorld~ The reaction i8 carried out at a temperaturo
within the range o~ ~rom -20C to 100C, preferably ~rom
-5C ~o 50C. ~he reaction time Gan be between 1 hour
and 20 hour3 depending o~ thc reaction temperature.
~ or the ~y~thesi~ of the lp2,3-thiadia~ole-5-carbo~-
lic acid e~ter~, the ~eactant~ can be used in appro~l-
mately equimolar amou~ts. ~hionyl chloride may, houever,
alter~atively be u~ed in a large exce~s qua~i a~ a sol~entO
. ~dvantageousl~, however, the molar ratio of the ~-
acylazo-pr~pionic acid e~ter to the thio~yl chloride used
~or the reaction ~a 1:3. ~he reactio~ may al~o proceed
in the presence o~ sol~ent~ that are inert with re~pect
to the reactant~. ~B ~uch ~olYent~ there may be mentioned :
~halogenated hydrocarbon~, for e~a~ple methglene chloride~
chloro~orm and carbon tetrachloride, al~phatic ~nd aro-
.. matic hydrocarbon~, for e~ample petrol0um ether, pentane,
cyclohexane, benzene~ toluene and ~ylene~ ethere, ~or 20 example aieth~l ether, tetrahydro~ura~9 dio~anp ~thylene
glycol diet~yl ether and dieth~le~æ glycol diethyl ether,
and e~ters, for example ethyl acetate~
The ~-ac~lazo-propionic acid e~ter, optionally dis-
~olved or suspended in a suitable 801~ent, iS normally
added ~n p~tion~ to the thionyl chloride optiona~ly di-
luted with an organlc ~olvent, but the reactant~ may also
be added i~ the reYerse order~ ~he hydroge~ chloride that

62~2
` 15 --
i9 formed during the r~action can be remo~ed continuously
from the reaction ve~sel by mean~ o~ an inert gas current
or by applying a vacuum~
~ ter the reaction ha~ taken place, the reaction
mi~ture may ~e worked up in a manner known ~ e.
~ fter di~tilling o~f the ~olvent and any ~xce~
thiongl chloride, the reaidue can be ~ractionally dis-
tilled; ~lternatively~ however~ any e2cess thionyl chlorlde
i8 de~troyed with a saturated ~oda ~olution, ~odium bicar-
bo~ate ~olution, pota~lum bicarbonate solution or sodiumacetate ~olution or with a sodium hydroxide solution or
potassium hydro~ide 801utio~ or directly with water and
the reaction solution i3 ~ubjected to steam di~tillation
or e~raction~ it be~ng pos~ible to use the solYents em-
ployed in the cour~e of the reaction also as e~tractingage~t~0 ~he e~tracts may then be worked up in a kno~
manner; for ~sample, after appropriate drying a~d ai~-
tilling-off o~ the ~olvent, the residue i~ ~ractionall~
distilled ~nd~r a reduced pre~sure or ~imply dlge~ted ~ith
a ~uitable ~ol~ent 9 ior example an aliphatic hydrocarbon,
for example pentane, he~ane, cyclohe~a~e or petrole~m ether.
~ he 1,293-thiadia~ole-5~carbo~ylic acid e~tere ar~
thus obtained in an extremel~ pure form and i~ ve~y high
yields, ~o that they can be further reacted ~o ~orm the
desired end productQ without being purlfiedO

~ ~292
-- 16 ~
The following ~xample~ illu3trate the invention:
F~
a)
ESTER
In a three-nacked 2-litre round-bottomed ~la~k
equipped with a stirrer, thermom~ter and re~lux condenser
ha~ng a drying tube, 17~.0 g ~145 mole3) of pulveri~ed
semicarbazide hydrochloride were ~uspended in 300 ml o~
methanol; to thi6 a sodium metho~iae solution ~re~hly pre-
pared from ~4.4 g (1~5 mole~ o~ sodium and 500 ml of
methanol was added dropwise ~ the course o~ 10 minute~
the temperature ;n the ~lask being kept at between 15C
and 20C~ ~h~ react~vn mi~ture wa~ then stirred ~or a
further 15 minute~ at 20C, and then the ~odium c~loride
was ~iltered off with suction. The ~iltrate was coll~ctod
~ in a three-~ecked 2 litre rou:~d-bottomed Ila~k arld 90 ~nl
(~.0 mole) of acrylio æid methyl e~ter were added whil~t
~tirring at 20a in the course oi one hour. ~he m~ture
wa3 le~t to ~tand for ~ days at room temperature, wa~ then
- 20 filtered again and then the ~iltrate ~as concentrated
in vacuo at 4QC~ 205 g oi a yello~ oily product ~as
obtained which was the~ extracted by stirring ~or a i~rther
hour, at room temperature, with 1 litre cf ethyl acetate.
The undissolved material wa~ ~iltered o~ and the ~i7trate
was then concentrated to 500 ml at 40a~ White crystal~
were obtained by trituxatio~ ~hioh were filtered o~ with
suction and dried in vacu,o at room temperature until th~ir
. .

- 17 -
weight wa~ constant.
Yield: 134~4 g - 83~4~ o~ the theoretical yield~
M~p.: 67 - 69C~
bl)
~TER
In a three-necked 1 litrs flask equipped with a ther-
mometer a~d stirrer, 16~1 g (0.1 mole) of 3 sem~carbazido-
propionic acid methyl ester were di~olved in 100 ml o~
water and, ~hilst coollng with ice~ 246.0 g (0~3 mole) o~
an approximately 10% ~re~hly prepared sodium hypochlorite
~olution were added in the cour~e o~ 20 minute~, th~ tem-
peratur~ in the fla~k bei~g ~ept at between 5 and ~C~
~fter ~tirring the yello~ raaction solution 80 obtained
~or 10 minutee i~ an ice bath~ 85 g of sodium chloride wer~
added ~nd the mixture was e~tracted carefully five tlme~,
~ith 400 ml o~ chloro~orm e~ch time~ ~hee~rac~s, dr~ed
over mag~e~ium ~ulphat~, wer~ concentrated i~ ~acuo at ~0~.
A ~ellow cry~talline product was obtained~
Yield: 12.9 g - 81.1% o~ the theoretical ~isld.
.-. 20 M.p.: 85 87C with decompo~itionO
b2)
ESTE~
In a three-necked 1 litre ~lask equipped with a st1rrer
and a thermometer, 16.1 g ~0.1 mole) o~ 3-~emicarba~ido-
propionic acid methyl ester were di~ol~ed i~ a mixture o~150 ml o~ water and 10.~ g o~ approximately 95% ~ulphuric
acid. Whilst cooling ~ith iC~9 a ~olut~o~ o~ 9~79 g (0.03~3

- 18 -
mole~ of pota3sium dichromat~ in 70 ml of water and 1~.8 g
oi appro~imately 95~ ~ulphuric acid were added dropwise,
in the cour~e of 10 minute~, at a reaction t~mperature of
from 7C to lO~C~ ~he mi.~ture was then left to react ~or
a further 10 minute3 and then 29.0 g of ~olid potas~ium
bicarbonate were added. Yellow cry~tals separated. The
reaction ~olution was e~tracted intensi~ely five ti~e~
with 300 ml of chloro~orm each timeO ~he chloro~orm ex-
tracts~ dried over magnesium ~ulphate, were concentrated
in vacuo at 40C. Yellow crystals were obtained.
~ield: 9.0 g - 56~5% o~ the theoretical yield~
M.p~: 85 -- 87C ~ith decomposltion.
c~
~S~R
__
I~ a three necked 250 ml ~ g equipped with a ther-
~ mometer and a ~tirrer, 15.9 g (O.:L mole) o~ 3-carbamoyl-
azo-propionic acid methyl e~ter wo~re di~olved in 100 ml
o~ chloro~orm and 0.5 ml o~ triethylamine wa9 added~ the
temperature in the ~lask be~g kept at ~0C by cool~ng.
.- 20 ~he ml~ture was then ~tirred ~or a ~urther hour at room
temperature and then the resultlng crystall~ne magma wa~
concentrated to dryne~ by evaporatlon in ~vacuo at 40a.
The residue wa~ digested ~ith 150 ml of diisoprop~l ether~
~iltered ~ith suction and dried ~n vacuo until its weight
was con~tant~
Yield: 14.5 g = 91.1~ o~ the theoretical yield.
N.p~: 159C with decompositlonO

~ ampl~
a~
D ~3~~
I~ a three-necked 1 litre flask equipped with a
~tirrer, thermometer and reflux condenser, 114.4 g
(1.1 mole~) o~ hydra~ino~ormic acid ~th~l ester were dis-
~olved in 600 ml of ethanol and 90 ml (Ool mole) of acrylic
acid methyl e~ter were added at 20C ~ the cour3e oi on~
hour. The m~xtur~ wa~ le~t to ~tand ~or 4 day~ at room
temperature in a sealed ~la~k and then the reaction ~olution
wa~ concentrated iQ vacuo at 40C~ The liqu~d ~o obtained
was diGtilled ~ vac~o.
~ield: 111.1 g - 58.43~3 of the theoretical yield~
~p.: 110 - 1I1~ / 0.1 torr.
b~ ~ OX~CARBON~IAZO-PROPIO~ CID MET~YL
ESTE$
I~ a three-~ecked 250 ml flaE;k equipped with a stirrer
and a thermometer, 9~5 g ~0.05 mole) o~~etho~ycarbonyl- ..
h~drazino-propionic acld meth~l e~ter were d~olved in
--- 20 50 ml oi ~ater and 82 g (0.1 mo~e) o~ an approximately 1~
~re~hl~ prepared sodium hypochlorit~ solution were aaded in
the course o~ 2~ minutes~ the te~perature in the flask
being kept at betwe0n 5C and 7~ yello~ oil separated.
~he mixture wa3 then ~irred for a ~urther 10 minute~ in ~n
ice bath, extr~c~ed three time~, with 75 ml of ohloroform
each time~ and a ~ello~ Vi~Gou~ oil ~a~ obtai~ed after
drying over magnesium ~ulphatc and conce~trating the chloro-

-20 -
form pha~es by e~aporatio~ in vacuo at 40C.
Yield: 8~7 g = 92.4~ o~ th~ theoretical yi.eld.
n~ : 1~4424.
c) _~
ACID M~THY~ ESTE~
I~ a three-nec~ed Ila~ equipped wi.th a stirrer and
a thermometer, 18.8 g (0.1 mole) of ~-ethox~carbonylazo-
proplonic acid methyl e~ter ~ere di~olved in 100 ml o~
chloroform and 0.5 ml of triethylamlne was added at 30C,
during which operation the ml~ture had to be cooled owing
to the e~othermic cour~e of the rea~tion. ~tirring wa~
then subsequently carried out for a ~urther hour at room
temperature and then the reaction ~olution wa~ concen~
trated in vacuo at 40C. he oil remaining a~ residue
wa~ dige~ted with 5~ ml of diieopropyl ether and th~
cry~tal8 ~o obtained were filtered with suction ancl dried.
Yield: 17 . 9 g = 95 0 2~ o~ the theoret~cal yield~
. ~q.p.: 60 - 61C~,
-- 2
~STER (continuous~
In a three-necked 1 litre ~la~k equ$pped with a ther-
- mometer and a ~tirrer, 1501 g (0~1 mole~ of 3-semicarba-
z~do-propionic acid methyl e~ter, prepared as de~cribed in
E~ample la)~ were dissol~ed in lOQ ml of water and, whilst
cooling with ice, 141.6 g (0.2 mole) of an appro~imately
10~ ~reshly prepared soaium hypochlorite 801ution were

~ 9~
add~d in the cour~e oi 20 minutee, the temperature i~ the
fla~k being kept at betwee~ 5~ and 7C. The yello~ reac-
tlon ~olutio~ wa~ then ~tirred ~or a further 20 minute~
in an ice bathp 66 g o~ sodium chloride were added and
then the mi~turc wa~ e~tracted care~ully ~ive time~, with
400 ml o~ chloroform each time. The chloroform phase~,
dried o~er magnesium ~ulphate, were concentrated to 100
ml at 40C in vacuoO 0.5 ml o~ triethylamine was added
-to the chloro~orm ~olution concentrated to 100 ml, -the
temperature ~ the ~lask being kept at 30~ by cooling.
~ter stirr.ing ~or onc hour at room temperature, the re-
~ulting ory~talline magma ~as concentrated to d~yne~s at
40C ln vacuo~~ The re~idue ~a~ digest~d with diisoprop~l
ether, filtered w~th ~uction and cLried ~ vacuo until it~
weight was conatant~
Yield: 12~0 g ~ 75~5~ o~ the theoretical yielaD
M~p.: 15805 - 159.5C with ~ecomposition~
.. ~ , .
~ 20 ~
In a three-~eckecL 500 ml ~la~k equipped with a stirrer
and a thermometer, 19.0 g (0.1 mole~ of 3-etho~ycarbon~l~
h~draz~.~o-proplonic aoid methyl e~ter, prepared as de~cribed
in ~xample 2a~9 were di3solved in 100 ml o~ water and 141~6 g
(0.2 mole) o~ an appro~imately 10% sodium hypochlorite
301ution were added in the course of 20 minutes, the tempera-
-~ure i~ the flask being ~ept at between 5~C and 7C~ ~

2~ ~
yellow oil ~eparatedO The mi:~ture was then ~tirred for
10 minutes, ~d e:ctracted three times, ~ith 150 ml o:~
chloroform each time, and the chloroform pha~e was con;
centrated to 100 ml a~ter dr;sring over magneE3ium sulphat~.
0"5 ml of triethylamine was added to the chl oro~orm
solution concentrated to 100 ml9 dur~g which operation
the temperature ahould not exceed 30Co A~ter subsequent
stirrin~ for o~e hour at room temperature, the reaction
~olutio~ ~as concentrated by ev~por~tion in vacuo at 40C;
10 the oily reaidue was the~ digested with 50 ml of dii30-
propyl ether and the colourless crgstal~ Ior~ed were fil-
tered with suction a~d dried~,
Yield: 12~,9 g = 68.57~ o~ the theoretlcal yield.
M.p.: 59 - 61a~
15 ExamPl~ ~
In a three-necked 50û ml ~ 3k equipped w~th a stirrer
and a thermometer, 19.0 g 50~.1 mole~ oi 3-ethox;src~Lrbonyl~
-- 20 hydrazino-propionic acid methyl e~ter" prepared as de~cribed
in E~ample 2a~7 wer~ dissolv~d i~l 150 ml o~ wa~er and a
solutio~ o~ 9.79 ,g (0.03~3 mole~ oi potas~ium dichromat~
in 70 ml o~ wate:r and 17.2 g (0.167 mol~ of g576 sulphuric
aeid were added in the course o~ 15 min~teq. ~he tempera-
25 t~ in the fla~k was kept at bet~eell -2C an~ 0C for 30
minute~. The mixture wa~ then e~racted twice, with 40 ~nl
of` chloro~orm each time. After dr~ing over magne~ium BUl-
1.

~ :~6~9
-- 23 --
phate~ the chloro~orm ~olut~on was concentrated by
e~aporatio~ in ~ Q a~ 40a. The oil remaining a~
~esidue was digested wLth diisopropyl ether and the re-
~ulting cr~tals were ~iltered with suction.
Yield: 12.4 g = 65~% of the theoretical yield.
M.p.: 57 ~ 61Co
MA~UFACTURE OF ] 2 -TEIADI~ZOIæ-~-CARBOX~IC ACID METE~
EST~R ,
10I~ a three-necked ~50 ml round~bottomed ~las~ equlp-
ped with a ~tirrer, thermometer and a conden~er havi~g an
outlet into ths ~ume cupboard, 21.8 ml (0~3 mole) of
th~on~l chloride were cooled to -10C and 15091 g (0~1
mole) o~ 3-carb~moylazo-~ropionio acid methyl ester, pre~
pared as de~oribed in ~xample 1 b;L~ or 1 b2~, were added
in portion~ i~ the cour~e o~ 15 m:Lnute~, the temperature
in the ~laak being kept at betweel~ -5C and 0C~ After
the additivn ~ d been completed the yellow reaction ~olu- ..
tion wa~ ~irred ~or a ~urther two houre~ ~hile allowi~g
the temperature in the ~laek to riae ~lowly to ~2C~ The
~olutio~ was then diluted wlth ~0 ml o~ chloroform a~d
careiully decompo~ed with 60 ml oi a ~aturated pota~ium
bicarbonate ~olution, the temperature in the flask being
~ept ~t between 10 and 20C, ~he chloro~orm phase sa~
separated oi~ wa~hed until neutral with 30 ml of a
pota~ium bicarbonate ~olution9 dried o~er magne~ium
~ulphate and concentrated in ~ at 40a. ~he resulting
.... ~ .. .... , ... .... . .. . . .... , ... . . . . . ... .. .. _ . . ..

-- 24 w
liquid wa~ d:Lstilled irL a water-Jet vacuumO
Yield; 11.6 g - 80~.5~ of the theoretica:L yieldO
B.p.: 110 - 111C / 14 torr.