Note: Descriptions are shown in the official language in which they were submitted.
il'~5'~'83
HA165a
Thioalkanoylalkanoic Acid Compounds
This invention relates to new thioalkanoyl-
alkanoic acid compounds which have the formula
(I)
R3 R2 A B
I ~
R5-S-(C) - CH- C - CH- CH - COOR
wherein Rl, R2, R3 and R4 each is hydrogen
or lower alkyl;
R5 is hydrogen, lower alkanoyl,
benzoyl, or
R3 R2 A B
11 1
-S-(C)m- CH - C - CH - CH - COOR
R4
A and B each is hydrogen or join
" llZS ~8~
HA165a
--2~
together to compl~ea cycloalkyl ring;
m is 0 or 1;
to basic salts thereof and to intermediates therefor.
The invention relates preferably to those
compounds of formula I, and salts thereof, wherein
A and B join to complete a cycloalkyl group, i.e.,
compounds of the formula
(II)
R3 R2 ~ (CH2)n\
R5-S-(C)m- CH- C - CH - _ CH-COOR
R4
Rl, R2, R3, R4, R5 and m have the same meaning as above
lS (especially when m is 1) and n is 2, 3 or 4 resulting
in a cyclobutane, cyclopentane or cyclohexane ring,
respectively, and to intermediates therefor.
Compounds of lesser activity and interest are
the compounds of formula I, and salts thereof, wherein
A and B are both hydrogen, i.e., 3-oxohexanoic or
3-oxopentanoic acid derivatives of the formula
(III)
R3 2
l 11
25R5-S-(C) _ CH - C -CH CH2-- COOR
I
R4
wherein the symbols have the same meaning as above.
l~S~B3 HA165a
--3--
The new intermediates which ~re also the
subject o~ this invention include intermediates which
are useful in preparing compounds of formula II,
particularly when m is 1, i.e., intermediates
which have the formula
(IV)
R3 l2 ll ~ (CH2)n ~
C=C - C - CH CH - COOR
R
wherein R2, R3, R4 and n have the same meaning
as above and R is hydrogen, phenyl-lower alkyl or
diphenyl-lower alkyl, preferably benzyl or
diphenylmethyl.
, . .
5~'83
~IA165a
--4--
Especially preferred modifications are compounds
of formula I wherein Rl, R2, R3 and R4 are hydrogen or
lower alkyl, most especially hydrogen or methyl, and
primarily hydrogen; and R5 is hydrogen or lower alkanoyl,
most especially hydrogen or acetyl. These preferred
meanings for the symbols apply to both the compounds
of formula II and formula III, but as indicated
above, the compounds of formula II are preferred
over those of formula III.
The lower alkyl groups represented by the
symbols are straight or branched chain hydrocarbon
radicals having up to seven carbons like methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, and the
like. In general, the Cl-C2 members, are preferred.
The lower alkanoyl groups are the acyl
radicals of the lower (up to seven carbon) fatty
acids, e.g., acetyl, propionyl, butyryl, isobutyryl
and the like. In general, the members mentioned,
and especially acetyl, are preferred. The compounds
of this invention can be produced by several
procedures. According to one method, particularly
when m is 1, an acid having the formula
(IVa)
R o A B
R 2
C~C - C-CH-- CH _ COOH
is made to react with the thiol R5-SH, wherein R5
is lower alkanoyl or benzoyl, to obtain the product
having the formula
~1~5 7i 33
~ lA165a
--5--
(V) 3 2 A
11 1
R5- S - C - C - C--CH CH -- Cool]
I
R4
This reaction can be effected by dissolving or
suspending the compound of formula IVa in an inert
organic solvent such as chloroform, dichloromethane,
tetrahydrofuran, dioxane, or the like, and slowly
adding the thiol, preferably at a reduced temperature
in the range of about 0 to 25C. The product of
formula V, wherein R5 is lower alkanoyl or benzoyl,
can then be converted to the corresponding product
wherein R5 is hydrogen, by treatment with aqueous
ammonia or sodium hydroxide solution.
According to a variation of this procedure,
the compound of formula IVa can be treated with the
thiol as above followed directly by treatment with
concentrated ammonium hydroxide solution to obtain
directly the product wherein R5 is hydrogem.
An alternate procedure comprises reaction of
an ester of a compound of formula IVa above, e.g.,
phenyl-lower alkyl or diphenyl-lower alkyl ester
preferably the diphenylmethyl ester, with the thiol
as above, removal of the ester protection, e.g., with
trifluoroacetic acid and anisole when the ester
is a diphenylmethyl ester, then treatment with
aqueous ammonia to remove the R5 group, resulting
in a product wherein R5 is hydrogen.
Another procedure, particularly when m is 0,
comprises utilizing an ester of the formula
:
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HA165a
--6--
(VI )
A B
l l
HOOC- CH CH COO - lower alkyl
which is converted with a halogenating agent like oxalyl
chloride to the acyl halide of the formula
(VII)
O A B
X - C- CH`-CH-COO - lower alkyl
Treating this intermediate with adiazoalkane yields
a diazoalkylketone of the formula
(VIII)
O A B
R2
N2C C-CH- CH - COO _lower alkyl
The compound of formula VII can then be made to react
with the thiol R5-SH as described above to obtain the
product of formula I wherein R5 is lower alkanoyl
or benzoyl. Treatment of the last named product with
ammonia or sodium hydroxide solution also as described
above yields a product wherein R5 is hydrogen.
The esters wherein Rl is lower alkyl can be
produced by conventional esterification methods or by
utilizing an ester as starting material. They can
similarly be converted to the free acid by conventional
techniques such as hydrolysis, etc.
The disulfides or bis compounds wherein R5 in
formula I is
S ~'~3
IIA165a
--7--
R O A B
13
- S-( C ~ CH - C - CH --CH -- COOR
I
R4
are produced from a compound of formula I wherein R5
is hydrogen by direct oxidation, e.g., with an
alcoholic solution of iodine.
The acid of formula TVa is obtained by reacting
10 an anhydride of the formula
(IX)
A B
`\f~/
0~ O
O
with ethylene in the presence of a Friedel-Crafts
catalyst like aluminum chloride in a solvent
preferably 1,2-dichloroethane or by reacting
a starting material having the formula
(X)
A B
OHC - CH - CH _ COO - lower alkyl
with a Grignard reagent having the formula
(XI) R2
R ~
C =C - MgBr
hydrolyzing the product of this reaction with an
-8- HA165a
aqueous base like sodium hydroxide to form the
hydroxy acid, converting this to the diphenylmethyl
ester with diphenyldiazomethane, and oxidizing the
alcohol group to a keto group with chromium trioxide
or manganese dioxide.
The aldehyde-esters of formula X can be
produced by treating an anhydride of formula IX with
methanol, reducing the acid obtained to an alcohol
with diborane and oxidizing the aleohol with chromium
trioxide. Alternatively, a halogenated compound of
the formula
(XII) A B
Br2CH-CH-CH - COO -lower alkyl
can be converted to the compound of formula X with
aqueous silver nitrate.
The compounds of formula I form basic salts
with various inorganic or organic bases. They are
also included in the scope of the invention. Such
salts include alkali metal salts, especially the
sodium and potassium salts, alkaline earth metal
salts, especially ealeium and magnesium salts,
aluminum, dicyelohexylamine salt, benzathine salt,
N-methylglucamine salt, hydrabamine salt, salts with
naturally oecurring amino aeids like arginine,
lysine and the like, lower alkylamine salts like
methylamine, ethylamine, dimethylamine, triethylamine
salts, ete. The non-toxie, physiologieally
aeeeptable salts are preferred, although other salts
are also useful, e.g., in isolation or purifying the
product as illustrated in the examples below. The
~;Zcj~33
HA165a
_9_
salts are formed in conventional manner by reacting
the free acid form of the product with one or more
equivalents of the appropriate base providing the
desired salt ion in a solvent or medium in which the
salt is insoluble, or in water and removing the water
by freeze drying. By neutralizing the salt by
conventional methods the free acid form can be obtained,
and if desired, another salt formed.
Additional experimental details are found
in the examples which are preferred embodiments
and also serve as models for the preparation of other
members of the group.
The products of this invention have one or more
centers of asymmetry. The compounds accordingly exist
in stereoisomeric forms or in racemic mixtures thereof.
All of these are within the scope of the invention.
The compounds of this invention inhibit the
conversion of the decapeptide angiotensin I to
angiotensin II by angiotensin converting enzyme
and therefore are useful as hypotensive agents,
particularly in reducing or relieving hypertension.
By the admlnistration of a composition containing
one or a combination of compounds of formula I or
physiologically acceptable salt thereof, angiotensin
dependent hypertension in the species of mammal,
e.g., rats, cats, dogs, etc., suffering therefrom
is alleviated. A single dose, or preferably two
to four divided daily doses, provided on a basis
of about 0.1 to 100 mg. per kilogram per day,
preferably about 1 to 50 mg. per kilogram per day
is appropriate to reduce blood pressure as indicated
11;2S783
HA165a
--10--
in the animal model experiments described by
S. L. Engel, T. R. Schaeffer, M. H. Waugh and
B. Rubin, Proc. Soc. Exp. Biol. Med. 143, 483 (1973).
The substance is preferably administered orally, but
parenteral routes such as subcutaneously, intra-
muscularly, intravenously or intraperitoneally can
also be employed.
The compounds of this invention can be
utilized to achieve the reduction of blood pressure
by formulating in conventional compositions such
as tablets, capsules or elixirs for oral administration
or in sterile solutions or suspensions for parenteral
administration. About 10 to 500 mg. of a compound or
mixture of compounds of formula I or physiologically
acceptable salt is compounded with a physiologically
acceptable vehicle, carrier, excipient, binder,
preservative, stabilizer, falvor, etc., in a unit
dosage form as called for by accepted pharmaceutical
practice. The amount of active substance in these
compositions or preparations is such that a suitable
dosage in the range indicated is obtained.
Sterile compositions for injection can be
formulated according to conventional pharmaceutical
practice by dissolving or suspending the active
substance in a vehicle such as water for injection,
a naturally occurring vegetable oil like sesame
oil, coconut oil, peanut oil, cottonseed oil,
etc., or a synthetic fatty acid like ethyl oleate
or the like. Buffers, preservatives, antioxidants
and the like can be incorporated as required.
5';'83
HA165a
The followinc3 examples are illustrative of the
invention and constitute~ especially preferred
embodiments within the framework discussed above.
`` All temperatures are in degrees Celsius.
Example 1
cis-1,2-Cyclopentanedicarboxylic Anhydride
Method A: [cf. S.F. Birch, et al., J. Org.
Chem., 20, 1178 (1955)]. A mixture of 5.0 g.
(31.6 mmoles) of trans-1,2-cyclopentanedicarboxylic
acid and 30 ml. of acetic anhydride is refluxed
under nitrogen for eighteen hours. The acetic
anhydride is removed in vacuo, and the residue dis-
tilled to give 2.75 g. of cis-1,2-cyclopentane
dicarboxylic anhydride, b.p. 110-120 /0.3 mm.,
which solidifies on standing. Direct recrystallization
of this material from isopropyl ether/ether gives
1.8 g. of crystalline material, m.p. 50-60 . A
second recrystallization from ether affords
1.4 g. of analytically pure anhydride, m.p. 69-72.
Method B: [cf. Chem. Pharm. Bull., 6, 446
(1961)]
a) l-Cyclopentene-1,2-dicarboxylic acid
..
A mixture of 200 g. (1.28 moles) of ethyl-2-
oxocyclopentanecarboxylate, 400 g. (430 ml., 4.50 mole)
of acetone cyanohydrin, 5 g. of anhydrous potassium
carbonate, and 20 drops of 10~ aqueous potassium
cyanide solution is stirred at room temperature
overnight in the hood. The mixture is then filtered,
the filtrate carefully acidified with 10% sulfuric
acid to pH ~3, and insoluble material is removed
by filtration. Methanol is removed from the filtrate
by distillation at atmospheric pressure. Distillation
~S ~'83
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of the residue affords 128.3 g. (55~) of the desired
cyanohydrin, b.p. 150-157/8 min., which is used
immediately.
The distilled cyanohydrin (128.3 g., 0.7 mole)
is cooled in an ice-bath and diluted with 250 ml. of
pyridine. To this cold stirred solution is added
68 ml. of phosphorus oxychloride dropwise over forty-
five minutes, and the resulting mixture left at
0-5 for eighteen hours. The reaction mixture is
heated on a steam bath for one hour, cooled and added
to excess dilute hydrochloric acid-ice. This is
thoroughly extracted with ether, and the combined
extracts dried and concentrated in vacuo. Distillation
of the residue gives 91.4 g. (79%), b.p. 118-120/3 mm.
lS A mixture of the above liquid (91.4 g., 0.55 mole)
and 200 ml. of concentrated hydrochloric acid is
refluxed for six hours, cooled, and the resulting
precipitate is filtered off. Direct recrystallization
from water (~ 200 ml.) [charcoal decolorization),
followed by drying in vacuo over phosphorus pe~toxide
at 60, affords 59.3 g. (69~) of 1-cyclopentene-1,2-
dicarboxylic acid, m.p. 177-179 .
b) cis-1,2-Cyclopentanedicarboxylic acid
l-Cyclopentene-1,2-dicarboxylic acid (10.0 g.,
0.064 mole) in 200 ml. of absolute ethanol is
hydrogenated (Paar shaker) in the presence of Raney
nickel at 40-50 psi/60. After uptake of one
equivalent of hydrogen (~ 24 hours), the mixture is
cooled, filtered through a Celite (diatomaceous
earth) pad, and the filtrate concentrated in vacuo to
a solid. Direct recrystallization from water (~ 30 ml.)
5~83
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~13-
followed by dryiny in vacuo over phosphorus pentoxideyiclds 6 q. (60~) oE cis-1,2-cyclo~entanecarboxylic
acid, m.p. 132-135. The mother liquor from the
recrystallization can be lyophilized to a solid, which
is sufficiently pure for use in the next step.
c) cis-1,2-cyclopentanedicarboxylic anhydride
A mixture of 43.15 g. (0.273 mole) of the above
diacid and 350 ml. of acetyl chloride is refluxed for
two hours, and then taken to dryness in vacuo.
Distillation of the residue gives 34.6 g. (91%) of
cis-1,2-cyclopentanedicarboxylic anhydride, b.p.
100-110/0.5 mm., which crystalli~es on standing.
Example 2
cis-2-(3-Methyl-l-oxo-2-butenyl)cvclopentanecarboxylic
acid
To a stirred suspension of 4.38 g. (32.86 mmole)
of anhydrous aluminum chloride in 100 ml. of 1,2-di-
chloroethane at room temperature is added 2.30 g.
(16.43 mmoles) of cis-1,2-cyclopentanedicarboxylic
anhydride. Ethylene is then bubbled through the clear
solution with stirring for four hours.
The solution is poured into 150 ml. of 5%
aqueous hdyrochloric acid and the layers are separated.
Th~ aqueous layer is extracted with ether, the ether
extracts combined with the dichloroethane solution,
dried, and concentrated in vacuo. The residual oil
is heated fifteen minutes on a steam bath with 25 ml.
of 10% aqueous potassium carbonate, cooled, and
extracted with ether. The aqueous layer is acidified
with cold concentrated hydrochloric acid, and the
resulting solution thoroughly extracted with ether.
st,~83
HA165a
-L~~
The combined extracts are dried and concentrated in
vacuo to give 1.9 g. of oil.
The oil is taken up in chloroform, applied to
a silica gel column (60 g.) and eluted with chloroform
(100 ml. fractions collected). Fractions 10-15 are
combined, concentrated in vacuo, and triturated with
petroleum ether, yielding 0.460 g. (14.3%) of cis-2-
(3-methyl-1-oxo-2-butenyl)cyclopentanecarboxylic acid,
which is recrystallized from hexane, m.p. 85-88.
Example 3
trans-2-[3-(Acetylthio)-l~oxopropyl]cyclohexane-
carboxylic acid
a) trans-2-[1-Oxo-2-propenyl~cyclohexane
carboxylic acid
A mixture of aluminum chloride (66.7 g. ,
0.5 mole),trans-1,2-cyclohexanedicarboxylic anhydride
(38.5 g., 0.25 mole) and 1,2-dichloroethane (1 liter) in
a 2 liter 3-neck flask equipped with a gas inlet tube,
a mechanical stirrer and a drying tube is stirred
rapidly and ethylene is bubbled in for 4.5 hours.
This mixture is poured into 900 ml. of 5% hydro-
chloric acid and ice. The layers are separated and
the organic layer is washed with water and taken to
dryness in vacuo. The aqueous layer is extracted with
ether (300 ml.). This extract is washed with water
and combined with material from the original organic
layer and taken to dryness. The residue is heated
with 300 ml. of 10% potassium carbonate on a steam
bath for fifteen minutes. After cooling, the mixture
is extracted three times with ether. The aqueous
layer is acidified and the product trans-2-[1-oxo-
5"~83
HA165a
2-propenyl]cyclohexanecarboxylic acid (31.6 g.)
is ex~racted into ether, dried and concentrated in
vacuo. The crude crystalline trans-2-(1-oxo-2-propenyl)-
cyclohexanecarboxylic acid is recrystallized from
ether-hexane, m.p. 101-102.
b) trans-2-[3-(Acetylthio?-l-oxopropyl]-
cyclohexanecarboxylic acid
The crude olefinic acid obtained above (22 g.)
is dissolved in 100 ml. of chloroform and while
cooling slightly and stirring, 15 ml. (0.21 M) of
thiolacetic acid is added dropwise over a period of
ten minutes. After stirring one hour at room
temperature, the mixture is taken to dryness in vacuo
leaving a yellow rubbery material. This is dissolved
in chloroform and chromatographed on silica gel
(1 lb.), eluting with chloroform, to give 17 g. of
oil which crystallizes on trituration with hexane.
A 3.0 sample is recrystallized from isopropyl e~her
to give 1.7 g. of trans-2-[3-(acetylthio)-1-oxopropyl]-
cyclohexanecarboxylic acid, m.p. 65-68.
Example 4
trans-2-(3-Mercapto-l-oxopropyl)cyclohexanecarboxylic
acid
trans-2-[3-(Acetylthio)-l-oxopropyl]cyclohexane-
carboxylic acid (3.0 g., 11.6 mmol.) is added to a
cold mixture of 5 ml. of concentrated ammonium
hydroxide and 5 ml. of water under argon. The mixture
is stirred at room temperature for 30 minutes. While
cooling to 0, the solution is acidified with concen-
trated hydrochloric acid. The mixture is extracted
four times with ethyl acetate. The extracts are dried
and the solvent is removed in vacuo. The oily product
S ~'83
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-16-
is chromatographed on 90 g. of silica gel eluting with
ethyl acetate. A total of 2.2 g. (88~,) of material
is obtained which is contaminated with some more polar
material. Chromatography of 1.9 g. of this material
on 60 g. of silica gel and eluting with chloroform
and 2% methanol in chloroform gives 1.4 g. of trans-
2-(3-mercapto-1-oxopropyl)cyclohexanecarboxylic acid,
recrystallized from isopropyl ether-hexane, 1.0 g.
(46%), m.p. 71-74.
Example 5
cis-2-[3-(Acetylthio)-l-oxopropyl]cyclohexane-
carboxylic acid
a) cis-2-[l-Oxo-2-propenyl]cyclohexane
carboxylic acid
A mixture of 66.7 g. (0.5 mole) of anhydrous
aluminum chloride and 38.5 g. (0.25 mole) of freshly
distilled cis-1,2-cyclohexanedicarboxylic anhydride
in 1 liter of 1,2-dichloroethane is stirred vigorously
while bubbling in ethylene for 4.5 hours. The mixture
is then poured into 900 ml. of 5% aqueous hydrochloric
acid and ice. The layers are separated and the organic
layer is washed with water and taken to dryness in
vacuo. The aqueous layer is extracted with 300 ml. of
ether, the extract is washed with water and then
combined with material from the original organic
layer and taken to dryness in vacuo.
The residue is heated with 150 ml. of 10%
aqueous potassium carbonate solution on a steam bath
for 15 minutes. After cooling, the mixture is
extracted with ether. The aqueous layer is acidified,
5783
HA165a
-]7-
and the product cis-2-[1-oxo-2-propenyl]cyclohexane-
carboxylic acid is extracted into ether.
The original ether extracts are extracted with
150 ml. of 10% aqueous potassium carbonate. This
aqueous layer is then acidified with dilute aqueous
hydrochloric acid and the product is extracted into
ether. After drying and concentration in vacuo,
23.4. g. of viscous foam is obtained and used without
further purification.
b) cis-2-[3-(Acetylthio)-l-oxopropyl]-
cyclohexanecarboxylic acid, dicyclohexyl-
amine sa _
To a stirred solution of 22 g. of the above
crude foam in 100 ml. of chloroform at 0-5 is added
dropwise 15 ml. of thiolacetic acid. After the
addition is complete, the solution is left at 0-5
for one hour, and then taken to dryness in vacuo.
The residue is taken up in chloroform and
applied to a silica gel column (450 g.) and eluted
as follows:
Fractions Size Solvent
1-2 500 ml. CHC13
3-18 200 ml. CHC13
19-21 200 ml. 1% MeOH/CHC13
22-35 200 ml. 5~ MeOH/CHC13
Fractions 30-32 are combined, treated with hot
isopropyl ether, filtered to remove polymeric material,
and the filtrate concentrated in vacuo. The resulting
oil is taken up in ether (total volume = 200 ml.)
and treated with 10 ml. of dicyclohexylamine. The
resulting crystalline solid dicyclohexylamine salt
S783
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-18-
is filtered off, washed with ether, and dried in
vacuo to give 9.45 g., m.p. 134-138 .
c) cis-2-[3-(Acetylthio)-l-oxopropyl]-
cyclohexanecarboxylic acid
A suspension of 2.0 (4.5 mmole) of the dicyclo-
hexylamine salt from part b in ethyl acetate is treated
with excess 10~ aqueous potassium bisulfate and the
layers separated. The aqueous layer is extracted
with ethyl acetate, and the combined organic layers
dried and concentrated in vacuo to give 1.35 g. of
oil. Trituration of 1.2 g. of this oil with
petroleum ether gives 0.80 g. (69~) of cis-2-
[3-(acetylthio)-1-oxopropyl]cyclohexanecarboxylic
acid which is recrystallized from isopropyl ether,
m.p. 79-81.
Example 6
L-cis-2-(3-Mercapto-l-oxopropyl)c_clohexanecarboxylic
acid
A solution of 2.5 g. (9.68 mmoles) of cis-2-
[3-(acetylthio)-1-oxopropyl]cyclohexanecarboxylic acid
in 5 ml. of concentrated ammonium hydroxide and 5 ml.
of water is kept at 0-5 for one hour. The cold
reaction mixture is then acidified with cold concentra-
ted hydrochloric acid and thoroughly extracted with
ethyl acetate. The com~ined extracts are dried and
concentrated in vacuo to 2.3 g. of oil. This oil is
taken up in chloroform and applied to a silica gel
column (60 g.) and eluted as follows:
Fractions Size Solvent
1-5 50 ml. CHC13
6-15 50 ml. 2% MeOH/CHC13
_ _
33
HA165a
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Fractions 6-13 give a solid on trituration with
hexane. The solids are combined (total = 1.5 g. =
72~) and recrystallized from isopropyl ether/hexane to
give L-cis-2-(3-mercapto-1-oxopropyl)cyclohexane-
carboxylic acid (1.1 g.), m.p. 82.5 - 84.5 .
Example 7
trans-2-[3-(Acetylthio)-2-methyl-1-oxopropyl]cyclohexane-
carboxylic acid (Isomer A)
a) trans-1,2-Cyclohexanedicarboxylic acid,
monomethyl ester
A mixture of 53.3 g. (0.346 mole) of trans-l,
2-cyclohexanedicarboxylic anhydride and 75 ml. of
methanol is heated under reflux for two hours. After
cooling the methanol is removed in vacuo. The residue
is treated with hexane and crystalline material is
deposited. This is harvested and washed with more
hexane to give 58.2 g. (90%) of trans-1,2-cyclohexane-
dicarboxylic acid, monomethyl ester, m.p. 93-97
[cf. J. Amer. Chem Soc. 72, 4406 (1950)].
b) trans-2-(Hydroxymethyl)cyclohexane-arboxylic
acid, methyl ester
A solution of 18.6 g. (0.1 mole) of the acid
ester from part a in 50 ml. of dry tetrahydrofuran
under nitrogen is treated dropwise over a period of
one hour with 100 ml. of lM borane solution (in
tetrahydrofuran) maintaining the temperature at 20-30
with intermittent cooling. After addition is complete,
the mixture is stirred at room temperature for one
hour. Water is added dropwise to decompose any
excess borane. The solvent is removed in vacuo.
Water is added to the residue and the product
l~S~133
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trans-2-(hYdrXYmethYl)cyclohexanecarboxylic acid,
methyl ester is extracted into ether. After drying
and removal of solvent 16.8 g. (98~) of product
remains as an oil.
c) trans-?-Formylcyclohexanecarboxylic acid
methyl ester
-
Chromium trioxide (60 g., 0.6 mole)is added
to a mechanically stirred cooled solution of 95 g.
(1.2 mole) of pyridine in 1.5 liters of methylene
chloride. The mixture is stirred at room temperature
for twenty minutes. A solution of 16.8 g. (0.098 mole)
of the product of part b in 100 ml. of methylene
chloride is added. The mixture is stirred at room
temperature for twenty minutes. The solution is
decanted from the dark gummy material on the side
of the flask. A small amount of methylene chloride
is used as a wash. The solvent is removed from the
decanted solution in vacuo. Ether is added to the
residue. Chromium salts are removed by filtration
through diatomaceous earth. The solvent is removed
in vacuo leaving 15.2 g. (91~) of trans-2-formylcyclo-
hexanecarboxylic acid, methyl ester as a reddish oil.
d) trans-2~ ydroxy-2-meth~1-2-propenyl)-
cyclohexane carboxylic acid
The Grignard reagent of 2-bromopropene is
prepared in tetrahydrofuran using 2.19 g. (0.09 mole)
of magnesium and 12.1 g. (0.1 mole) of 2-bromopropene.
This is added dropwise over thirty-five minutes to a
cooled (0-5) stirred solution of 15.2 g. (0.09 mole)
of the crude aldehyde from part c in 125 ml. of
tetrahydrofurar.. Stirring and cooling is continued
5~3
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for fifteen minutes after addition is complete.
Saturated aqueous ammonium chloride solution (~ 100 ml.)
is then added dropwise. The layers are separated and
the aqueous portion is reextracted with ether. The
combined organic layers are washed twice with saturated
salt solution, dried and the solvent is removed in
vacuo leaving 12.8 g. (79~) of oil which is chroma-
tographed on one pound of silica gel, eluting with
benzene and 20~ chloroform in benzene. Fractions
appearing clean on thin layer chromatography are
combined to give 7.2 g. of oily addition product.
The above oil (5.2 g., 29 mmole) and 29 ml. lN
sodium hydroxide are heated under reflux under nitrogen
for ninety minutes. After cooling, the solution is
extracted twice with ethyl acetate to remove any
neutral material. The aqueous layer is acidified
with cold 10% potassium bisulfate solution while under
a layer of ethyl acetate. The layers are separated
and the aqueous portion is extracted two more times
with ~thyl acetate. The combined organic layers are
dried, filtered, and freed of solvent in vacuo ~eaving
5.5 g. (96%) of largely crystalline product, trans-2-
(l-hydroxy-2-methyl-2-propenyl)cyclohexane carboxylic
acid. The material is used immediately.
2~ e) trans-2-(1-Hydroxy-2-methyl-2-propenyl?-
cyclohexanecarboxylic acid, di~henylmethyl ester
The olefinic hydroxy acid from part d (5 5 g.,
27.7 mmoles) is partially dissolved in 100 ml. ethyl
acetate. While stirring under nitrogen, diphenyl-
diazomethane (5.4 g., 27.7 mmol.) is added protionwise
over a period of thirty minutes. The mixture is
~ ~s l ~
HA165a
-22-
stirred overnight at room temperature. The solution
is washed twice with saturated sodium bicarbonate
solution, dried and freed of solvent in vacuo to give
crude ester, trans-2-(1-hydroxy-2-methyl-2-propenyl)-
cyclohexanecarboxylic acid, diphenylmethyl ester, asa reddish oil, 9.8 g. (97%).
f) trans-2-(2-Methyl-l-oxo-2-propenyl)cyclo-
hexanecarboxylic acid, diphenylmethyl ester
Chromium trioxide (24 g., 240 mmoles) is added
to a cooled stirred solution of 38 g. (480 mmoles) of
pyridine in 600 ml. of methylene chloride. The
mixture is stirred at room temperature for twenty
minutes. A solution of 9.8 g. (27 mmol.) of the
ester from part e in a small amount of methylene
chloride is added and stirring is continued for
twenty minutes. The solution is then decanted from
the dark gummy residue. A small amount of methylene
chloride is used to wash the residue and combined
with the original decanted solution. This is taken
to dryness in vacuo. Ether is added and filtered
through diatomaceous earth to remove chromium salts.
The solvent is removed in vacuo leaving 8.4 g.
partially crystalline product trans-2-(1-oxo-2-
methyl-2-propenyl)cyclohexanecarboxylic acid, diphenyl-
methyl ester which is recrystallized from hexane
(150 ml.) to give 4.5 g. (46%), m.p. 90-95.
A portion (0.5 g.) is recrystallized from
hexane to give an analytical sample (450 mg.), m.p.
92-9~ .
, _
~ S783 HA165a
-23-
~) trans-2-[3-(Acetylthio)-2-m thyl-1-
oxopropyl]cyclohexanecarboxylic acid,
diphenylmethyl ester
The crystalline material from part f (4.0 g.,
11 mmoles) is dissolved in 40 ml. of methylene chloride.
Thiolacetic acid (4.5 ml.) is added andthe solution is
stirred at room temperature for two hours. The solvent
is removed in vacuo to leave an oil. This is dissolved
in benzene and chromatographed on 250 g. of silica gel.
After eluting trace amounts of impurities with
benzene and benzene-chloroform (1:1), the product
trans-2-[3-(acetylthio)-2-methyl-1-oxopropyl]cyclo-
hexanecarboxylic acid, diphenylmethyl ester 4.7 g.
(97%) is eluted as an oil.
h) trans-2-[3-(Acetylthio)-2-methyl-1-
oxopropyl]cyclohexanecar~oxylic acid
(Isomer A)
The chromatographed compound of part g (4.7 g.,
10.7 mmol.) and anisole (21.6 g., 200 mmoles) is
cooled to 0 under nitrogen. Trifluoroacetic acid
(60 ml.) is added dropwise over a period of sixty
minutes while stirring and cooling. After cooling an
additional sixty minutes, the trifluoroacetic acid
is removed in vacuo. Ether is added and the product is
extracted three times into saturated sodium bicar-
bonate solution. The combined aqueous layer is
washed twice with ether and then acidified with
hydrochloric acid. The product is extracted into
ether, dried and taken to dryness in vacuo leaving
3.0 g. of oil. The NMR of this material shows two
sharp peaks for the S-acetylmethyl groups indicating
1 ~5~7~3
llA165a
-24-
a mixture of isomers. This is crystallized from
isopropyl ether/hexane to give 1.3 g. of material
enriched in trans-2-~3-(acetylthio)-2-methyl-1-
oxopropyl]cyclohexanecarboxylic acid, isomer A. The
mother liquor is taken to dryness to give 1.1 g.
of oil, very much enriched in isomer B and is used
in Example 9. The crystalline material is recrystalli-
zed from isopropyl ether-hexane to give 700 mg.
t24%) of trans-2-[3-tacetylthio)-2-methyl-l-oxopropyl]
cyclohexanecarboxylic acid, which NMR indicates is
a single isomer tA), m.p. 103-108 .
Example 8
trans-2-t3-Mercapto-2-methyl-1-oxopropyl)cyclohexane-
carboxylic acid (Isomer A)
The crystalline trans-2-[3-(acetylthio)-2-methyl-
l-oxopropyl]cyclohexanecarboxylic acid, Isomer A from
part h, Example 7 (680 mg., 2.5 mmoles~ is added to a
cold mixture of 1.5 ml. concentrated ammonium
hydroxide and 1 5 ml. water under argon. The mixture
is stirred at room temperature for thirty minutes, then
cooled and acidified with hydrochloric acid. The
product is extracted into ethyl acetate, dried and
freed of solvent in vacuo leaving a yellow oil which
crystallizes on standing. This material is dissolved
in chloroform and chromatographed on 15 g. of silica
gel. The product is eluted with 2~ methanol in
chloroform. Fractions giving strong sulfhydryl positive
test with sodium nitroprusside spray and appearing
clean on thin layer chromatography tsilica gel,
developed with ethyl acetate) are pooled and freed
of solvent in vacuo to give 500 mg. of crystalline
~5'~33
HA165a
-25-
trans-2-(3-mercapto-2-methyl-1-oxopropyl)cyclohexane-
carboxylic acid which is recrystallized from isopropyl
ether (~ 3 ml.) to give 230 mg. (40~) of very dense
white crystalline material, m.p. 87-90.
Example 9
trans-2-(3-Mercapto-2-methyl-1-oxopropyl)cyclohexane-
carboxylic acid (Isomer B)
. . _ . _ . . . _
The mother liquor from the first crystallization
of trans-2-[3-(acetylthio)-2-methyl-1-oxopropyl]cyclo-
hexanecarboxylic acid in Example 7 is taken to
dryness and found by NMR to be nearly clean isomer B.
This oil (900 mg., 3.3 mmoles) is treated with a
cold mixture of 2 ml. of concentrated ammonium
hydroxide and 2 ml. of water in an argon atmosphere.
After stirring thirty minutes at room temperature,
the mixture is washed once with ether. The aqueous
layer is cooled and acidified with hydrochloric acid.
The product is extracted into ethyl acetate, dried and
freed of solvent in vacuo leaving 0.65 g. of material
which is largely crystalline. This is dissolved in
chloroform and chromatographed on 20 g. silica gel.
The product is eluted with 2% methanol in chloroform.
Fractions appearing clean on TLC (silica gel, EtOAc or
10% MeOH in CHC13, detected with sodium nitroprusside
spray) are combined to give 550 mg. (~ 72%) of
crystalline material. Recrystallization from ~ 2 ml.
isopropyl ether gives 165 ml. (22%) of fluffy white
crystalline trans-2-(3-mercapto-2-methyl-1-
oxopropyl)cyclohexanecarboxylic acid, m.p. 91-93.
L2~783
~IA165a
-2~-
Example 10cis-2-(3-Merca~to-3-methyl-1-oxobutyl)cyclopentane-
__ _
carboxylic acid
A solution of 600 mg. (3.06 mmoles) of crude
cis-2-(3-methyl-1-oxo-2-propenyl)cyclopentanecarboxylic
acid in 5 ml. of chloroform is treated with 1 ml. of
thiolacetic acid and left at room temperature for
sixty-four hours. The solution is concentrated in
vacuo to an oil, which is taken up in chloroform,
applied to a silica gel column, and eluted with chloro-
form (50 ml. fractions collected). Fractions Pight and
nine afford 437 mg. (50%) of cis-2-(3-acetylthio-3-
methyl-l-oxobutyl)cyclopentanecarboxylic acid as an
oil.
The oil is stirred thirty minutes at room
temperature in a mixture of 1 ml. each of water and
concentrated ammonium hydroxide. The solution is
cooled, acidified with dilute hydrochloric acid and
thoroughly extracted with ethyl acetate. The combined
extracts are dried and concentrated in vacuo to 277 mg.
(74%) of oil. The oil is taken up in chloroform and
applied to a preparative TLC plate (silica gel, 20 X 20
cm., 2 mm, 5% MeOH/CHC13). The major band (Rf = 0.4)
is extracted with hot ethyl acetate, affording 140 mg.
of oil. The oil is taken up in 5 ml. of ether and
treated with 0.2 ml. of dicyclohexylamine, affording
73 mg. of dicyclohexylamine salt, m.p. 127-130.
The dicyclohexylamine salt is converted into the
free acid by treatment with 10% aqueous potassium
bisulfate and extraction with ethyl acetate, affording
~ 783 ilA165a
-27-
31 mg. of low melting solid cis-2-(3-mercapto-3-
methyl-l-oxobutyl)cyclopentanecarboxylic acid.
The potassium salt is obtained by treating the
oil with potassium hydroxide solution and lyophylizing.
Example 11
trans-2-[3-(Acetylthio)-l-oxopropyl]cyclopentane-
carboxyl_c acid
a) trans-2-Formylcyclopentanecarboxylic acid,
methyl ester
.
A solution of 25 g. (83.3 mmoles) of trans-2-
dibromomethyl-l-cyclopentanecarboxylic acid, methyl
ester [prepared as described in Chem. Ber. 110, 1823
(1977), from cyclopentene and dibromoketene] in
140 ml. of tetrahydrofuran is heated to reflux in a
nitrogen atmosphere. Whil~ stirring, a solution
of 33.0 g. (194 mmole) of silver nitrate in 55 ml. of
water is added over a period of ten minutes. After
an additional thirty minutes of heating and stirring,
the mixture is cooled and saturated aqueous sodium
chloride solution is added. The mixture is then
neutralized with saturated aqueous sodium carbonate
solution and the insoluble salts are removed by filtra-
tion through a Celite (diatomaceous earth) pad.
The pad is washed with ether and some solid sodium
chloride is added to the filtrate~ The layers are
separated and the aqueous portion is reextracted twice
with ether. The combined organic layers are dried
over magnesium sulfate, filtered and taken to dryness
in vacuo leaving 7.5 g. of amber oil. This is
distilled at reduced pressure collecting 4.1 g. (32%)
~ ~5'~83
HA165a
-2~-
of product, trans-2-formylcyclopentanecarboxylic
acid,methyl ester, boiling at 60-85 /0.4 mm.
b) trans-2-(1-}~ydroxy-2-propenyl)cyclo-
pentanecarboxyl~c acid
The Grignard reagent of vinyl bromide is
prepared in tetrahydrofuran using 0.39 g. (16 mmoles)
of magnesium and 2.5 g. of vinyl bromide. This is
added dropwise over thirty minutes to a cooled (0-5 ),
stirred solution of 2.5 g. (16 mmol.) of distilled
aldehyde from part a in 20 ml. of tetrahydrofuran.
Stirring and cooling is continued for fifteen minutes
after addition is complete. Saturated aqueous
ammonium chloride solution (20 ml.) is then added
dropwise. The layers are separated and the aqueous
layer is reextracted with ether. The combined
organic layers are washed twice with saturated sodium
chloride solution, dried and the solvent is removed
in vacuo leaving 2.3 g. of trans-2-(1-hydroxy-2-
propenyl)cyclopentanecarboxylic acid as a yellow oil.
The oil including a small amount of the
corresponding lactone is added to 18 ml. of lN sodium
hydroxide and heated under reflux in a nitrogen
atmosphere for 1.5 hours. After cooling, the solution
is extracted twice with ethyl acetate to remove any
neutral material. The aqueous layer is acidified
with cold 10~ potassium bisulfate solution. The
product is extracted into ethyl acetate, dried and
freed of solvent leaving 2.0 g. (73%) of product.
c) trans-2-(1-Hydroxy-2-propenyl)cyclo-
pentanecarboxylic acid, diphenylmethyl ester
The material obtained in part b (2.0 g.,
.
HA165a
_~9_
11.7 mmoles) is dissolved in 50 ml. of ethyl acetate.
While stirring under nitrogen, diphenyldiazomethane
(2.2 g., ~11.5 mmol.) is added in several portions over
a period of thirty minutes. The mixture is stirred
overnight at room temperature. The solution is
washed twice with saturated sodium bicarbonate
solution, dried and freed of solvent in vacuo
leaving 3.65 g. of reddish viscous oil. The oil is
dissolved in chloroform and chromatographed on a
100 g. silica gel column using chloroform to elute.
Fractions appearing clean on TLC are combined and
taken to dryness in vacuo leaving 1.35 g. (35~) of
trans-2-(1-hydroxy-2-propenyl)cyclopentanecarboxylic
acid, diphenylmethyl ester as an oil.
d) trans-2-(1-Oxo-2-propenyl)_yclopentane-
carboxylic acid, diphenylmethyl ester
_
The oil obtained in part d (1.35 g., 4.0 mmoles)
is dissolv~d in 60 ml. of methylene chloride and 13 g.
activated manganese dioxide are added and stirred
overnight under argon. The manganese dioxide is removed
by filtration. The filtrate is taken to dryness
leaving 1.0 g. of yellow oil. This is chromatographed
on 25 g. of silica gel using benzene to elute.
Fractions appearing nearly clean on TLC are combined
and taken to dryness in vacuo leaving 0.7 g. (52%) of
trans-2-(1-oxo-2-propenyl)cyclopentanecarboxylic acid,
diphenylmethyl ester as a yellow oil.
e) trans-2-~3-(Acetylthio)-l-oxopropyl]cyclo-
pentanecarboxylic ac d, dlphenylmethyl ester
The oil obtained in part d ~0.7 g., 2.1 mmoles)
is dissolved in 10 ml. chloroform and 0.7 ml. of
~ ~ZS~83 HA165a
-30-
thiolacetic acid is added. After stirring one hourat room temperature, the mixture is taken to dryness
in vacuo leaving 0.8 g. of pale yellow oil. This is
chromatographed on 25 g. of silica gel using benzene
to elute. Fractions appearing clean on TLC are combined
and taken to dryness in vacuo leaving 625 mg. (72%)
of trans-2-[3-(acetylthio)-1-oxopropyl]cyclopentane-
carboxylic acid, diphenylmethyl ester as an oil.
f) trans-2-[3-(Acetylthio)-l-oxopropyl]cyclo-
_
pentanecarboxylic acid
The oil obtained in part e, (625 mg. ~1.5 mmoles)in 3.25 g. ~30 mmoles) of anisole is stirred and
cooled (0-5) in a nitrogen atmosphere and 10 ml. of
trifluoroacetic acid are added dropwise over a period
of forty minutes. After addition is complete the
mixture is stirred with cooling for an additional
sixty minutes. The trifluoroacetic acid is removed
in vacuo. The residue is dissolved in ether and
extracted three times with saturated sodi~m bicarbonate
solution. The combined aqueous layers are washed
twice with ether to remove any neu~ral materlal. The
aqueous portion is then acidified with hydrochloric
acid and extracted three times with ether. These
etller extracts are dried (MgS04), filtered and the
solvent is removed in vacuo leaving 400 mg.
(quantitative) of trans-2-[3-(acetylthio)-1-oxo-
propyl]cyclopentanecarboxylic aci~ as a yellow oil.
TLC (silica gel, 10% MeOH in CHC13, I2) shows a
major spot at Rf = 0.55.
5~3
HA165a
-31-
Ex mple 12
trans-2-(3-Mercapto-l-oxopropyl)cyclopentane-
carboxylic acid
.
A cold argon saturated mixture of 1 ml.
concentrated ammonium hydroxide and 1 ml. of water
is added to trans-2-[3-(acetylthio)-1-oxopropyl]-
cyclopentanecarboxylic acid (1.5 mmoles) swirled at
room temperature for thirty minutes, cooled and
then acidified with concentrated hydrochloric acid.
This is extracted three times with ethyl acetate.
The combined ethyl acetate extracts are dried, filtered
and the solvent is removed in vacuo leaving ~350 mg.
which is dissolved in chloroform and spotted on a
20 x 20 cm. preparative silica gel plate. The plate
is developed in 10~ methanol in chloroform. Detecting
by W, the band corresponding to a spot giving a
positive SH test on an analytical plate is removed
and eluted with warm ethyl acetate. The ethyl acetate
solution is washed twice with water, dried and taken
to dryness in vacuo leaving 135.7 mg. (45~) of
trans-2-(3-mercapto-1-oxopropyl~cyclopentanecarboxylic
acid as a yellow oil.
This oil (0.67 mmol.) is dissolved in a small
amount of isopropyl ether and converted to the dicyclo-
hexylamine salt by adding a slight excess of dicyclo-
hexylamine. Crystalline material (202 mg.) is
harvested and recrystallized from isopropyl ether to
give trans-2-(3-mercapto-1-oxopropyl)cyclopentane-
carboxylic acid, dicyclohexylamine salt (171 mg.,
b7%) m.p. 126-128.
~l ~LZ5'~83
~165a
-32-
The bulk of the salt (150 mg., 0.39 mmol.) is
reconverted to the free acid with 10% potassium
bisulfate solution. The acid is extracted into
ethyl acetate, dried and freed of solvent in vacuo
to give 74.4 mg. of the acid (94%) as an oil. TLC
(silica gel, 10% MeOH in CHC13, detected SH spray and
I2), large maljor spot (SH positive) Rf = 0.41.
Example 13
cis-2-[3-(Acetylthio)-l-oxopropyl]cyclobutane-
carboxylic acid
a) cis-2-[1-Oxo-2-propenyl]cyclobutane-
carboxylic acid
A mixture of aluminum chloride (66.7 g., 0.5 M),
1,2-cyclobutanedicarboxylic anhydride (31.5 g., 0.24 M)
and 1,2-dichloroethane (1 liter) in a 2 liter 3-neck
flask equipped with a gas inlet tube, a mechanical
stirrer and a drying tube is stirred rapidly and
ethylene is bubbled in for 4.5 hours. This mixture
is poured into 900 ml. 5% hydrochloric acid and ice.
~o The layers are separated and the organic layer is
washed with water and taken to dryness in vacuo. The
aqueous layer is extracted with ether (300 ml.). The
extract is washed with water and combined with
material from the original organic layer and taken to
dryness. The residue is heated with 150 ml. of
10% potassium carbonate on a steam bath for fifteen
minutes. After cooling the mixture is extracted
three times with ether. The aqueous portion is
acidified and the product (1.5 g.) is extracted into
ether. The original ether extracts are combined and
extracted with 150 ml. of 10~ potassium carbonate
S~783
HA165a
-~3~
solution. ThiS aqueous layer is then acidified with
hydrochloric acid and the product cis-2-[1-oxo-2-
propenyl]cyclobutanecarboxylic acid (24.3 g.) is
extracted into ether. Both samples (25.8 g., 67~)
crystallize on standing.
b) cis-2-[3-(Acetylthio)-l-oxopropyl]cyclo-
butanecarboxylic aci_
The crude acid obtained in part a (24.3 g.,
0.16 M) is dissolved in 100 ml. of chloroform. The
solution is cooled in an ice bath and 15 ml.
(~0.21 M) of thiolacetic acid is added dropwise
over a period of twenty minutes. After stirring one
hour at room temperature, the mixture is taken to
dryness in vacuo leaving a viscous oil (36 g.). This
is dissolved in chloroform and chromatographed on
1 pound of silica gel to give material which crystalli-
zes on trituration with hexane. The crystalline
material (10.6 g., 29~) is recrystallized from
isopropyl ether to give cis-2-[3-(acetylthio)-1-
oxopropyl]cyclobutanecarboxylic acid, 6.6 y.,
m.p. 50-54.
Example 14
cis-2-(3-Mercapto-l-oxopropyl)cyclobutaneearboxylie
acid
eis-2-[3-(Acetylthio)-l-oxopropyl]cyclobutane-
carboxylic acid (2.5 g., 10.9 mmol.) is added to a
eold mixture of 5 ml. of concentrated ammonium
hydroxide and 5 ml. of water in an argon atmosphere.
The solution is stirred at room temperature for
thirty minutes. While cooling, the mixture is
aeidified with hydrochloric acid and the product is
~5 ~83 HA16Sa
-34-
extracted into ethyl acetate, dried, and freed of
solvent in vacuo leaving 2.1 g. of oil. This is
chromatographed on 50 g. of silica gel eluting with
chloroform and 2% methanol in chloroform. The oil
obtained (clean by TLC, silica gel, 10% methanol in
chloroform - Rf = 0.43) (1.35 g. ,66%) is dissolved in
ether and converted to cis-2-(3-mercapto-1-oxopropyl)-
cyclobutanecarboxylic acid, dicyclohexylamine salt,
by adding a slight excess of dicyclohexylamine. The
white solid is recrystallized from ethyl acetate to
give 2.0 g., m.p. 129-132.
The salt is converted to the free acid with 10%
potassium bisulfate solution and extracted into ethyl
acetate to give 0.95 g. of cis-2-(3-mercapto-1-
oxopropyl)cyclobutanecarboxylic acid as an oil.
Example 15
trans-2-(3-Mercapto-l-oxopropyl)cyclobutane
carboxylic acid
A solution of 460 mg. (2 mmol.) cis-2~[3-(acetyl-
thio)-l-oxopropyl]cyclobutanecarboxylic acid in 10 ml.
of methanol is cooled to 0 in an argon atmosphere and
324 mg. (6 mmol.) of sodium methoxide is added. The
mixture is stirred at 0 for two hours and then
acidified with 2N hydrochloric acid. The methanol is
removed in vacuo. ~ater is added and the product
is extracted into ethyl acetate to give 320 mg. of an
oil. This is purified on a preparative TLC plate
(silica gel, developed 10% MeOH in CHC13). The band
containing product is scraped off and eluted with
ethyl acetate to give 150 mg. of oil (40%). This oil
is dissolved in ether and converted to the dicyclo-
S~83
IIA165a
-35-
hexylamine salt by adding a slight excess of
dicyclohexylamine. The white solid is recrystallized
from ethyl acetate to give 250 mg. of trans-2-(3-
mercapto-1-oxopropyl)cyclobutanecarboxylic acid,
dicyclohexylamine salt, m.p. 140-144 .
The salt is converted to the free acid with 10%
potassium bisulfate solution. The acid is extracted
into ethyl acetate, dried, and freed of solvent leaving
trans-2-(3-mercapto-1-oxopropyl)cyclobutanecarboxylic
acid as an oil (120 mg.) which is dissolved in water
containing a few drops of ethanol and lyophillized.
The sodium salt is ohtained from the oil by
adding an equivalent amount of sodium hydroxide solution
then lyophilizing.
Example 16
6-(Acetylthio)-4-oxohexanoic acid
a) 4-Oxo-5-hexenoic acid
[cf. J. Chem. Soc., 3922 (1958)]. A mixture
of aluminum chloride (66.7 g., 0.5 M), succinic
anhydride (25 g., 0.25 M) and 1,2-dichloroethane
(1 liter) in a 2 liter 3 neck flask equipped with a
gas inlet tube, a mechanical stirrer and a drying tube
is stirred rapidly and ethylene is bubbled in for
4.5 hours. This is poured into 900 ml. 5~ hydrochlorc
acid and ice. The layers are separated and the organic
layer is washed with water and taken to dryness in
vacuo. The aqueous layer is extracted with ether
(300 ml.). This extract is washed with water and
combined with the material from the original organic
layer. After removal of solvent, 150 ml. of 10~
potassium carbonate solution is added and the mixture
~l~25~783
HA165a
-3fi-
is heated on a steam cone for 15 minutes. After
coolin(~, ~he product 4-oxo-5-hexenoic acid is extracted
;nto ethcr, dried and freed of solvent in vacuo
leaving 10.9 g. (34~) of brownish liquid which solidifies
on standing. This is distilled to give 7.1 g. (22~) of
colorless liquid which solidifies on standing, b.p.
~120-130/0.5 mm.
b) 6-(Acetylthio)-4-oxohexanoic acid
The distilled 4-oxo-5-hexenoic acid (6.8 g.,
58 ~mol.) from part a is dissolved in 30 ml. of
methylene chloride. Thiolacetic acid (4.0 g., 65 mmol.)
is added dropwise. After stirring at room temperature
45 minutes, a very small amount of insoluble material
is removed by filtration. The solvent is removed in
vacuo leaving 9.9 g. (84~) of near white solid.
Petroleum ether is added and the crystalline material
is harvested by filtration. This is recrystallized from
benzene to give 6-(acetylthio)-4-oxohexanoic acid,
6.2 g. (52%), m.p. 72-74.
Example 17
6-Mercapto-4-oxohexanoic acid
. .
6-tAcetylthio)-4-oxohexanoic acid (3.5 g.,
17 mmol.) is added to a cold solution of 5 ml. of
concentrated ammonium hydroxide and 5 ml. of water
under argon. The solution is stirred at room
temperature for 30 minutes. While cooling in an
ice-bath,the mixture is acidified with concentrated
hydrochloric acid. The mixture is continuously
extracted with ethyl acetate for 24 hours to give a
total of 3.6 g. of extracted material, largely oil
but containing some crystalline material. Trituration
with ether gives 240 mg. of solid material.
9~ S~ ~ 3
HA165a
-37-
The ether soluble portion of the ethyl acetate
extract is taken to dryness and chromatographed on
90 g. of silica gel using chloroform as the eluant.
The crystalline material obtained (1.6 g., 58~) is
S recrystallized from ether-hexane to give h-mercapto-
4-oxohexanoic acid, 850 ~g. (31%), m.p. 40-42.
The sodium salt is formed as in Example 15.
Example 18
trans-2-(Mercaptoacetyl)cyclohexanecarboxylic acid
a) trans-1,2-Cyclohexanedicarboxylic acid,
monomethyl ester is prepared as described in
Example 7a. This is converted to the acid chloride
by dissolving 7.4 g. (40 mmol.) in 100 ml. ether and
treating with 4 ml. of oxalyl chloride and a few
drops of dimethylformamide. The solution is stirred
ninety minutes at room temperature and the solvent
is removed in vacuo without heating. The acid chloride
is dissolved in 200 ml. of ether, cooled in an ice
bath and treated with an ether solution of diazomethane
(prepared from 20 g. N-methyl-N'-nitro-N-nitroso-
quanidine). The solution is stirred with cooling for
two hours, and one hour and fifteen minutes at room
temperature. A very small amount of insoluble material
is removed by filtration. The filtrate is washed once
with saturated sodium bicarbonate solution and once
with saturated sodium chloride solution, dried and
freed of solvent in vacuo leaving 7.4 g. (88%) of
material which solidifies on standing.
b) The diazomethylketone obtained in part a
(7.4 g., 35.2 mmol.) is dissolved in 70 ml. of
chloroform and 10.5 ml. thiolacetic acid. After
~ 7~3 HA165a
-38-
standing for four days at room temperature, the solvent
is removed in vacuo leaving 9.1 g. of yellow oil. The
material is dissolved in benzene and chromatographed
on 200 g. of silica gel. After removal of the
contaminants with benzene and mixtures of benzene
and chloroform, the desired 2-(acetylthio)cyclo-
hexane carboxylic acid is eluted eith chloroform.
Fractions appearing clean by TLC are combined to give
2.15 (24%) of material as an oil. Another pool of
fractions (2.5 g.) contaminated with an appreciable
amount of slower moving material is set aside.
c) Chromatographed S-acetyl compound from
part b (2.6 g., 10 mmol.) is treated with 50 ml. of
lN sodium hydroxide which has been saturated with argon
and the mixture is stirred overnight under argon.
After extracting twice with ether to remove any
non-acidic material, the aqueous solution is cooled
and acidified with hydrochloric acid. The product
is extracted into ethyl acetate, dried and freed of
solvent in vacuo to give 2.1 g. of yellow oil. The -
oil is dissolved in chloroform and chromatographed on
60 g. of silica gel, eluting with chloroform. Fractions
giving strong positive reaction with SH spray are
checked on TLC and the fractions appearing clean are
combined and taken to dryness to give 900 mg. (44%)
of crystalline material. This is recrystallized from
isopropyl ether with a charcoal decolorization to
give trans-2-(mercaptoacetyl)cyclohexanecarboxylic
acid, 618 mg. (30~), shrinking 102, m.p. 112-117.
~ 783 HA165a
-39-
Example 19
(trans)-2,2'-[Dithiobis(l-oxo-3,1-~opanediyl)]bis-
c l hexanecarboxylic acid
3.0 g. (13.89 mmole) trans-2-(3-mercapto-1-
oxopropyl)cyclohexanecarboxylic acid is partially
dissolved in a mixture of 15 ml. of lN sodium
hydroxide and 100 ml. of water. To this rapidly
stirred mixture (almost all solid in solution) is
added dropwise 0.5 M of iodine in absolute ethanol.
During the addition, the pH of the reaction mixture
is maintained at 5.5 - 6.5 by dropwise addition of lN
sodium hydroxide. The solution is stirred for fifteen
minutes at room temperature, a trace of excess iodine
is discharged with aqueous sodium thiosulfate, acidi-
fied with concentrated hydrochloric acid, and thoroughly
extracted with ethyl acetate. The combined extracts
are dried and concentrated in vacuo to give 2.1 g.
(70%) of crude (trans)-2,2'-[dithiobis(l-oxo-3,1-pro-
panediyl)]biscyclohexanecarboxylic acid. The oil is
taken up in 25 ml. of ether, treated with 3 ml. of
dicyclohexylamine, and allowed to stand overnight
in the cold, yielding 3.3 g. (85% conversion) of
bisdicyclohexylamine salt. Recrystallization from
ethyl acetate/methanol gives the analytical sample
(2.9 g.) m.p. 167-170.
The dicyclohexylamine salt is converted into
(trans)-2,2'-[dithiobis(l-oxo-3,1-propanediyl)]bis-
cyclohexanecarboxylic acid by treatment with 10%
aqueous potassium bisulfate and extraction with ether.
11~S~83
HA165a
-4~-
Example 20
(trans)-2,2'-[Dithiobis(l-oxoethyl)]biscyclohexane
_rboxylic acid
By substituting trans-2-(mercaptoacetyl)cyclo-
hexanecarboxylic acid for the trans-2-(3-mercapto-1-
oxopropyl)cyclohexanecarboxylic acid in the procedure
of Example 19, (trans-2,2'-[dithiobis(l-oxoethyl)]bis-
cyclohexanecarboxylic acid is obtained.
