Note: Descriptions are shown in the official language in which they were submitted.
~Sl~
The present invention relates to a process for preparing
cyclopentane derivatives of the formula I
~ 2 H
H2C~ ~H2 S
~ ~ 5-
H2
CHO
wherein yl and Y~ are identical or different from each other
and represent a simple bond, a -CH2-group or a ICH3 group.
-,C-
The process comprises CH3
al) reacting a 3-(2-oxopentyl)-propionic aci.d ester of the
formula II
1 II
~ C02R
wherein Rl is a straight-chained or branched alkyl having
1 to 4 carbon atoms or cycloalkyl having up to 6 carbon
atoms, with the enol ester of a low boiling ketone to a
compound of the formula III
o ' ~ .,
R2 11_
III
~-- C02R
wherein Rl has the same meaning as in formula II, and
R is an alkyl radical having 1 to 7 caxbon atoms,
a2) converting the enol ester of the formula III with a
- 2 -
:, . . . ~ . :: - :~
halogenating agenk inko a halogen ketone o~ the formula
IV
~ CO2Rl IV
:~
wherein Rl has the same meaning as in formula II and X
is chlorine or bromine, or , .
a2,) halogenating the keto ester of the formula II directly
to compounds of the formula IVr ...
a3) splitting off hydrogen halide from the halogen ketone of
the formula IV with an acid~binding compound, whereby ~
an unsaturated keto ester of the formula V . :
f~ 1 `'
~ C2R
wherein Rl has the same meaning as in formula II, i5
formed,
a~) reacting the unsaturated keto ester of ~he formula V
with hydrogen cyanide or a cyan hydrine in an alkaline
medium to a nitrile of the formula VI
CO2Rl VI
CN
-25 wherein R has the same meaning as in formula II,
a5) .reacting the nitrile of the formula VI with a diol of
the formula VII
_~ _ 3 _
~o~
HO - CH2 - Y - CH2 - OH VII
wherein Y has the same meaning as in formula I, in
he presence of acidic catalysts to a ketal of the formula VIII
y2
H2 ~C fH2
o O ~O2Rl VIII
CN
wherein R has the same meaning as in formula II and ~.
Y has the same meaning as in formula I,
a6) reducing a ketal of the formula VIII with a suitable
reducing agent to an alcohol of the formula IX
H2~ 1CH2
CH20H
~ IX
C~ '
wherein Y has the same meaning as in formula I, or :.
a6,) saponifying selectively a ketal of the formula VIII with
aqueous bases to a carboxylic acid of the formula X
H2 ~ C1~2
~ ~ C~2H X
CN .
wherein Y has the same meaning as in formula I and
- 4 - :
,.,
~"
reducing this acid subsequently to the alcohol of the
formula IX,
a7) oxidizing the alcohol of the fo.rmula IX to an aldehyde
of the formula XI -
2 - :
H2 ~ ~H2 ~
o CHO XI ~-
~/ ,-, ;,~'.~''
~ .
CN
wherein Y has the same meaning as in formula I, or
a7,) reducing an ester of the formula VIII to an aldehyde of
the formula XI,
a8) converting the aldehyde of the formula XI with a dithiol
of the formula XII
HS - CH2 - Y - CH2 - 5H XII
wherein Y has the same meaning as in formula I, in the
presence of acidic catalysts into a compound of the formula
XIII
~2 ~~/ l XIII
Cl~ ~:
wherein yl and y2 has the same meaning as in formula I,
and
a9) reducing the compound of the formula XIII to an aldehyde
of the formula I, or
, . .
~ _ 5 - -~
"' ., . . , . ...... : ,, . ; ' ' , . !: ,. ' -
' " . ' . ' '. . : ' '' ' ' ' " ' ' l i~
-
~L~5~
b1) reducing a compound of the formula VI
~ CO~Rl VI
~\ . :
CN
wherein Rl has the same meaning as .in formula II, with
a suitable reducing agent to the diol of the formula XIV,
HO
C~12H
~ XIV
10 ` L~ "
CN . ,
b2) oxidizing the diol of the formula XIV to a keto aldehyde
of the formula XV,
R CHO
~
XV
CN
b3) reacting the keto aldehyde of the formula XV selectively
with a dithiol of the formula XII
. HS- C~ _ yl _ CH~ - SH XII
wherein Y has the same meaning as in formula I, to a
compound o~ the ~ormula XVI
H2
~ C ~ _ ~ 1 XVI
CN
;:
wherein yl has the same meaning as in formula I,
b4) converting the compound of the formula XVI with a diol of
the formula VII
HO CH2 - Y - CH2 - OH VII
wherein Y has the same meaning as in formula I, in the
presence of an acidic catalyst into a compound of -the
formula XIII
~ H2 - XIII
CN
wherein Y~ and y2 has the same meaning as in formula I
~15 and
b5) reducing the compound of the formula XIII to an aldehyde
of the formula I, or
cl) reacting a cyclopentanone derivative of the formula XVII
: ~ R3
~ XVII
wherein R3 is the nitrile group or a low molecular di-
: alkyl-amino-carbonyl group, with the enoI ester of a low
boiling ketone to a compound of the formula XVIII
1 ¦ R3 XVIII
. ,
wherein R has the same meaning as in formula III and R3
-- 7 --
has the same meaning as in formula XVII,
c2) convering the compound of the formula XVIII into a
halogen ketone of the formula XIX
X R
~ ~ / XIX
wherein R3 has the same meaning as in formula XVII and X
represents chlorine or bromine, or
c2,) halogenating a cyclopentanone derivative of the formula
XVII directly to a compound of the formula XIX,
C3) splitting off hydrogen halide from the halogen ketone of
the fonmula XIX, whereby a cyclopentenone derivative of
the formula XX
. ~ R3
I5 ~ / XX
wherein R has the same meaning as in formula XVII, is
formed, :,
C4) preparing from a cyclopentenone derivative of the
formula XX or V by reaction with a diol of the formula VII
HO - CH2 - Y - CH2 - O~ VII
wherein Y has the same meaning as in formllla I, a ketal
of the formula XXI
~2
H2~ f~2 ` ~
~ R . XXI ~.~
~ .
~ .
.
~s~
wherein R represents nitxile, an alkoxycarbonyl group haviny
2 to 7 carbon atoms or a low molecular dialkylaminocarbonyl
group, and Y has the same meaning as in formula I,
C5) reducing the ketal of t~e formula XXI to an aldehyde of
th~ formula XXII
H2 ~ ICH2
~ _ CHO XXII
wherein Y has the same meaning as in formula I,
c6) conve~ing the aldehyde of the formula XXII by reaction
with a dithiol of the formula XII
HS - CH2 _ yl _ CH2 - SH XII
wherein yl has the same meaning as in formula I, into a
thioacetal of the formula XXIII
H C/ \CH S~q~l XXIII
~ H2
wherein yl and y2 has the same meaning as in formula I,
C7) removing selectively from the compound of the formula
XXIII the ketal group, whereby a compound of the formula
XXIV
.. , . , ~ :
-
~ ~ S ~ 1 XXIV
wherein Y has the same meaning as in formula I, is
obtained,
c8) adding hydrogen cyanide to the compound of the formula
XXIV, whereby a compound of the formula XVI
0 S-C2y1
~ \S-C/ XVI
1 ~ H2
CN
wherein yl has the same meaning as in formula I, is
obtained,
c~) converting the compound of the formula XVI with a diol
of the formula VII
HO - CH2 - Y - CH2 - OH VII
wherein Y has the same meaning as in formula I, in the
, .
presence of an acidic catalyst into a compound of the formula ;.. .
XIII :
H ~/ ~ CR 2 :
o ,p ~ ~1 XIII ~:
~ S-C~
CN
and
- -- 10
... : . .. . . : . . - . ; .. :
51a~
c10) reducing the compound of the formula XIII to an aldehyde
of the formula I, or
dl) adding hydrogen cyanide to 2-allyl-2-cyclopentane-1-one
of the formula XXV
O
Il XXV
~~ .
in an alkaline medium to yield the 2-allyl-3-oxocyclopentane-
carboxylîc acid nitrile of the formula XXVI
Q
~ ' .
XXVI
CN
d2) conver~ng the nitrile obtained of the formula XXVI with
a diol of the formula VII
HO - CH2 ~ Y C~2 VII
wherein Y has the same meaning as in formula I, .,
in the presence of an acidic catalyst into a ketal of
the formula XXVII
y2
H2l ICH2 XXVII
~ ' ,.
CN .
wherein Y. has the same meaning as in formula I,
d3) hydroborating the ketal of the formula XXVII, whereby an
alcohol of the formula IX
: ~ ' ' ' . , ' ' :-
..
y2
CH20H
\
2 :~
wherein Y has the same meaning as in formula I, is
obtained,
d4) oxidizing the alcohol of the formula IX to an aldehyde :;
of the formula XI ~2
/ \ XI
CHO
~ CN
wherei~ y2 has the same meaning as in formula I,
d5) reducing the aldehyde of the formula XI with a dithiol
of the fo.rmula XII
HS - CH2 ~ Y ~ CH2 ~ SH XII
wherein Y has the same meaning as in formula I, in the :~
presence of an acidic catalyst into a compound o the formula
XIII
/ \ 2
H21C ICH2 S-C\l XIII
O O / Y
~>~/\S-Ct
L H2
CN
wherein yl and Y has the same meaning as in formula I and
~ - 12 -
d6) reducing the compound of the ormula XIII to an aldehyde
o~ the formula I.
Among the meanings mentioned for the radicals Rl and R2
alkyl radicals having 1 to 4 carbon atoms are pre~erred for
Rl, and alkyl radicals having 1 to 3 carbon a~oms are preferred
for R .
The process of the invention begins (al) with the reaction
of 3-(2~oxocyclopentyl)-propionic acid esters of the formula II, ~;
which may be prepared according ~o a process described in
J.Amer.Chem. Soc. B5~ 207 (1963) to enol esters of the formula
III. This reaction is obtained according to known methods,
for example by reaction with esters of enols deriving fxom low
boiling ketones. As enol ester there is preferably considered
isopropenyl acetate. The reaction is carried out in the
presence of acidic catalysts such as p-toluene-sulfonic acid,
concentrated sulfuric acid or acidic ion exchangers in the
presence or absence of an inert solvent as for example cyclo-
hexane or benzene.
A preferred variant of the process consists in heating a
3-~2-oxocyclopentyl)-propionic acid-low alkyl-ester with iso-
propenyl acetate in the presence of catalytical amounts of
p-toluene-sulfonic acid and distilling off the acetone formed
in the reaction. When the reaction is finished the acid is
removed or example with sodium carbonate and the enol ester
III desired is obtained by vacuum distillation.
Enol esters of the general formula III may be converted
into halogen ketones of the formula IV (a2) with halogenating
agents, as for example N-bromo-succinimide or elementary
29 halogen, preferably bromine.
- 13 -
1`' . , . -
As reaction medium there are suitable inert solvent3 such
as hydrocarbons, for example petroleum ether or cyclohexane or
halogenated hydrocarbons such as carbon tetrachloride, chloro-
form or methylene chloride, if desired in combination with
water.
The reaction is carried out at temperatures between -10
and +50~C, preferably between -5 and +5C, whereby it is
more pr ferably to work in the presence of acid-binding agents
such as sodium hydrogen carbonate or calcium carbonate.
A preferred variant of the process consists in adding
dropwise at OC the molar amount of bromine to a mixture of
the enol ester III in chloroform/water and isolating the bromo-
ketone desired after washing and evaporating the organic phase.
The crude product is preferably subjected to the following
dehydrohalogenation reaction without further puri~ication.
The halogen ketones of the formula IV may be prepared in
a simple way (a2') by reacting the keto esters of the formula
II directly with a halogenating agent as for example elementary
halogen, preferably chlorine or bromine, a hypohalogenite such
as sodium hypobromite, a N-halogenimide as for example N-chloro-
succinimide or N bromo-succinimide or preferably with sulfuryl
c'hloride.
The reaction may be carried out without solvents, but is
preferably carried out in inert solvents, as or example in
hydrocarbons such as pentane or cyclohexane, in halogenated
hydrocarbons such as carbon tetrachloride or chloroform or
1,2-dichloro-ethane, or in low molecular carboxylic acids such ?
as acetic acid, i~ desired in the presence of an acid-binding
29 agent such as sodium hydrogen carbonate or calcium carbonate~
- 14 -
~.~
- ~5~ ~
Halogenation is carried out at temperatures of 50 to
100C, preferably at -10 to 30C.
A preferred variant of the process consists in adding
dropwise sulfuryl chloride at 0 to 30 C to a solution of the
ester II in carbon tetrachloride and evaporating the reaction
mixture when the development of the gas has finished~ The
residue is taken up in a solvent not miscible with water and
washed until neutral reaction with a bicarbonate solution.
By evaporating the crude chloroketone is obtained which is It'
expediently further reacted without any further reaction.
For the splitting of hydrogen halide from the halogeno-
ketones IV to the compounds V (a3) there are suitable acid-
binding substances, for example organic and inorganic bases,
as for example aliphatic and heterocyclic amines such as tri-
ethyl amine, ethyl-dicyclohexyl amine, N,N dimethyl aniline,
N-phenyl-morpholine, 1,5-dia~abicyclo/3,3,07-nonene-5, pyridine,
quinoline, collidine, hydrazines such as tetramethyl hydrazine i~
or dinitrophenyl hydrazine, alcoholates such as sodium methylate
or potassium tert.-butylate, amides such as sodium amide,
hydrides such as sodium hydride, phosphines such as triphenyl-
phosphine, phosphites such as trimethyl phosphite, metal oxides
such as silver oxide, basic ion exchangers or salts of organic
or inorganic acids such as sodium acetate, benzyl-trimethyl-
ammonium mesitoate, potas~ium carbonate, calcium carbonate,
sodium hydrogen carbonate, sodium phosphate
or halides such as sodium fluoride, tetraethyl-ammonium chloride,
lithium chloride or lithium bromide.
Dehydrohalogenation may be carried out in the presence or
29 absence of a suitable solvent. Suitable solvents are aliphatic
- 15 -
, .
~()5~
or ar~matic hydrocarbons such as pe~roleum ether, cyclohexane
or benzene, halogenated hydrocarbons such as methylene Ghloride,
carbon tetrachloride, tetrachloro-ethylene, ethers such as
diethyl ether, dioxane or tetrahydrofurane, low-molecular
alcohols such as ethanol, esters such as ethyl acetate, ketones
such as acetone, nitriles such as acetonitrile, or in combination
with the above-mentioned aprotic solvents such as dimethyl~
formamide, dimethyl sulEoxide, sulfolane, N-methylpyrrolidone
or hexamethyl-phosphoric acid triamide.
The reaction is carried out at temperatures of -30 ~
~50C, preferably at 0 to 50C. In a preferred variant of the
process the hydrogen halide is split off in an inert solvent
such as benzene or carbon tetrachloride with triethyl amine at
temperatures of 10 to 50C. The reaction mixture is sub-
sequently washed with water and diluted acetia acid and the
compound is obtained by distillation. It contains to a low
extent the saturated cyclopentanone derivative II, which, how-
ever, can easily be split off in the distillation of the
following reaction step VI.
2n To prepare the nitriles VI (a4~ hydrogen cyanide is added
in the presence of basic catalysts to the ~ unsaturated
ketone V. As source for the hydrogen cyanide there are con-
sidered cyanides such as sodium and potassium cyanide, pre-
~erably in the presence of a somewhat smaller molar amount o
an acid, so that the reaction medium remained alkaline.
Especially suitable are hydrocyanic acid or a cyanohydrine,
as for example acetone cyano hydrine in -the presence o an
alkaline catalyst such as sodium cyanide, potassium carbonate,
29 an alkali metal alcoholate such as sodium methylate or a basic
~; . :: : ., , ,, ~ , ~-,
~ 5~0~L
ion exchanger ~or this reaction.
The reaction may be carried out in the absence or presence
o~ a suitable solventO Suitable solvents are hydrocarbons as
for example benzene or cyclohexane, chlorinated hydrocarhons,
for example methylene chloride or carbon tetrachloride, ethers
such as diethyl ether, tetrahydrofurane or dioxane, ketones
such as acetone, nitriles such as acetonitrile, and dipolar
aprotic solvents, as for example dimethylformamide or dimethyl-
sulfoxyde.
Especially preferred are low molecular alochols such as
methanol, ethanol or tert.-butanol. The hydrogen cyanide
addition may be effected at temperatures of from -20 to
+100C, preferably at 10 to 50Cc
A preferred variant of the process consists in reacting at
room temperature the cyclopentenone V with a small excess of
acetone cyanohydrine in the alcohol Rl-OH in the presence of
catalytical amounts of an alcoholate Rl-OMe, whereby Rl has
the same meaning as in formula II and Me is a metal, preferably
an alkali metal such as sodium.
When the reaction is finished and, if desired, the solution
is adjusted to neutral, the reaction mixture is distribu~ed
between water and a solvent not miscible with water and the
nitrile VI is obtained by distillating khe organic phase.
On prlnciple, this reaction step implies the appearance
of cis-trans-isomers. On account of the tests of D.Varech et.
al., ~ull. Soc. Chim. 6, 1622 (1965) the more stable trans-
configuration is preferred under alkaline conditions.
In the course of the process described for preparing comp-
29 ounds of the general formula I several spirocyclic nitriles
- 17 -
.. ~. ~ . . ., . . . , .. :
~s~
(for example compounds of th0 formula VIII, IX, X, XI, XII,
XXVI) are described in which under conditions o~ balance/
i.e. in an alkaline medium, cis-trans-isomer mixtures may
appear which may be separated chromatographically. The further
process may be carried out with the pure isomers or the isomer
mixtures, which, however, is not important for the further
course of the synthesis, since at the end of th~ prosta-
glandine synthesis the two aliphatic side chains at the cyclo-
pentanone ring accept under alkaline conditions the trans-
configuration which is more stable with respect to thermo-
dynamics.
Hence, the uninterrup~ed binding iines in tha mentioned
formulae of the cyclopentane-carboxylic acid nitrile deri-
vatives imply cis and trans-isomers.
Ketals of the formula VIII (aS) are obtained from the
ketones VI by acidical].y catalyzed condensation with diols o~ ;
the formula VII. The reaction preferably proceeds in the
presence of water-binding substances such as MgSO4, CaCl2,
molecular sieve (poxe diameter preferably 3 - 4 A) r or an
oxtho ester by azeotropic distillation of the water formed.
As acidic catalysts there are suitable for example acids
such as p-toluene-sulfonic acid, oxalic acid or fumaric acid,
acidic ion exchangers or Lewis acids such as borotrifuloride
ethexate. The ~ormation o~ ketal is preferably carried out in
aprotic solvents, such as chlorinated hydrocarbons, for example
methylene chloride or chloroform, or open-chained or cyclic
ethers such as dialkyl ethers, glycol dialkyl ethers, diglycol-
dialkyl ethers, tetrahydrofurane or dioxane.
29 Especially preferred are hydrocarbons such as benzene,
~- - 18 - ~
~'`.
~I)Sl~
toluene or xylene.
In a preferred variant of this process step the ketone VI
is heated wi~h l to 3 mols of the diol VII in benzene or
toluene in the presence of borotrifuloride etherate and the
reaction water is distilled off azeotropically. The reaction
product may be puri~ied by distillation after working up.
The ester function of the compounds VIII may be reduced
selectively to the alcohols of the formula IX (a6). There are
suitable ~omplex metal hydrides, for example sodium bis-(2-meth-
oxy-ethoxy)-aluminium hydride ~vitrides) or lithium boro-
hydride. The lithium borohydride may also be prepared in situ
from sodium borohydride and lithium chloride. Preferred
solvents in this reduction are hydrocarbons such as benzene
and especially ethers such as tetrahydrofurane, dioxane,
dimethoxy-ethane or diethylene-glycol dimethyl ether.
In a preferred variant of the process of the invention the
esters VIII are h~ated with lithium borohydride in tetrahydro-
furane for about 2 to 4 hours under reflux, neutralized with
glacial acetic acid, and after evaporation of the solvent the
product is taken up in a solvent not miscible with water, for
example diethyl ether. After washing with water and con-
centrating the crude alcohol IX is obtained, which may be
directly further reacted or purified by distillation or chroma-
tography.
Alcohols o the Eormula IX are also obtained (a6,) by
saponifying the esters VIII selectively to the carboxylic acids
X, for example with (1 to 1.5 mols of) a base such as KOH in
a suitable solvent such as ethanol or a dioxane/water mixture
29 at temperatures between 0 and 50C, preferably at room
., -- 19 --
.
,
. . . , ~ :
~ s~
temperature, and reducing the carboxylic acids X thus pre-
pared with a selective reducing agent to the alcohols IX.
For this reaction there are especially suitable boron hydrides,
for example dihorane in a suitable solvent such as dimethoxy-
ethane or tetrahydrofurane.
The oxidation of compounds of the formula IX to compounds
of the formula XI (a7) is effected with oxidizing agents,
which are usual for the oxidation of aliphatic alcohols to
aldehydes. Some methods are indicated for example in Houben-
Weyl, Methoden der Organischen Chemie, volume 7/1, GeorgThieme Verlag Stuttgart 1954, page 159 et seq.
Further suitable oxidizing agents are lead tetra-acetate,
manganese dioxide, the complexes formed from thioethers such
as dimethysulfide or thioanisole with chlorine or N-chloro-
succinimide (J. Amer. Chem. Soc. 94, 7586 (1972), J. Org. Chem.
38, 1233 (1973) 5 and dimethyl sulfoxide with different core-
actants (J. Amer. Chem. Soc. 87, 5661 ~1965), 88, 1762 (1966),
89, 5505 (1967) Chem. Rev. 67, 247 (1967)).
A particularly preferred process is the oxldation with
chromium trioxide in the presence of pyridine, if desired with
methylene chloride as solvent, as described in Tetr. Lett. 3363
(1968).
It is also possible to prepare aldehydes of the ~ormula XI
directly from the esters of the general formula VIII (a7,)~ ;
For this selective reduction there are suitable complex metal
hydrides such as lithium aluminum hydride, sodium aluminum
hydride, sodium-bis(2 methoxy-ethoxy)-aluminum hydride or metal
hydrides. The calculated amount of reducing agent or if
29 desired, a small excess (1 - 1.2 redox equivalents) is used;
. ~:
~. ,, ;
- 20-
~510~
the temperatures axe between +20 and -100C, pre~erably between
-30 and -80C A~ solvents there are suitable such which are
inert with regard to reducing agents for example hydrocarbons
such as toluene or cyclohexane or ethers such as diethyl ether,
tetrahydrofurane ar 1,2-dimethoxy-ethane.
In a preferred variant of the process a solution of 1.2 mols
of diisobutyl aluminum hydride in toluene is added dropwise
under an argon atmosphere and with stirring at -65 to -75 C,
to a solution of 1 mol of nitrile ester VIII. After stirring
for 1 to 3 hours at this temperature the reaction mixture is
heated to -30C and a~ter another hour the reducing agent
in excess is destroyed with methanol. After the hydrolysis of
the aluminum-organic compounds with water and acetic acid the
aldehyde XI is obtained by evaporating the organic phase.
Aldehydes ofthe formula XI may be prepared in pure form
in usual manner, for example by distillation or chromatography,
but it is advantageous to react them directly in pure form in
the presence of acidic catalysts in inert solvents with
dithiols of the formula XII to the dithioacetals of the general
formula XIII (a8).
For this reaction there may be used the solvents and acidic
catalysts as they are described above for the reaction of the
ketones VI to the ketals VIII.
A preferred variant of the process ofthe invention con-
sists in reacting the crude aldehyde XI with a small excess ofa dithiol of the formula XII in the presence of borotrifluoride
etherate and, if desired, of a water-binding agent such as
magnesium sulfate in benzene or methylene chloride at temper-
29 atures between 10 and 50.
- 21 -
, . ., , , ~ .
~L~51~
The dithioacetals XIII thus obtained may ~inally be re-
duced in known ma~ner to the aldehydes of the formula I (a9),
expediently after chromatograhic purification. There axe
suitable all reducing agents known for the reduction of
nitriles to aldehydes, preferably complex metal hydrides such
as lithium triethoxy-aluminum hydride. Especially preferred is
diisobutyl-aluminum hydride in nert solvents such as aliphatic
or aromatic hydrocarbons or ethers free from water such as
diethyl ether~ tetrahydrofurane or 1,2-dimethoxy-ethane.
Compounds of the formula XIII are obtained from the com-
pounds VI also according to the following process-steps:
At first the keto esters VI are reduced to the diols of
the formula XIV (bl). As concerns reducing agent and reaction
conditions it is possible to proceed in analogy to the process
described for the reduction of the ketal esters VIII to the
ketal alcohols IX. Lithium borohydride in an ether such as
tetrahydrofurane is the preferred reducing agent.
For the oxidation of the diol XIV to the ketoaldehyde XV
(b2) the methods mentioned for the oxidation of the alcohols IX
to the aldehydes XI may be used. Since both hydroxyl groups of
XIV have to be oxidized, the double amount of the oxidating
agent is required.
The keto aldehyde XV may be purified in usual manner, for
example by distillation or chromatography.
However, it is advantageous to react it in a crude form in
inert solvents with dithiols of the general formula XII to the
thioacetals XVI (b3).
A preferred variant of the process of the in~ention con
29 sists in reacting the aldehyde XV obtained with about 90~
.
, - 22 -
.,. . '.'' '. ," ,.' ,'~'' `, .' ' .'` :
~o~
purity with the equimolar amount of a dithiol of the
formula XII, as for example 1,2-dimercapto-ethane in the
presence of acidic catalysts, preferably borotrifuloride
etherate in the presence of a protective gas free from oxygen
such as nitrogen or argone in an aprotic solvent such as for
example benzene or toluene between 30 minutes and 5 hours at
temperatures between 15C and 50C. In the compounds of the
formula XV the aldehyde group is protected selectively.
The remaining keto group in the thioacetals of the
formula XVI is protected by ketalization with the diols of
the formula VII in aprotic solvents in the presence of acidic
catalysts, whereby the ketal thioacetals of the formula XIII
are obtained (b4). An especially preferred process is the
ketalization of X~ with diols of the formula VII, for example
ethylene glycol or neopentyl glycol, whereby the reaction
components are heated in benzene or toluene for 3 to 5 hours
at the water separator in the presence of p-toluene-sulfonic
acid or borotrifluoride, whereby the ketal-thio-acetals of the
formula XIII are obtained.
The compounds of the ~ormula XIII may then be ~urther
reduced, as described abovej to the aldehydes of the formula
I (b5)-
Dithioacetals of the formula XVI may also be prepared on
the basis of the cyclopentanone derivatives XVII. At first
the compounds of the formula XVIII are pxepared (cl) from the
compounds of the formula XVII. m e preparation is completely
analogous to the preparation of the compounds of the formula
III from the compounds of the formula II described above.
29 There is also preferred in this case the reaction of the
- 23 -
: . . .: - . : .
. . ' . ; ` ` ' ' ' "` ''' ~ ' ~ ":
~ 51~
compounds of the formula XVII with isopropenyl ~cetate in the
presence of an acidic catalyst such as p-toluene-sulfonic acidr
with simultaneous distillation of the acetone formedO
The further development of the reaction, i.e. the halogen-
ation of the enol ester~ of the general formula XVIII to thehalogenoketones XIX (c2) an~ the following dehydro-halogenation
to the cyclopentenones XX (c3) also proceeds in a way com-
- pletely analogous to ~he development of the reaction des~
cribed above for the halogenation of compounds of the formula
III to the halogeno-ketortes IV and the dehydrohalogenation
thereof to the cyclopentenones V. ~.
As described above for the preparation of the compounds of
the formula IV from the compounds of the formula II, it is also
- possible to ob~ain the halogenoketones XIX directly by halogen-
a~ion from the cyclopentanones XVII, without the reaction with
the enol esters XVIII (c2~).
The cyclopentenones XX are then reacted with diols of the `~.
formula VII in the presence of acidic catalysts in an inert
solvent to the ketals of the formula XXI (c4), whereby the
resulting reaction water is dis~illed off azeotropically or is
taken up with a water-binding.agent. The individual reaction
steps are the same as described above for the reaction o the .
formula VI to compounds of the formula VII.
The ketals o~ the formula XXI are reduced to the aldehydes
of the general formula XXII (c5). For this purpose there are
considered the reduction of esters, nitriles or dialkyl amides .
to aldehydes. There may be mentioned for example diisobutyl
aluminum hydride, sod.ium aluminum hydride, lithium aluminum
29 hydride, lithium trîethoxy aluminum hydride, bis-3-methyl-2-
~,."~ .
- 24
.... ,, .,, .,: .:. ,. .. ~ ,..... . , : . : . .
..... .: . ., ::. :: , .. ,., ~ , . , .. , : . .. , :
5~
butylborane ("disiamyl borane") and sodium-bis-(2-methoxy-
ethoxy)-aluminum hydride ("vi~rides").
As solvents there are considered those which are inert
wlth regard to the reducing agent used, for example aliphatic
or aromatic hydrocarbons such as hexane, cyclohexane, benzene
or toluene or ethers such as diethyl ether, tetrahydrourane,
dioxane or 1,2-dimethoxy-ethane~
The reduction is carried out at temperature~ between -80
and +30C, according as an ester, nitrile or carbonamide group
is reduced to an aldehyde group and depending on the reducing
agent used. Thus, the reaction is carried out or example
between -60 and -80C, if an ester group is reduced with di-
isobutyl aluminum hydride to an aldehyde group, whereas for
the reduction of a dimethylamino-carbonyl group to the formyl
group with l~thium triethoxy-aluminum hydride temperatures of
from -10 to ~10C are maintained.
The aldehydes of the formula XXII are converted with
dimercapto compounds of khe formula XII into the dithio-
acetales of the formula XXIII (c6). The reaction is com-
pletely analogous to that described above for the reaction of
the aldehydes XI with the dimercapto compounds XII to the
dithio-acetales XIII.
The dithio-acetales XXIII obtained by this way may be
purified chromatographica~ly or directly further reacted.
The splitting of the ketal yroup from the compounds of
the formula XXIII proceeds under acid catalysis (C7). This
reaction may be carried out in a mixture of an organic solvent
with water, either in a homogenous or two phase system, for
29 example in 1,2-dimethoxy-ethane/water or diethylether/water.
- 25 -
.. ~ ~ : , ; . :.:: ............ .. : :. ., :
- : ~ :: '. : : ::
It is al~o possible to tran~fer the ketal group to a ketone
present in excess, such as acetone.
As catalysts there are used inorganic and organic acids,
for example phosphoric acid, sulfuric acid, p-toluene-sulfonic
acid, oxalic acid or fumaric acid, furthermore acidic salts
such as sodium hydrogen sulfate or acidic ion exchangers.
The temperatures range between -10 and +100C, preferably
at 20 - 50C.
When the reaction is finished the product is taken up in
a solvent not miscible with water such as diethyl ether or
benzene and the organic phase is washed free from acid. After
evaporation the crude cyclopentenones-XXIV are obtained which
may be purified chromatographically or by distillation.
Hydrogen xyanide may be added to the cyclopentenones of
the general formula XXIV in an alkaline medium, whereby
nitriles of the general formula XVI are formed (c8).
The procedure is the same as described above in detail
for the addition of hydrogen cyanide to the cyclopentenones of
the formula V to the compounds of the formula VI.
The nitriles of the formula XVI are then reacted, as
described above, to compounds of ~he formula I (cg, c10) after
chromatographic purification, if desired.
Alcohols o~ the formula IX may also be prepared from
2-allyl-2-cyclopenten-1-one (XXV). 2-Allyl-2-ayclopentèn-
l-one may be obtained for example from 2-allyl-1,3-cyclohexane-
dione, as described in Il Farmaco (Ed.Sci) (12), 1040 (1973).
By hydrogen cyanide addition onto 2-allyl-2-cyclopenten-1-one
catalyzed with a base the ketonitrile of the formula XXVI (d
29 is obtained. The reaction conditions for this reaction are
:
~.~.
- 26 -
the same as described above for the addition of hydrogen
cyanide onto the cyclopentenones V to the ketonitriles VI.
The keto nitrile XXVI may be purified by distillation.
In the next reaction step the lceto group of the compound
XXVI is protected by a reaction with the diols o~ the
formula VII (d2), catalyzed wi~h an acid. The procedure i5
the same as described above for the ketalization of the
compounds of the formula VI to compounds of the general formula
VIII. The ketals XXVII prepared by this way may be purified
by distillation or chromatography.
The ketal~ of the formula XXVII are converted into the
alcohols of the formula IX by hydroboration of the olefinical
double ~onds~ Hydroborations of olefins are described in
detail in H. C. Brown "Hydroboration", (W.A. Benjamin, Inc.,
1962) and in "Organic Reactions", volume 13 (John Wiley U.
Sons Inc., New York, London, 1963) on pages 2 to 54.
In hydroboration react.ion which proceeds in two phases
a borane is fi.rst added to the olefinical double bond. As
boranes there are considered: diborane, dialkyl borane such
as bis-(3-methyl)-2-butyl)-borane or 9-borabicyclo/3,3,17nonane
(9"-BBN") or monoalkyl boranes such as 2,3 -dimethyl 2-butyl
borane ("thexyl borane").
Suitable solvents are those which are inert with regard
to boranes.
Especially preferred are ethers such as diethyl ether,
tetrahydrofurane, 1,2-dimethoxy~ethane and diethyleneglycol-
dimethyl ether (diglyme)~
The addition of the borane onto the oleines of the
29 formula XXVII is caxried out at temperatures between -20 and.
- 27 -
- . :,:i ^ . . . , ~
~ 35~0~4
+60C, preferably between 0 and 30 and at reaction times of
15 minutes to 10 hours. The reaction is expediently carried
out under an inert gas atmosphere such as nitrogen or argone.
The resulting organoboro compounds are oxidized by addition
of sodium hydroxide solution, then of hydrogen peroxide,
whereby t~mperatures of 0 to 80, pxeferably 20 to 50 C,
are maintained. 3 N sodium hydroxide solution and 30% hydrogen
peroxide have proved particularly suitable. ~-
When the oxidation is finished a solvent not miscible
with water such as diethyl ether, is added, the aqueous phase
is preferably saturated with sodium chloride or ammonium
sulfate, and the reaction products of the formula IX are
isolated by drying an evaporating the orga~c phase. The
crude product may be purified by chromatography or by distil-
lation.
The alcohols thus obtained of the formula IX are con-
verted into compounds of the formula I as described above
4 6
The compounds obtained of the formula I are valuable inter-
mediate products for the synthesis of not naturally occuring ~`
prostaglandines. They may be reacted for example in the
following way to obtained analogous compounds of the prosta-
glandine.
Reaction according to Horner-Emmons-Wittig with a phos-
ponate of the formula
C 3 \ ~ "
-CH2-C-R3
CH3~/
- 28 -
: ~ : .. . :.. ::
j, ~o~
to an unsaturated ketone of the formula
y2 H
H C/ ~CH C~
5-
C=~-f-R
H O
Reduction with a complex metal hydride, partly an alkali ~:
boranate, whereby the keto group is converted into a 15-hydroxy
10 group, subsequent addition of dihydropyrane in the presence oP
usual acidic catalysts, as for example p-toluene-sulfonic acid,
whereby a tetrahydropyranyl ether of the formula
S2 ~ 2
H ~ C-R3 .~.
~ ~;'.
is ~ormed; conversion o this ether by heating with methyl -
iodide in acetone with addition of calcium carbonate to about
50 C to an aldehyde o~the formula
H ~/ \CH2
CHO
~
L~ H
C-R
Q ~ ~:
29 Reaction oP this compound with the yliaé from 4-carboxypropyl~
... -
. ~ , . . .
- 29 ~
~ ~ '.!f,~ 3 ~ f ~
~os~o'~ :
triphPnyl-phosphonium bromide in a solution of sodium hydride
in dimethylsulfoxide according to Wittig (J. Org. Chem. 28,
1128 (1963)) to the corresponding carboxylic acid of the
formula
COOH
l 1 ~ R3
Q--~o ~
whereupon the two ether protective groups are split off by
acid hydrolysis under mild conditions at 20 - 50C, either in
one step in the presence of a 10% aqueous vxali~c acid or in
two phases, at first by reaction with an about 2% aqueous-
alcoholic oxalic acid at room temperature and subsequent
heating in the presence of acetone and p-toluene-sulfonic acid.
The compounds ;thus synthetized are characterized by spasmo-
genic and spasmolytical properties, especially bronchodilatory :.
; and hypotensive properties. With regard to the natural prosta-
glandines E; F, and A they are characterized by a considerably
higher stabili~y. Therefore, they may be used as medicaments.
The following Examples illustrate the invention.
EXAMPLE 1
a) 3-(2-acetoxy-1-cyclopentenyl)-propionic acid methyl
ester (III)
85 g (0.5 mol) of 3-(2-oxocyclopentenyl)-propionic ;
acid metllyl es-ter (III) and 75 g (0.7S g (0.75 mol) of
isopropenyl acetate were heated with exclusion of humidity
29 with 1 g of p-toluene--sulfonic. acid and the acetone ~. :
- 30 -
, , . . , ,~, ,, , :, : ~ . . ~
formed during the reaction was distilled over a column.
After about 6 hours below 50 the distillation was
over. After cooling the reaction mixture was added,
while stirring, to hexane and saturated aqueous sodium
bicarbonate solution, thP organic phase was separated
after stirriny for 10 minutes, dried and distilled.
Boiling pointO 6: 84 - 90C
NMR 3.7 ppm (3H, singulet); ~.15 ppm (singulet)
b) 3-(2-Oxo-5-cyclopentene-l-yl3-propionic acid methyl
ester (V)
bI) Into a mixture of 97 5 (0.46 mol) of 3-(2-acetoxy-1-
cyclo-pentenyl)-propionic acid methyl ester, 370 ml of
chloroform, 500 ml of water and 47 g of calcium carbonate,
a solution of 75 g (0~47 mol) of bromine in 125 ml of
carbon tetrachloride was added dropwise at 0C while
stirring vigorously during 45 minutes. Stirring of the
reaction mixture was continued for 30 minutes, the
organic phase was separated and washed successively with
diluted sodium thiosulfate solution and saturated sodium
chloride solution, dried and evaporated. The oil ob-
tained was dissolved in 125 ml of absolute dimethyl-
formamide and added to 82 g of lithium bromide and 80 g
of lithium carbonate in 900 ml of absolute dimethyl-
formamide. The whole was refluxed for 30 minutes and
poured onto 2.5 1 of ice water after cooling. The pM
value was adjusted to 2 with 5N sodium chloride and the
mixture was extracted three times with ether. The com-
bined ether-extracts were dried and evaporated, whereby a
brown yellow oil was obtained. This oil was refluxed for
.
':'
- 31 -
i~, , : , .
~5~
5 hours, with 1 g vf p-toluene-sulfonic acid and 300 ml
of absolute methanol, in order to esterify again saponi-
fied material.
After cooling the whole wa~ evaporated, taken up in
benzene, washed twice with saturated sodium hydrogen
carbonate solution, dried and evaporated.
The mixed product was obtained by distillation of
the residue. Boiling pointO 5: 94 ~ 100
NMR: 7.4 ppm (lH) 3.7 ppm (singulet, 3H)
W : 225 m/u.
bII) To a solution of 340 g (2 mols) of 3-(2-oxocyclo-
pentyl)-propionic acia methyl ester in 750 ml of carbon
tetrachloride a solution of 324 g (2.4 mols) of sulfuryl
chloride in 500 ml of carbon tetrachloride was added
dropwise, while stirring, at 15 - 20C. When the
vigorous development of gas was nearly finished (2 to
S hours) the reaction mixture was concentrated in
vacuo at a bath temperature of 30C and the residue was
taken up in 700 ml of benzene. The benzolic solution
was washed until neutral with saturated sodium bi
carbonate solution, dried with anhydrous magnesium
sulfate, and while stirring, 303 g (3 mols) of triethyl
amine was added dropwise. The reaction temperature was
maintained below 45C by cooling rom time to time~
The reaction mixture was allowed to stand over night
and washed twice with ice water and with diluted acetic
acid until neutral reaction. After drying with an-
hydrous magnesium sulfate the organic phase was con-
centrated and the residue was distilled off.
- 32 -
.. .
~L~5~
c) 2-Methoxycarbonylethyl-3-oxocyclopentane-carboxylic ac1d
nitrile ( _
To 404 g (2.4 mols) of 3~(2-oxo-5 cyclopentenyl~-
propionic acid methyl ester and 246 g (2.9 mo]s) of
acetone-cyanohydrine in 470 ml of anhydrous methanol
21.6g (0.4 mol) of sodium methylate were added, and the
whole was stirred for 4 hours under argon at 45 - 50C.
After cooling 28 ml of glacial acetic acid were added
while stirring, then 1 liter of benzene and 1 liter of
water and 50 ml o~ saturated sodium chloride solution
were added. The aqueous phase was extracted twice
benzene, the combined organic phases were washed with
water, dried and evaporated, The fractional distillation
yielded a colorless viscous liquid having a boiling
point o 1 of 132 - 141C.
NMR: 3.75 ppm (singulet, 3H)
IR: 2235 cm~
d) 7-Methoxycarbonx~thyl-3.3-dimethyl-1.5-dioxaspiro ~5.47
dec-8-yl-carboxylic acid nitrile (VIII)
To a solution of 60.5 (0.31 mol) of 2-methoxycar-
bonyl-ethyl-3-oxocyclopentane-carboxylic acid nitrile and 48 g
(0.46 mol) of neopentylglycol in 1.5 1 of benzene 5 ml of
borotrifluoride etherate were added dropwise while
stirring, and the mixture was boiled ~or 4 hours at the
water separator. After cooling the whole was washed
with saturated sodium bicarbonate solution and water,
dried with anhydrous magnesium sulfate and evaporated in
vacuo. In the distillation a colorless viscous oil having
29 a melting point o 2 f 150 to 157C was obtained. It
:-
- 33 -
consisted of two stereo isomers, which could be sepaxated
by chromatography on silica gel and elution with chloro-
form/ethyl acetate 9 : 1~ The isomer migrating faster
melted at 57 - 61C, the isomer migrating slower melted
at 49 - 55C.
NMR (mixture): 3.7 ppm (3H, singulet); 3.5 ppm (4H,
singulet;
1.17 ppm (3H, singulet); 0.77 ppm singulet).
For the further reactions the mixture of isomers was ~-
used.
e) 7-Carboxyethyl-3.3-dimethyl-l 5-dioxaspiro/5.~/7-dec-8-yl-
carboxyllc acid nitrile (X)
A solution of 8.4 g of KOH (0.15 mol) in 100 ml of
methanol was added to a solution of 27.1 g (O.l mol) o~
7-methoxy-carbonyl-ethyl-3.3-dimethyl-1.5.dioxaspiro /5.47
dec-8-yl-carboxylic acid nitrile. After 4 hours at room
temperature and allowing to stand ~or 15 hours at 5C the
whole was neutralized with glacial acetic acid, the
solvent was removed in vacuo at a bath temperature of
20C, and the residue was distributed between ether and
an aqueous aodi~m dihydrogenophosphate solution.
The aqueous phase was extracted again with water and the
combined ether extracts were dried and evaporated. The
crude product was advantageously further reacted but it
cauld also be purified by chromatography on 300 g of
silica gel with chloro~orm/methanol 9 : 1 as eluent.
NMR: 10.5 ppm ~broad singulet, lH); -
3.5 ppm tsinguletr 4H); 1.17 ppm (singulet, 3H)
0.77 ppm (singulet, 3H)
IR: 2235 cm 1 (CN)
- 34 -
f) 7-Hyaroxy~opyl-3.3-dimethyl-l.5-dioxaspiro~5.47dec-8-yl-
carboxylic acid nitrile (IXj
.
fI) 38.6 g (0.137 mol) of 7-methoxycarbonylethyl-3.3~di~
methyl-1.5-dioxaspiro/5.47dec-8-yl-carboxylic acid nitrile
were added to a solution of 3.45 g (0.158 mol) of lithium
borohydride in 200 ml of dry tetrahydrofurane. The whole
was heated to the boil for 3 hours under an argon atmos-
phexe and after cooling glacial acetic acid was added
dropwise, while stirring, until the development of ~`
hydrogen was finished. The solvent was removed in vacuo
and the residue was distributed between ether and aqueous
sodium bicarbonate solution. The organic phase was sub-
sequently washed twice with water, then with saturated
sodium chloride solution and dried. ~fter evaporating
the solvent in vacuo and drying in high vacuum a colorless
oily crude product was obtained, which was sufficiently
pure for the further reactions.
Analytically pure material was obtained by chromato-
graphy on silica gel with chloroform/ethyl acetate 8 : 2
as eluent.
NMR: 3.7 ppm (triplet, 2H)
3.5 ppm (singulet, 4H)
1.15 ppm (singulet, 3H)
0.75 ppm (singulet, 3H)
25fII) With exclusion of humidity 1.35 ml of a lM-B2H6- solution
in tetrahydrofurane were added dropwise to 23.2 g
~90 mmols) of 7-carboxyethyl-3.3-dimethyl-1.5-dioxaspiro
/5.47dec-8-yl-carboxylic acid nitrile in 200 ml of
.
29 absolute tetrahydrofurane, and the whole was stirred.
35 -
~5~
After three hours at room temperature 20 ml of methanol
were added dropwise and the solvent was evaporaked in
vacuo~ The residue was evaporated twice with methanol
and, if desired, as described under fl, purified chromato-
graphically or used as crude product in the following
reaction.
g) 7-Formylethyl-3.3-dimethyl-lo5-dioxaspiro/5~47dec-8
carboxylic acid nitrile (XI)
. _ . .
gI) While stirring, under an argonate atmosphere and
with exclusion of humidity 4.0 g (40 mmols) of chromium tri-
oxide were added at 0C to a mixture of 40 ml of dry
methylene chloride and 6.4 g (80 mmols) of dry pyridine.
Stirring was continued for 30 minutes at room temperature
and then 2.53 g (10 mmols) of 7-hydroxypropyl-3.3-di-
methyl-1.5 dioxaspiro /5.47dec-8-yl-carboxylic acid
nitrile in 10 ml of dry methylene chloride were added.
After stirring for 5 hours further 50 ml of methylene
chloride and 30 ml of water were added and the reaction
mixture was suction-filtered from the undissolved material.
The organic phase was separated, washed free from pyridine
with an ice-cold 0.5 N hydrochloric acid, washed until
neutral with a sodium bicarbonate solution and dried.
The crude product thus obtained was preferably
~urther reacted, but it could also be puri~ied chromato-
graphically 8 : 2 on silica gel (120 g) and by elution
with chloroform/ethyl acetate.
NMR: 9.85 ppm (lH)
3~45 ppm (4H, singulet)
29 1.17 ppm (3H, singulet)
- 36 -
0.7s ppm (3H, singulet)
IR: 2237 cm~l (CN)
1715 cm~1 (C = O)
gII) In an aryon atmosphere, 1.5 ml of dimethyl sulfide
were added at 0, while stirring, to a suspension of
2.0 g (15 mmols) of N-chlorosuccinimide in 50 ml of dry
benzene~ After 10 minutes, the whole was cooled to -25C,
and a solution of 2.53 g (10 mmols) of 7 hydroxypropyl-
3~3-dimethyl-1.5-dioxaspiro/5~47dec-8-yl-carboxylic acid
nitrile in 5 ml of toluene was added dropwise.
Stirring was continued for 2 hours at -25C, and ;~
subsequently a solution of 1.52 g (15 mmols) of tri-
ethyl amine in 5 ml of toluene was added dropwise.
The cooling bath was removed and after 5 minutes 100 ml
of ether was added. The reaction mixture was washed
with 25 ml of 0.3 N hydrochloric acid and subsequently
twice with water.
After drying with magnesium sulfate and evaporating
the organic phase the crude aldehyde was obtained which
could be further purified, if desired, or further reacted
as described under 81).
~III) To a solution cooled to -100C of 7.0 g (25 mmols)
of 7-methoxycarbonylethyl-3.3-dimethyl-1.5-dioxaspiro
~.47dec-8-yl-carboxylic acid nitrile in 100 ml of
absolute toluene a solution of 5.35 ml (30 mmols) of
diisobutyl-aluminum hydride in 80 ml of aksolute toluene
were added dropwise within 40 minutes under an argon
stream and exclusion of humidity, and the whole was
29 stirred vigorously~ The temperature was maintained for
- 37 -
: ~:: : :. - :: : . : i . :;. : : :; .; : :: .:: : . .
90 minutes at -lOO~C and for 60 minutes at -70C, then
8 ml of methanol were added and at 0C 3.5 ml of
glacial acetic acid, 100 ml o water and 2Q0 ml of
ether were also added. After 30 minutes the solution
was suction-filtered from the undissolved material
through a clarifying layer filter, the organic phase
was washed with water and a sodium hydrogen carbonate
solution and dxied. When evaporating the solution
the crude oily aldehyde was obtained which could be
purified, if desired, as described under gl).
h) 7-_~1.3-dithia-2-cyclop~yl)-ethyl7-3.3-dimethyl-1.5-
dioxaspiro/5.47dec-8- l-carbox lic acid nitrile (XIII)
Y Y
5~13 g of crude 7-formylethyl-3.3-dimethyl-1.5-dioxa-
spiro/5.47dec-8-yl-carboxylic acid nitrile ~purity about
gO to 95 ~), 1.88 g ~2 mmols) of 1.2 dimercaptoethane
and 5 g of anhydrous magnesium sulfate in 50 ml of absolute
benzene were stirred at room temperature in an argon
atmosphere and 0.7 ml of BF3 - etherate is added. After
4 1~2 hours 2 ml of triethyl amine and 50 ml of ether
were added, the whole was filtered and the filtrate was
washed with cold lN sodium hydroxide solution and water~
By drying and evaporating the organic phase an oil was
obtained which could be purified by chromatography on
SiO2 and elution with chloroform/ethyl acetate 8 : 2.
NMR: 4.5 ppm (tripletr lH); 3.5 ppm (singulet, 4H)
3.23 ppm (singulet, 4H); 1.18 ppm ~singulet, 3H)
0.77 ppm (singulet, lH)
IR: 2235 cm 1 (CN)
- 38 -
. .. , :, , . ~. - ., ., : : ,
i~ 7~ .3-dithia-2~cyclopentyl)-ethyl7-3.-3-d~ L~
-
dioxa~Lro/S.47dec-8-yl-alde~y~
~ )
To 4~08 g (12.5 mmols) of 7-/(dithia-2-cyclopentyl)-
ethyl7-3.3-dim~thyl-1.5-dioxaspiro /5.47dec-8-yl-carboxylic
acid nitrile in 60 ml of absolute -toluene, a solution of
3.2 ml of diisobutyl aluminum hydride in 25 ml of toluene
were added dropwise at 0 to 5C, while stirring and under
a protective gas atmosphere (argon). Stirring was con-
tinued for 2 hours and successively 3 ml of methanol,
3 ml of glacial acetic acid and 40 ml of water were added
and then 150 ml of ether. The resulting mixture was
washed with watex and sodium hydrogen carbonate solution
and dried. The product was sufficiently pure for fur~her
reactions, but it could be purified by chromatography on
silica gel and elution with chloroform/ethyl acetate
8 : 2.
N.M.R. 9.35 ppm dublet 1 H
4.4 ppm triplet 1 H
3.5 ppm singulet 4 H
3.2 ppm singulet 4 H
E X A M P L E 2
a) 6-MethoxYcarbonYleth~l-l.4-dioxaspiro ~.47non-7-Yl-
carboxyl.ic acid n~trile (VIII)
Test in analogy to Example 1 d~ from 2-methoxy-
carbonylethyl-3-oxo-cyclopentane-carboxylic acid nitrile and
ethylene glycol.
Boiling point o 15 : 125 - 130 (colorless, viscous oil).
NMR: 3.94 ppm (singulet, 4H); 3.69 ppm (singulet, 3H)~
.- :: , . : . : : ,.,. :, .::: -: . : . ; . ; .: . .:
b)
acld nitrile
Test in analoyy to Example 1 fl) from 6-methoxy-
carbonylethyl--1.4-dioxaspiro/4.47non-7-yl-carboxylic acid
nitrile.
Boiling ~oint 0 4 159 - 164
NMR: 3.95 ppm (singulet, 4H~
3.65 ppm (triplet, 2H)
; c) 6-Form~ethyl-1 4-dioxas~iro/4.47non-7-yl-carboxylic acid
nitrile (XI)
P~eaction in analogy to Example 1 gl) from 6-(3-
hydroxypropyl)-1.4-dioxaspiro/4.47non-7-yl-carboxyl acid
nitrile RF = 0.41 (cyclohexane/ethyl acetate 6 : 4
NMR: 9.87 ppm (lH)
3.95 ppm (4H)
IR: 2235 cm 1 (nitrile)
1720 cm~l (carbonyl)
d) 6-/(1.3-dithia-2-cyclopentyl)-ethy 7-1.4-dioxaspiro/4.47
. . _ . . _
non-7-yl-carboxylic acid nitrile (XIII)
Reaction in complete analogy to Example 1 h) from
6-formyl-ethyl-1.4-dioxaspiro/4.47non-7-yl-carboxylic acid
nitrile and 1.2-dimercaptoethane.
NMR: 4.5 ppm (triplet, lH); 3.95 ppm (singulet, 4H)
3.2 ppm (singulet, 4H)
IR: 2230 cm~l (CN)
e) 6-/(1.3-dithia-2-cyclopentyl)-ethyl7-1.4-dioxasp:iro/~.47-
non-7-yl-aldehyde (I)
This compound is prepared from 6-~tl.3-dithia-2-cyclo-
pentyl)-ethyl7-1.4.dioxaspiro/4.47non-7-yl-carboxylic acid
nitrile, as described in complete analogy to Example li).
. .
40 -
: :
;,`. '' ~' ' ~ ':`' .' ' :''""'
: ` :
~15~
NMR 9.6 ppm (lH); 4.5 ppm (lH); 3.95 ppm (4H),
3.25 ppm (4H)
IR 1730 cm~l (C = O)
E X A M P L E 3_
a) 3-Hydroxy-2~(3-hydroxypropyl)-cyclopentane-carboxylic aeid
nitrile (XIV)
29.2 g (O.lS mol) of 2-methoxycarbonylethyl-3-
oxocyclopentane-carboxylic acid nitrile were added to a solu-
tion of 3.27 g ~0O15 mol) of lithium borohydride in 150 ml of
absolute tetrahydro-furane~ The whole was refluxed for
4 hours with exclusion of humidity. At 0C the pH-value
was adjusted to 7 by dropwise addition of concentrated
hydrochloric aeid and the solvent was evaporated in vaeuo.
The viseous residue was taken up in about 300 ml of tetra-
hydrofurane and the organic phase was washed twice with
a small amount of saturated ammonium sulfate solution.
It was filtered, i~ desired, from the undissolved material,
dried with anhydrous magnesium sul~ate and evaporated in
~acuo. The crude produet was finally dried in high
vaeuum and used without any further punifieation in the
following oxidation. It was also possible to purify by
ehromatography on silica gel with chloroform/methanol
9 : l as eluent.
RF = 0.41 (CE~Cl3/CH30H 3 : l)
NMR: 3.5 - 3.9 ppm (3 H)
IR: 3400 - 3000 cm -l (broad hydroxyl band)
2230 cm l (CN)
- 41 -
. ,, . ,: . ,. ., . ~. .. . ........... . . .
.,. .:- .:. , - ' ' .. .,' . :'. '' ''' ~"- . ' : ., ' . . :
~L~S~
b) 3-Oxo-2~(formYlethYl)~cycloPentane-carboxylic acid
nitrile ~XIV)
. _ _
Reaction in analogy to Example lg) from 120 ml of
methylene chloride, 19.2 g of pyridine, 12.0 g of CrO3 and
2.54 g (15 mmols) of 3-hydroxy-2-(3-hydroxypropyl)-cyclo-
pentane-carboxylic acid nitrile.
NMR: 9.83 ppm (1 H)
IR: 2235 cm~l (nitrile~ broad carbonyl band at 1730 -
1740 cm~l, ~-
no hydroxyl band at 3400 - 3500 cm~l
c) 2-/~1.3-dithia-2-dyclopentyl)-ethyl7-3-oxocyclopentane-
carboxylic acid nitrile (XVI)
.. .. _ . _
To 3.47 g (21 mmols) of crude 3-oxo-2-(formylethyl)-
cyclopentane-carboxylic acid nitrile in 50 ml of benzene
1.94 g (20.6 mmols) of 1.2-dimercaptoethane and 0.5 ml of
borotrifluoride etherate were successively added while
stirring. After 3 hours at room temperature the whole was
diluted with 100 ml of benzene and washed with 20 ml of
0.5N sodium hydroxide solution, then with water. The dried
organic phase was evaporated and, if desired, purified by
çhromatography on silica gel (eluent chloroform/ethyl
acetate 95 : 5).
NMR: 4.5 ppm (lH, triplet); 3.2 ppm (4H, singulet)
IR: 2230 cm~l (CN), 1730 - ~740 cm~l (C = O)
d) 7-/(1.3-dithia-2-cyclopentyl)-ethyl7-3.3-dimethyl-1.5-
dioxaspiro/5.47dec-8-yl-carboxyl c_acid nitrile (XIII)
2.6S g (11 mmols) of 2-(1.3-dithia-2-cyclopentyl)-
ethyl-3-oxocyclopentane-carboxylic acid nitrile and 2.3 g
29 (22 mmols) of 2~2-dimethyl-1.3-propanediol were heated to
:
~s~
the boil for 4 hours in 60 ml of benzene in the p~sence
of 150 mg of p-toluenesulfonic acid at the water separator.
After cooling the whole was washed twice with saturated
sodium hydrogen carbonate solution, dried with anhydrous
magnesium sulfate and the solvent was evaporated in vacuo.
The product could be purified as described under 1 h)
and reacted to the 7-/~1.3-dithia-2-cyclopentyl)-ethyl7-3.3-
dimethyl-1.5-dioxaspiro/5.47dec-8-yl-aldehyde, as described
vnder 1 i).
E X A M P L E 4:
a) 3-(2-acetoxy-1-cyclopentyl)-propionic acid nitrile W III) ;
Test in analogy to Example 1 a) from 3-(2-oxocyclo-
pentyl)-propionic acid nitrile (JACS 85, 207 (1963 and ~-~
isopropenyl acetate~ Boiling pointo,g: 98 - 110C
IR: 2230 cm~
NMR: 2.15 ppm (singulet)
b) 3-(2-oxo-5-cyclopentene-1-yl)-propionic acid
nibrile (XX)
Test in analogy tG Example 1 b) from 3-(2-acetoxy-
l-cyclo-pentenyl)-propionic acid nitrile
boiling point: 0.2 94 - 107
NMR' 7.58 ppm (lH)
IR: 2235 cm 1 (CN)
a) 3-(1~4-dioxaspiro/4~47non-6-en-6-yl)-propionic acid
nitrii?e (XXI
Test in analogy to Example 1 d) from 3-~2-oxo-5-cyclo~
pent.ene-l-yl)-propionic acid nitrile (45 g), ethylene ~?
glycol (41 g) and borotrifluoride etherate (5 ml) in
benzene (1.2 1).
IR: 2230 cm 1
- 43 - ;
::
~5~
d) 3-(1.4-dioxaspiro/4.47non-6-en-6~yl)-propionaldehyde (XXII)
Reaction in analogy to Example l i) from 3-(].4-dioxa-
spiro/4.47non-6~en-6-yl)-propionic acid nitrile and
diisobutyl-aluminum hydride in toluene.
Preferably, the crude aldehyde was directly further
reacted, but could also be purified by chromatography on
silica gel with a chloroformiethyl acetate mixture 9 : 1. -
NMR: 917 ppm (lH)
IR: 1720 cm l
e~ 6-/(1.3-dlthia-2-cyclopentyl)-ethyl7-1.4-dioxyspiro/4.47
non-6-ene (XXIII)
Reaction in analogy to Example 1 h) from 3-(1.4.dioxa-
spiro/4.47non-6-en-6-yl)-propionaldehyde and 1.2-di-
mercaptoethane. The product could be purified on silica
gel with chloroform as eluent.
NMR: 4.5 ppm (lH, triplet); 3.9 ppm ~singulet, 4H)
3.2 ppm (singulet: 4H)
f) 2-~ tl. 3-dithia-2-cyclopentyl)-ethyl7-2-cyclopentene-1-one
~XIV)
3 g of oxalic acid were added to a solution of 5.16
(20 mmols) of 6-/(1.3-dithia-2-cyclopentyl)-ethyl7 1~4-
dioxaspiro/4.47non-6-ene in lO0 ml o acetone and lO ml
of water. The whole was stirred for 7 hours at 50C in
an argon atmosphere. After cooling 30 ml of water were
added and the main part of the acetone was evaporated in
vacuo. The product was taken up in benzene and the
aqueous phase was extracted twice with benzene. The
combined benzene phases were washed with a bicarbonate
29 solution, dried with anhydrous magnesium sulfate and the
- ~4 -
. :.,
: ~ . .. , . . . . , .~ , . :
5~
solvent was evaporated. The product could be used with-
out any fllrther purification in the following reaction.
It could be purified by chromAtography on SiO2 (eluent
CHC13).
NMR: 3.25 ppm (singulet, 4H) 4.5 ppm (triplet, lH)
UV~ 225 m~.
g) 2~ .3-dlthia-2-c~clopentyl)-ethyl7-3-oxocyclopentane-
carboxylic acid nitrile (XVI)
A solution of 10.7 g (50 mmols) of 2-(1.3-dithia-
2-cyclopentyl)-ethal-2-cyclopenten-1-one and 5.95 g (70 mmols)
of acetone cyanahydrine in 80 ml of methanol was stirred
under an argon atmosphere in the presence of 0.5 ml of
saturated aqueous sodium carbonate solution at 40 - 50C.
After 3 hours 100 ml of water were added to the reaction
solution and the whole was extracted three times with
50 ml of benzene in each case. The combined organic
phases were washed with water, dried and evaporated.
The reaction product was identical to the product
prepared according to Example 3 c) and could be purified
in the same way and further reacted.
E X A M P_L E 5
a) 2-Allyl-3-oxocyclc{~tyL-e~bg~ylic acid nitrile (XXVIj
To 183 g (1.5 mols) of 2-allyl 2-cyclopentenone
~Il Farmaco (12), 1040 ~1973) in 1.2 1 of methanol 195 g
(3 mols) of potassium cyanide were added dropwise and while
stirring at room temperature 144 g (2.4 mols) of glacial
acetic acid were added dropwise in the course of two hours.
After another two hours the whole was added to 2 liters of
29 cold 0.5N sodium hydroxide solution and extracted three times
- . . . . .; . .......... ~
~ - ., , . ~ .: , :;: ,
with benzene. The organic phase was washed until neutral
with water, dried and the solvent was distilled off.
The residue was distilled.
Boiling point: 0.4 99 - 104~
NMR: 4.8 - 6.2 ppm ~3 olefinical protons3
R: 2235 cm 1 (CN)
1730 cm~l (CO)
b) 6-Allyl-1.4-dioxaspiro/4.47non-7-yl-carboxylic acid
nitrile (XXVII)
3.5 ml of borotrifluoride-etherate were added *op-
wise, while stirring to 15 g o ethyIeneglycol and 42 g
of 2-allyl-3-oxo-cyclopentyl-carboxylic acid nitrile in
1 liter of benzene, and the whole was boiled for 5 hours
at the water separator. After cooling it was washed with
diluted sodium hydroxide solution and water, dried with
magnesium sulfate and the solvent was evaporated.
The desired product was obtained by distilla~ion in vacuo.
Boiling pointO 5 103 - 115
NMR: 3.95 ppm ~4H, singulet)
IR: 2230 cm~l
c) 6-(3-hydroxypropyl)-1.4-dioxaspiro/4.47non-7-yl-carbox~lic
acid nitrile ~IX)
To a solution of 19.3 g (0.1 mol) of 6-allyl-1.4-
dioxaspiro/4.~7non-7-yl-carboxylic acid nitrile in 30 ml
of dry tetrahydrofurane 25 ml of a lN solution of di-
borane in tetrahydrofurane were added dropwise at 0C
under an argon atmosphere. The whole was allowed to stand
for one hour at room temperature and the diborane in
29 excess was destroyed by adding dropwise and carefully
- 46 -
~s~
5 ml of water. At 409C~ while stirring vigoxously,
12 ml of 3N sodium hydroxide solution were added dropwise
to the reaction mixture, then 12 ml of a 30~ H202.
After another hour S0 ml of diethyl ether were added,
and the aqueous phase was saturated with sodium chloride.
The organic phase was sepaxated, the aqueous phase was
extracted twice with ether and the combined organic
extracts were washed twice with saturated sodium chloride
solution. After drying and evaporating the organic
solution the oily 6-(3-hydroxypropyl)-1.4-dioxaspiro
/4.4/non-7-yl-carboxylic acid nitrile was obtained which `
was sufficiently pure for the further reactions and was
identical to the product described in Example 2 b).
- 47 -
... ,. : . . . ., , , ... , ~ . . . .
