Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
z~
PRO~ESS ~OR THE PREP~RATION O~ 2-/~/-P~Y~T~YL~N~-
CY~LO~EPT~N-l-O~E~ O~I~E
~he i~Yention relate~ to a proces~ for the pxeparatio~
o~ 2-JE/-phenylmethylenecycloheptan-l-o~e-/E/-o~ime of the
formula /I/
~ O H
\ )
~ree of other i~omers. ~he compound o~ the for~ula /I/ 3erve~
a~ i~termediate u~e~ul i~ the ~ynthesi~ o~ deriYative3 ha~ing
valuable pharmacautical propertie~, e.g~ in the ~ynthe~i~ o~
the compou~d~ de~cr~bed i~ Hungarian Patent Specification
No. 1~ B~.
~o method ha3 bee~ ~o ~ar described i~ literature ~or
2Q the preparation of the compo~nd of ~or~lla ~
It 1~ known that ketona~ i~teract ~ith hydro~yl~mine
obtalned "in ~itu" from ~ hydro~lamine ~alt i~ the pre~e~Ge
of a ba~e~ The reactio~ r~ult~ in a~ o~ime. Takin~ th~
structural properti~ o~ the ~tarti~æ keto~e i~to account, two
i~omer~ may be ~or~sd in the reaction. I~ 3impler case~ they
are called ll~yn~ and "~ti9', re~pectively, while in ca~e of
compound~ of more complicated ~tr~cture the designatio~ tfZ
- ~nd "~"~ re~pectively, are u~ed.
It is known that -the different isomers possess different
biological properties. That is why in many instances it is
necessary to prepare them in pure form, which can be accomplished
only from intermediates free of isomers.
The aim of our investigations was to elaborate a method
suitable for the production of the 2-[E]-phenylmethylenecycloheptan-
l-one-[E]-oxime of the formula I substantially free of ot'ner isomers.
It has been found that when reacting the 2-[E]-phenyl-
methylenecycloheptan~l~one of the formula [II]
~ ~ [II]
with hydroxylamine obtained "in situ" from a hydroxylamine salt in
the presence of a base in water and/or in a lower, with water un-
restrictedly miscible aliphatic alcohol and if necessary adjusting
the alcohol content of the reaction medium to ~0-60%, preferably
to 50%. The 2-[E]-phenylmethyleneacycloheptan-l-one-E-oxime can
be isolated by known method~ The product contains at most 5% of
other isomers, which can be removed, if desired, by known methods.
The starting compound of the formula [II] is known and
can be prepared by methods described in iiterature [e.~.: Gazz.
Chim. Ital. 91, 326-48(1961)~. The hydroxylamine salts[sulfate,
hydrochloride] are commercial products.
The reaction of the 2-[E]-phenylmethylenecycloheptan-1-
one with the hydroxylamine obtained "in situ" from a hydroxylamine
salt ~preferably sulfate or hydrochloride] is carried out in water
and/or in an aqueous alcohol as medium. For this
~,:'
-- 2
~z~
purpo3e straight or branched, with water u~restrictedly
mlscible aliph~tic alcohol~ can be u3e~, such
metha~ol, ethanol, n-propanol, isopropanol~ etc. '~he reactio~
i3 pre~erably performed i~ the ~ixtuxe of n alcohol and ~a-ter,
preferably in ~ /50 98/:/2-50/ mixture of the~e Yol~enta.
When the reactio~ termi~ate~, the Qlcohol concentratio~ i3
adju~ted to 40-60, pre~erably to about 50 ~0 bg the addition
o~ water /ice/ or ~lcoholO
The reactio~ i~ carried out in the presence of a ~a3e~
~or thi~ purpo~e organic base~ /pyridi~e or pyridine ba~es,
that i~ the mi~ture~ of 2-, 3- and 4-picoline a~d lutidi~e,
re~pectiYely/ or o~ ~ ic base~ ~alkali hydro~ide~, carbonate~
or hydrogan carbonate~J can be u~ed.
The reaction temperature doe~ not influence the yield
e~e~ially and m~y be varied in a wide intarval. ~ne proceed~
generally between 20 C and 90 C, preferably betwee~ 75 ~
~nd 85 C.
~ha ~tereochemical purity of the th~s-obtained 2-/E/-
-phe~ylmethylenecyclohept~n~l one-/E/-o~ime depe~dq o~ that
o~ the 2-/~/phenylmethylenecycloheptan-l-o~e u~ed for the
reaction. ~amely, i~ thi3 latter compou~d i~ contami~ated
with a greater amount of it~ 2-/Z/-iJomer, the number o~ the
po~ible isomer co~taminations i~crea~es twofold, and the im~
purity of the thu~-obtained product may e~ceed the limit ~ive~
above~
If a particularl~ pure product i~ needed, the crude
product obtai~ed in the re~ctio~ c~n be pured b~ methods knowm
per 3e /e~g~ col~mn chromatogxaphy~ di~tillatio~, melti~g
in zone3, cry3tallization from petroleum ether or from eth~nol~.
3 The inve~tion i~ illu~tr~ted by ~he ~ollowi~g E~mple3
27
4 --
o~ non-limiti~g character:
E~ample 1
20 g ~Ool mole/ o~ 2~/E/-phenylmethylenecycloheptan-
-l-one and 7.65 g /0.11 moles/ o~ hydroxylamine hydrochloride
~re di~olved in 100 cm3 of 96 /o ethanol, and ~.94 g /o~o56
mole ~ of ~odium carbo~ate a~e added to the raaction mixtuxe,
under ~ti~ring. ~he~ it i.s heated to boiling and kept at the
~ame temperature until the gaq formation /carbon dioxide/
terminate~. Thereafter 98 g of crushed iC2 are added to the
reaction mixture, and the 2~ phe~ylmethylenecycloheptan-
-l-one-/E/-o~ime 3eparated in ~orm of cry3t~1~ i3 filtered
off.
Yield: 19~8 æ /92 ,'/ o~ white cry~tal~. M~p~o 67 C
Analy~ 4H17~0 /215.29f
Calculated: C: 7~ . 7.96 ,'0 ~: 6.5 ,0
Fou~d: G: 78.0 -~0 H: 8.0 ,~0 ~: 6.5 Yo
~P~ /CDC13~: 6 . 95 pp~
6055 ppm
2020 5 ppm
U-V-; ~ m~x 258 n~ mh /258/ ~ 740.23
EgamPle 2
To a 301ution of 20 g /0.1 mole/ of 2-/E/-phenylmethyle~e-
cyclohepta~ one in 100 cm3 of methanol 7.64 g /0,11 moles/
of hydroxylamine hydrochloride a~d 8.7 g /0.11 mole~ o~ py-
ridine are addedO The reaction mi~ture i~ ~tirred at room
temperatu~e for 2 hour~, a~d 100 g o~ cru~hed ice a~e added.
The desired compound 3eparate~ i~ Porm oP while cryatal~O
Yield~ 16.55 g /76.97 ~! Mop~ 66-67 C
0`2~'
-- 5 --
~naly3i3: the data are identical to tho~e give~ in E2ample 1.
E~ample 3
20 g /0.1 mole/ of 2-/E/-phenylmethylenecyclohepta~-:L-
-one, 7.64 g /0.11 mole~/ of hydroxylamine hydrochloride an~
5.83 g /0 D55 mole~/ of sodium carbonate are allowed to react
in 200 cm o~ a ].:1 mi~ture o~ ethanol and water at the boil-
ing point of the reaction mi~ture, the~ it i~ cooled ~o a
temperature between 5 C and 10 C under ~igorou~ stirring.
~he crystalline 2-~E/-phe~ylmethylenec~cloheptan~l-one~
-o~ime i~ i~olated from the reaction mixture by filtrationD
Yield: 17.65 g /82 -~0/. M.p.: 66-67 C
~xample 4
20 g /Ool mole~ of 2-/E/-phenylmethyle~ecycloheptan-
-l o~e, 100 cm3 of water, 8.7 g ~0.11 mole3/ o~ pyridi ~ a~d
7.64 g ~0.11 ~ole3/ of hydroxyl~Ine hydrochloride are vigorou~-
ly 3tirred at 80 C for a ~ew hours, the~ 100 cm3 o~ ethanol
are added to the reaction mixture, ~nd it i~ stirxed u~til
crystalli~tion~ under 310w cooli~gO
Yield: 15.7 g f72O92 5~/ of white, cry~talline 2-~E/-phenyl-
methyl~necycloheptan-l-one /E/-o~ime. ~Op~` 65-67 C.
E:gamPle 5
2~ 20 ~ /0.1 mole/ o~ 2w/E/-phenylmethylenecycloheptan~l-
-one and 21.4~ g ¦0~11 molesf o~ hydxo~yl~;ne sul~t~ are
mea~uxed to a mixture o~ 95 cm3 o~ propanol a~d 5 cm3 o~
water. ~hen 10.94 g /0.056 mole~/ o~ po-t~s~ium carbo~ate are
added, under ~tirri~g. After boiling the mixture ~or a few
- ~o hour~ the reactio~ te~minate~ he~ t~e mixture i~ cooled
~2~
to about 50 C~ 100 g of cru3hed ice are added, the cry~tal~
are fil-tered off and dxied4
Yield: 18.48 g /a7.5 ~io/ of white cry~tal~ cont~i~in~ at lea~t
95 ~o of 2~E/ phenylmethyle~ecycloheptan-l~one-/EI-o~ime.
M.p.: 67 C
An~ly`~i~ C14~17~ /215~29/
~alculat~d: C: 78~ 7096 v/0 ~: 6,5 ~
~ound: C: 77.91 ,~ H: 7,8 ~0 ~: 6.47 ~0
ExamPle 6
20 g J0.1 mole~ of 2-/~/ phenylm~thylQnecycloheptan-l-
o~e ~nd 7.65 g /0.11 mole~/ of hydro~yl ~m; ne hydrochloride
~re heated to boiling in 100 c~3 of etha~ol, under vigorous
stirring, and a solution of 6.17 g /0.11 mole3/ of pota~ium
hydroxide in loo cm3 of water i~ dropped to the reactio~ mix-
ture~ The~ it i9 allowed to react for hal~ an hour, ~lowly
cooledl and the separated 2-/E/-phenylmethylenecycloheptan-1-
-one-/E~-oxime is filtared o~fO
Yield: 2003 g /94.3 ~/0/. Mop~ 67 C
~xample 7
20 g /0.1 mola/ o~ 2~/E~-phe~ylmeth~lenecycloheptan-l-
-o~, 7.65 g /0~11 mole~/ of hydro~ylamine h~drochloride, 90
cm3 o~ ethanol, 10 cm3 o~ water and 9.24 g /0.11 mole3/ o~
sodium hydroge~ carbo~ate are boiled for 3 hours, under s~xr ~ .
Then 80 g of cru3hed ice are added to t~e reaction mi~ture,
a~d th~ 2-JE/-~he~ylmethylenecgcloheptan-l-o~-/E/-o~ime ~e-
parated in ~orm of white Gry~q-tals i~ fil~ered off and dri2d~
YieldO 20.2 g /93.8 C,~o/- M.p.: 67 C
Analy~is: C14H17~0 /215~29J
~ , ~... . .
-- 7 --
Calculated: C: 78.1 ~7.96 ,0 N: 6.5 -~0
Found: C: 78.23 ~ioH: 7.72 ~ ~: 6.53 ~0
