PROCEDE DE PREPARATION DU 4-(2-PHENOXYETHYL)-1,2,4- TRIAZOLONE

4-(2-PHENOXYETHYL)-1,2,4-TRIAZOLONE PROCESS

Abrégé anglais

Abstract of the Disclosure
An improved process for the preparation of 5-ethyl-4-(2-
phenoxyethyl)-1,2,4-triazolone, a useful intermediate in the synthesis
of antidepressant 1,2,4-triazolones typified by 2-[3-[4-(3-chloro-
phenyl)-1-piperazinyl]propyl]-5-ethyl-4-(2-phenoxethyl)-2H-1,2,4-
triazol-3(4H)-one, also known as nefazodone. The improved process is
shorter and higher in yield than the former process, and the starting
materials are cheap and readily available.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE
IS CLAIMED ARE DEFINED AS FOLLOWS.
1. A process for preparing 5-ethyl-4-(2-phenoxyethyl)-2H-
1,2,4-triazol-3(4H)-one (I)
<IMG>
(I)
which comprises the consecutive steps of:
a) reacting phenol with 2-ethyl-2-oxazoline (V)
<IMG>
(V)
to give N-(2-phenoxyethyl)propionamide (IV)
<IMG>
(IV)
b) activating the amide functional group of compound IV by
reacting compound IV with an amide-activating agent, so as
to produce an imidoyl halide or ester intermediate of formula
III;
<IMG>
III
wherein Y is a halogen or alkoxy moiety and
wherein X is an anion which results from the reaction
between said amide activating agent and compound IV.,
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c) reacting the product of step b without isolating said compound
III with a carbazate ester of formula H2NNHCO2R to give an
alkyl [1-[(2-phenoxylethyl)amine]propylidene]hydrazine
carboxylate acid addition salt (II)
<IMG>
(II)
wherein
R is lower (C1-C4) alkyl, and
X is an anion, generally corresponding to the anion of the
amide-activating agent used in step b; and
d) converting compound II into compound I by means of suitable
thermal treatment of compound II in its free base form so
as to form compound I.
2. A process as in claim 1 wherein the activating agent is
chosen from thionyl chloride, thionyl bromide, phosphorus oxychloride,
phosgene and dimethyl sulfate.
3. The process of claim 1 wherein the amide-activating agent in
step b is phosgene.
4. The process of claim 1 wherein the amide-activating agent in
step b is phosphorus oxychloride.
5. The process of claim 1 wherein the thermal treatment of step
d) comprises refluxing the free base of compound II in a suitable inert
organic solvent.
6. A process for preparing the compound of formula II comprising:
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a) reacting phenol with 2-ethyl-2-oxazoline (V)
<IMG>
(V)
to give N-(2-phenoxyethyl)propionamide (IV)
<IMG> ;
(IV)
b) activating the amide functional group of compound IV by
reacting compound IV with an amide-activating agent, so as
to produce an imidoyl halide or ester intermediate of
formula III;
<IMG> ;
III
wherein Y is a halogen or alkoxy moiety and
wherein X is an anion which results from the reaction
between said amide activating agent and compound IV., and
c) reacting the product of step b without isolating said
compound III with a carbazate ester of formula H2NNHCO2R
to give an alkyl [1-[(2-phenoxyethyl)amine]propylidene]-
hydrazine carboxylate acid addition salt (II)
<IMG>
(II)
wherein
R is lower (C1-C4) alkyl, and
X is an anion, generally corresponding to the anion of the
amide-activating agent used in step b.
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7. A process as in claim 6 wherein the amide activating agent is
chosen from thionyl chloride, thionyl bromide, phosphorus oxychloride,
phosgene, and dimethyl sulfate.
8. The compound methyl [1-[(2-phenoxyethyl)-
amino]propylidene]hydrazine carboxylate or an acid addition salt thereof.
9. A process as in claim 6 which comprises forming the hydrochloride
salt of the product of formula II.
10. The compound methyl [1-[(2-phenoxyethyl)-
amino]propylidene]hydrazine carboxylate hydrochloride.
11. A process for the preparation of an imidoyl halide or ester of
formula III as defined in claim 6
<IMG>
III
wherein Y is a halogen or alkoxy moiety and wherein
X is an anion which results from the reaction between said amide
activating agent and compound IV; said process comprising the
step of activating the amide functional group of compound IV
<IMG>
(IV)
by reacting compound IV with an amide activating agent.
12. A process as in claim 11 wherein the amide activating agent is
chosen from thionyl chloride, thionyl bromide, phosphorus oxychloride, phosgene,
or dimethyl sulfate.
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13. An imidoyl halide or ester of formula III as defined in claim 11
<IMG>
III
wherein Y is a halogen or alkoxy moiety and wherein X is an
anion which results from the reaction between said amide
activating agent and compound IV.
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Description

B'~j
4-(2~PHENOXYETHYL)-1,2,4-TRIAZOLONE PROCESS
This invention describes an improved, more economical
process for the synthesis of a valuable chemical intermediate
(I)
~o ~N\H
~1)
used in the manufacture of ~he antidepressant agent 2-[3-[4-
~3-chlorophenyl)-1-piperazinyl]propyl3-5-ethyl-4-(2-phenoxy-
ethyl)-2H-1,2,4-triazol-3-(4H)-one which is also known as
nefazodone.
Cl
O ~ ~ ~ N ~ )
nefazodone

This suhje(t intermediate, 5-ethy~ 4~(2-ph~no~yethyl)-l,2,4-triazolonl,
of Formuln I is also known as MJ 148]4 ancl its c~lrrellt synthesis,
disclosed in ~.S. application SN 06/509~266 (now ~.S. Patent 4,338,317
issued July 6t 1982) as Example 5, is shown in Scheme 1. An overall yield
of 33% for Scheme I is predicted from yield calculations of the individual
steps in Example 5 of the ~.S. patent.
Sche~e 1
O 5t~p 1 ~ ~ 0 ~ Et
OC H
(1~ (2) 2 5 (3~
0 Step 2
0~ ~ ~2NNH2-~20 1) ~2NN~2
(5) . 2) ~Cl
Step 3 t 23 ~
6) NHNH2 ~4) ~Cl
¦ Step 4A
Step 5 [ ~ NGC~O ~ Step 4B [
~ rS~
(9)
H20 ¦ ~OH Step 6
.
(I; MJ ~4814
!

As can b~ s~en ln Schem~ 1, the prep~r~tion sf MJ 14814
6t~rts with phenol and ethyl ~c~yl~te, ~n obnoxlou~ ~aterl~l ~ith a
high vspor pre~ure. This pro ess hss been successfully scAled up
snd u~ed repeatedly giving MLJ 14814 in 25-30% overall yield from
5 phenol.
MJ 14814 i6 converted to thc nntldepres~ant ~ge~e nefazodone
(MJ 13754) as di~clo~ed ln the ~bove cited U.S. patent. This
conver~ion lnvolves reac~ion of MJ 14814 with 1-~3-chlorophenyl)~4-
(3-chloropropyl)pipera2ine hydrochloride ~10)
,~1
Cl
(10)
Preparation of MJ 14814 Yia Scheme 1 ~nvolYe6 6iX ~tep~ a~d
four l~olated intermed$ate6, two o ~hich are liq~lds requirln~
purification by vacuum di6tillatisn.
By contrast, the ~mproved process described
herelnafter i~; comprl~ed o f f our s~eps iDvol~ing
only three lsolated intermediates, all of which are solids, ~lth an
overall yield of ~J 14814 of 40-55X from phenol. In compari~on, the
prior art me~hod, represented by Scheme I, is 8 lon~er proce~s
requiring more labor and providing MJ 14814 ~n much lower yleld.
The following reference~ relate to component 6tep~ of the
20 iD6tant process described herein.
1. Dow Technical BulleeiD, "Developmental 2-Ethyl-2-
Oxazoline XAS-1454 Ethyloxazollne: An Intermediate for Am$noethyl~tion."
Thi6 reference describe~ ~he 6ynthe~i~ of N-(2-phenoxyethyl)propion-
a~ide, ~n ~nten~ediate c~mpound of the in~ant prvcess.

3~ x~,
2. W. Reid snd A. C~ck, Ann. 676, pp. 121-129 (1964).
Thifi reference teaches the reR^tion of lmldoyl ethers ~ith e~hyl
carbazste to ~ive am~drazones which ehen cyclize on further heaeing
to 1,2,4-triazoles as outllned below in Sche~e 2.
Scheme 2
R ~ OR 2NNHCO2R --~ R NHNHCO R"
R" ~ ethyl
~owever, there i6 no di6closure of the use of N-substi~u~ed lmidoyl
ethers which would be necessary to obtain a desired N-eub6tituted
~riazolone.
3. M. Pesson, et al., Bull. Soc. Chim., Fr., pp~ 13~7-71
(1962). This reference reports a very low yield synthesl6 (0.3~ of a
triazolone w*th the de~ired ~ub~titution pattern via ~he proces6
fihown below in Scheme 3.
Scheme 3
OH H ~ ~ N
+ H2NHC02~t
OMe ~ ~N ~ NH
0.3Z yield
The author~ state that imidoyl ether6 of 6econdary amides are difficult
to make (p. 1364, bottom 6econd column). Pesson, et al., do di~close
preparation of a triazolone with the desired sub~t$tution patte m but
~ia 8 synthesi6, 6hown as Scheme 4, which is dlfferent from that in

the instant process. The reference 6yn~hesi6 beglhs with ~n lmldoyl
e~her of a primary ~mide to glve an in~ermedlate carbethoxy hydrazone
which ls then reacted ~ith a primary amine.
Scheme 4
R ~ HCl ~ H2NNHC02Et e o R ~ OEt
O
Note that the carbazate dl~places the imine function ln Sche~e 4
representing another feature di~tingui6hlng the proces6 of the
instant lnventionO
Pesson, et al., 9160 di6clo6e that thioamide6 are more
reactive than amides, giving N-6ubstituted amidrazones on reactlon
with carbazate. Howevert whe~ the N-~ubstituent is alkyl, as required
in the instant process, no reaction with ethyl carbazate was observed.
Finally, Pesson, et al., teach activation of a thiobenzamlde wlth
dimethylsulfate followed by reaction with carbazste eo give the
triazolone product. Again, there is no disclosure involving activation
of alkyl carboxylic acid thioamides, a 6tructural prerequisite for
the instant ~rocess.
In summary, references 2 and 3 es6entially descr~be reactions
of certain smide derivatives with carbazate esters to eventually
yield triazolone products but with di~einguishing variat$ons in
structural relationship to the product produced by the instant
process.

This invention relates to an improved synthetie pr4ces6
which can be adapted for large-scale preparation of the useful
chemlc~l intermed$ate, 5-ethyl-4-(2-phenoxyethyl)-1,2,4-triAzolone.
The l~stant process start6 from phenol and 2-ethyl-2-oxazoline, raw
maeerials which are eheap and readily ~vailable. The ~ub~ect i~proved
process offers advantages in economies of both material and labor
costs by v~rtue of being Eh~rter in length, involving fewer intermediate
isolatlons, and psoviding a higher yield of product.
The following flo~ chart, Scheme 5, illustrates the preparstion
~f MJ 14814 fr~m readily available ~t~rting materials utilizing ~he
instant process.
Scheme 5
OH + ~ ~ l75 ~ ~ o
(1) (V) SIV)
Amide activation
Step 2 (SOX2; Me2SO4;
~ POC13; COC12; etc.)
~ H2~C
02R r~ ~ 1
O~ ' HX ~ L EX
II ~ III
\ OH, heat
Step 4 \
(I; MJ 14814)
40-55% yield

In Scheme 5, R 1~ Cl ~ alkyl; X is Cl, Brp or SO4; ~ i6 Cl,
Br, or OR; and amlde activation ls forma~ion of a reactive imidoyl
halide or ester by treatment of the amide wl~h a suitable activating
reagent fiuch a5 SOC12, SOBr2, POC13, dimethyl ~ulfate, phosgene, etc.
S Step 1 of the scheme outlined above lnvolves the reaction
of phenol (1) and 2-ethyl-2-oxazoline ~V) to glve the lneer~ediate
compound N-(2-pheno~yethyl)propionamide ~IV). ThP 6eartin~ ~aterial6
for step 1 are commercially available. Step 2, acti~at~on of the
~mide ~IV), is accomplihed by treatmen~ of IV with Rn amide-ac~i~ating
reagent such as thionyl chloride~ thionyl bromide, phosphorus
oxychloride, phosgene~dimet~l sulfate, and the like, to give an
i~idoyl hal$de or ester ~ntermediate (III). The preferred agent~ are
phosgene or phosphorus oxychloride. Intermedlate III is not l~olated
but ls allowed to react ~ith ~n alkyl carbazate of for~ula ~2NNHCO2R,
R ~ ~ethyl is preferred, in ~9tep 3 to give the novel triazolone
precursor (II). In step 4 the hydrazinecarboxylate acid additlon
salt (II) ~s converted to it6 ba6e form and cyclized to the desired
triazulone product (1~ by heating.
This four-seep improved process involves lsolation of orly
tWD intermediate products (IV and II) in addition to che target
co~pound, I. By way of comparison9 the current process invDlve6 6lx
~teps and the isolation of four intermediates, two of which are liquld
and require purification by vacuum distillation. The retuced handling
of lntermediates in the lDstant process 61gnificantly reduces labor
costs ln ~Anufscture.
The synthesis of ~J 14814 as represented in the ~mproved
proce~s is preferably carried out ~s a ~eries of four ~teps going

from the ~implest startiDg materialfi (phenol, 2-ethyloxazollne) to
MJ 14814. The steps comprlsing the process ~re as follow6:
(1) Addlng 2-ethyl-2-oxazoline to hot (150) phenol nnd
maintaining heating at about 175~ for 16 additional hours. The oil
is then quenched in water to give N-(2-phenoxyethyl)propionsmide (IV)
in approximately 90% yield.
(2) Adding phosgene or phosphorus oxychloride to a colution
of IV containing a catalyeic amount of $mida~ole in m~thylene chloride
to give a solution of the intPrmediate imidoyl chloride hydrochloride (III).
(3) Treating th~ solution of III with a ~olution of an
alkyl carbazate to give alkyl [1-[(2-phenoxyethyl)amino]propylidene]-
hydraz$ne carboxylate hydrochloride (II) 1~ about 75~ yield.
(4) The free base form of IIg resultlng from the trea~ent
of II with a basifying agent, is heated in solution for 6everal hour~
~o yield I in about 75X.
Descr~ption Of Spec~fic Embodiments
The process of this invention is illustrated in greater
detail by the following examples directed to preferred embodiments of
the here~nafter described process steps. These examples, however,
should not be construed as limlting the scope of the present lnvention
in any way. In exsmples which follow, used to illustrate the fore-
going processe6, temperstures are expressed, as in the foregoing, in
degrees centigrade (). Melting po~nts are uncorrected. The nuclear
magnetic resonance (NMR) spectral characteristics refer to chemical
sh$fts (~) expressed as parts per m$11ion (ppm) versu6 tetr~methyl-
silane (~MS) as reference standard. The relative area reported for

ehe varlous shlft6 ln the H NMR ~pectral data corresponds to the
nu~ber of hydrogen atoms of a particular functional type in the
molecule. The nature of the 6hift6 AS to multipliclty is reported as
broad inglet (bs), ~inglet (B), doublet (d), tr~plet (t), quartet (q),
or multiplet (m). Abbreviations employed are ~MSO-d6 (deutero-
d1methyl6ulfoxide), CDC13 (deuterochloroform), and are otherwi6e
conventional. The infrared (IR) 6pectral descr~ption6 include only
absorpt~on wave numbers (cm 1) having functional group identification
value. The IR determinations were employed using potassium bromlde
(KBr) as diluent. The elemental analyses are reported as percent by
weight.
EX~MPLE 1
Meth~l Carbazate
An alternate name for this co~mercially available chemical
is methyl hydrazinocarboxylate. Methyl carbazate ~ay also be ~ynthe6ized
by adding 85% hydrazine hydrzte (5805 g, 1.00 mole) w~th stir~n~ to
dimethyl carbonste (90.0 ~, 1.00 mole) over a 10 min period. The
mixture quickly warmed to 64D and became clear. The solution was
stirred for another 15 min and the volatile materials were 6tripped
in vaeuo at 70. Upon cooling, the residue ~olid$fied. It ~as
collected on a filter and after drying in a~r gave 69.3 g (76.9Z) of
white 601id, m.p. 69.5-71.5.
EXAMPLE 2
N-(2-Phenoxyethvl)propionamide (IV)
Phenol (13.1 mole6) was heated to 150 and 6tirred under N2
as 2-ethyl-2-oxazoline (12.2 moles) was added over 1 hr. The mixture
was heated to 175 + 3D. After heating 16 hr the oil W8S cooled to
_ g _

~L~3' ~ ;d~
about 140, ~nd then it was poured in~o waeer (12 L) with vigorous
stirring. The mixture was 6tlrred and cooled, and at about 25 the
mixture was 6eeded with crystalline amide product. The mfiterial
solidified and the supernatant was decanted. The residual 601id was
~tirred with 17 L of hot (85) water. The m~xture ~as cooled to 25,
~eeded with the amide product, and the mixture refrigeratet. The
resulting granular ~olid was collected on a fileer~ rinsed with
6everal portions of water and left to a~r dry. Thls gave ~ 92% yield
of material, m.p. 61.5-64~.
EXAMPLE 3
A. Methyl [1-[~2-Phenoxyethyl]amino]propyl~dene
Hydrazinecsrboxylate Nydrochloride (II~ _
PhosgeDe (57.4 g, 0.58 ~ole) was added to a solution of
N-(2-phenoxyethyl)propionamide (IV, 112.0 g, 0.58 uole) and imidazole
~0.4 g, 0.006 mole) in 450 mL methylene chloride over 1 hr employing
cooliag 60 that the te~perature did not e~ceed 25~. The reactio~
~olution was then stirred at 25~ for an additional 2.5 hr. A ~Dlution
of methyl carbazate (52.5 g, 0.58 mole) in 500 mL methylene chloride
was stirred over 25 g of a molecular sieve for 15 min and theD the
solution was filteret. The fll~rate was added under N2 over a 0.5 hr
period to the amide/phosgene 601ution whlle employing cDoling 15-20.
A voluminous precipitate formed and the mixture was left to stir at
25 under ~2. After stirring for a total of 16 hrs, the mixture was
filtered to isolate a solid. The 601id was stirred in 750 mL methylene
chloride for 15 min, refiltered, and then dried in vacuo at 65 for
2 hrs to give 135 g (77~) white solid, m.p. 150-154. Recrystallization
of the product from isopropanol glves analytically pure material,
.p. 157-159.
-- 10 --

An~l Calcd. for C13Hl~N303 ~Cl C~ 51-~4; H, 6-6~;
~, 13.92; Cl, 11.75. Found: C, Sl.73; ~9 6.76; N, 13.9h; Cl, 11.7B.
NMR (DMSO-d6): 1.15 (3,t 17.5 H~); 1.28 13.t [7.5 Hz~);
2.74 (2,m)9 3.66 ~3,6); 3.70 ~3,s); 3~81 ~2,m); 4.19 ~2,m); 6.g8 (3,m)~
~.31 (2,m); 9.67 (3,bt 16.8 H~]); 10.04 (3,bs); 10.40 ~3,bs~; 10.90
(3~bs); 11.72 (3,bs).
I~ (KBr): 695, 755, 1250, 1270, 1500, 1585p 1600, 1670,
1745, and 29Q0 cm 1,
By appropriate modification of tbe above procedure (A),
thionyl chloride, thionyl bromide, dlmethyl sulfate or ~thes amlde-
activating agents may be employed in place of phos~ene. A elightly
dif f erent procedure (B) may also be used.
B. Methyl [1~1~2-Phenoxyethyl~a~ino~propylid~ne
Nydrazinecarboxylate (II Base Form)
Phosphorus oxychloride t53.0 g9 0.346 mol2) ~as Blo~ly added
to a solution of N-(2-phenoxyethyl)propionamide (IV, 100~0 g, 0.518 ~ole~
in 200 mL methylene chloride while being stirred under DierOgen. This
sblution was stirred for 4 hrs at which tlme a solution (dried over
moecular sieYe 4A) of methyl carbazate (46.4 g9 0.518 ~ole) in 600 mL
methylene chloride ~as added to the stirring solution ~ver a 0.5 hr
period. The resulting mixture was stirred and hea~ed at gentle reflux
under nitrogen for 18 hr. The mixture was then stirred ~ith 1.0 L
ice-water. The layers were separated and the aqueous layers extracted
with an additional 200 mL methylene chloride. The aqueous layer was
made basic (pH 12) with aqueous sodium hydroxide. Thi5 resulted in
precipitation of the free base form of II which was collected by
filtration, rinsed with water and dried in air to gi~e 65.8 g of
product, m.p. 9~-99.
~1

q3~
Anal- Calcd- for C13H19N33 C~ 58-85; H~ 7-22; N~ 15-84-
Found: C, 59.02; H, 7.24; N, 15.92.
When this free base form of II is e~ployed for the conversion
to I, the preliminary basification ~tep outlined 1n Ex~mple 4 (which
follows) i6 skipped. The ba~e fDrm of II is cyclized dirPctly by gently
refluxing in xy;ene sccording to the procedure of Example 4.
EXAMPLE 4
5-Ethyl-4-(2-phenoxyethyl)-
2H-1 ? 2,4~triazol-3~4H)-one ~I)
Methyl [1-[(2-phenoxyethyl)amino]propylidenejhydrazine
carboxylate hydrochloride (II, 655.3 g, 2.17 ~ole) was ~tirred
vigorously with 4.0 L methylene chloride, 2.4 L water and 179.4 g 50%
~aOH (2.24 moles). The layers were separated and the organic layer
was dried (R2C03) and concentrated in vacuo. The residue was ctirred
in 1.2 L xylene at gentle reflux for 2.5 hrs and then the ~olution
was refrigerated. The solid was collected on a filter, rinsed wi~h
toluene and left to air dry. The w~ite cry6talline solid ~eighed
89.5 g (76.9%), m.p. 134.5-138.
Additional purification ~ay be accomplished ~n the following
manner. A portion of I (171.2 g~ 0.73 mole~ was dissolved iD a
boiling ~olution of 41.0 g (0.73 mole) ROH in 3.0 L ~ater. The
solution was treated with Celite filter-aid and activated charcoal
and filtered. The filtrate was stirred in an ice bath, and 37Z HCl
~61.0 mL, 0.73 mole) was added. The sol$d was collected on a filter,
25 rinsed with water and air dried to give 166.0 g (97X recovery~ of
fine white crystalline product, m.p. 137.5-138.
- 12 -