Note: Descriptions are shown in the official language in which they were submitted.
- ?
,_~
1038400
~ackground-of the Invention
~ ! `- 1. Field of the Invention:
., I --
¦ The compounds of the present invention relate to
i 5-cyclohexyl-1-indancarboxylic acids which compounds are usefulI non-steroidal anti-inflammatory agents.
2. Description of the Prior Art:
I The compounds 4-isobutylphenylacetic acid lSouth
4 African Patent 62/294 (1962, 4-isobutyl-~-methyl-phenylacetic
acid [5.S. Adams, E.E. Cliffe, B. Lessel, and J.S. Nicholson,
J. Pharm. Sci., 56, 1686 (1967)], 3-chloro-4-cyclohexyl-~- methyl-
phenyl-acetic acid [T.Y. Shen, Chim. Therap., II, 459, (1967)],
and 5-~-methoxyphenyl-2-indancarboxylic acid tM. Mlnssen - Guette,
M. Dvolaitzky, and J. Jacques, Bull Soc. Chim. France, N.5, 2111
~ (1968)~ have been described in the literature as being useful
- ~ anti-inflammatory agents.
.
Disclosure of the Invention
~hi8 inventlon relates to non-steroidal anti-
inflammatory agents useful in animals, including man, which com-
~ pounds are characterized by the formula
:~ , 20
,,
R ~ 2
in which
I R is cyclohexyl, I
¦ Y is hydrogen, bromo, chloro, iodo, fluoro, merc~pto,
cyano, hydroxy, trif~uoromethyl, (lower)alkyl, (lower)alkoxy,
~ ~
.
:,
-- -- --
i~ ~
: ~ ~
~ Q38400
nitro, amino or tlower)-alkylthio; or a nontoxic, pharmaceutically-
acceptable salt thereof. The carboxyl group in the compounds
of the instant invention is attanced to an asymmetric carbon
atom ~*) such that the compounds exist in two isomeric forms,
dextro- and levorotatory isomers. Both the substantially pure
dextro- and levorotatory isomers of these compounds, as well as
the racemic mixtures are considered to be an integral part of
the invention.
I It was an objec~ of the instant invention to prepare
non-steroidal anti-inflammatory agents that would be useful in
the treatment of a variety of inflammatory diseases such as
Theumatoid Arthritis, Rheumatoid Spondylitis, Osteoarthritis,
¦ Gout and other similar afflictions.
These objectives have been achieved by the provision
of a process for the preparation of compounds of the formula (I)
CO2A
''`. I 0/
.':' I
¦ in which A is hydrogen or lower alkyl, which comprises reducing
a compound of the formula (II)
,~ I
'' ' C02A
(II)
1 o
~ in which A has the meaning defined above, and recovering the
¦ compound of formula I so produced.
. ;
-- 2 --
. . . .
.. ! ~
. . ..
., ~031B400
j In one aspect the present invention provides such a
¦ process further comprising, when A is hydrogen, forming a nontoxic,
i pharmaceutically-acceptable salt of the compo~nd.
¦ In another aspect the invention provides the compounds
of formuLa ~I) and nontoxic, pharmaceutically-acceptable salts
thereof.
In another aspect the present invention provides a
~' process for the preparation of a compound having the formula
.: I .
C02A
~>
., .
. I wherein A is hydrogen or (lower)alkyl which comprises the follow-
¦ ing steps in sequence:
I (a) reacting a compound of the formula
.~. I
~ I ~ ~CHO
O
¦ with a malonic acid ester of the formula CH2(C02R)2, wherein R
is a (lower)alkyl radical, to produce a compound of the formula
~CH= C(C02R)
.,' I O
'' ' l . .
' wherein R has the previously recited significances;
i 30
. I ~ 3
,
l--;
0 ~
;~b) converting the compound obtained in step ~a) to a
compound having the formula
; i CN
~ ~ CH - CH2 - C02R
.' I ~
'', I V
~,,, ~ - -
' ' '.
;~ , 10wherein R is as specified above, by reaction with hydrogen cyanide
'~ ' or its salts;
...(c) hydrolyzing the compound obtained from step (b)to
~ obtain a compound of the formula
..
: C02H
.,, , ~ ~ CH2 - COOH
'' O
. . ,
(d) cyclising the compound obtained from step (c) or a
reactive derivative thereof to produce a compound of the formula
. ~ C ~H
III
(e) reducing the compound of the formula t~II) as obtained
, ~ . .
in step (d) to a compound of the formula
.
~ - 3(a) -
.,
: l . 1038400
-, C02~
~, C~ (rV)
'. :i
and recovering the product so obtained; and, in the event that
a compound within the scope of formula I, wherein A is (lower)-
I
alkyl, is desired;
(f1 e~terifying the product of step (e) above with an
. J alcohol of the formula R'O~, where R' is (lower)alkyl, and
I recovering the product so obtained.
: ¦ In one aspect, in step (d) the cyclization of the com-
` I pound obtained from step (b) is accomplished by converting the
.3 ¦ compound from step (b) to the corresponding anhydride and
reacting the anhydride with aluminum chloride in the presence
t ~ of methylene chloride to produce the compound of formula III.
I i The compound of formula II may preferablybe reduced by means
.~ I of catalytic hydrogenation.
~ i 20 In a further aspect the present invention provides
I , a process for the preparation of compounds having the formula
! (IV)
:.~ ' C2A :
'
; I in which Y ls halogen
and A is hydrogen, a (lower)alkyl radical or (lower)alkyl
radical possessing a t-amine function and pharmaceutically
:
~ - 3(b) -
. I
,
C~
, ~
acceptable ~lts thereof, which comprises halogenating a
i compound having the formula
: I C02A
0~
in which A has the meaning defined above,
or a salt or a functionally converted derivative thereof; and
where required converting the functionally converted derivative
into the compound of formula (IV) wherein A has the mean?ng
, defined above; and where required converting any free acid of
.; . the formula (IV) so produced to a pharmaceutically acceptable
salt thereof.
; In still another aspect the invention provides a
process for the preparation of a substantially pure isomer of
- ~ the compound having the formula (V)
. . . .
: ¦ C()2A
C ~ (V)
, '~
I in which Y is H,'Cl, Br, I or F;
A is hydrogen or (lower)alkyl
and pharmaceutically acceptable salts thereof, which comprises
I resolving the product of formula V occurring in the form of a
~ racemic mixture into a substantially pure isomer by treatment
I with an optically active resolving agent and recovering the
', 30 substantially pure isomer so obtained and where required
, converting said substantially pure isomer into a pharmaceutically acceptable salt thereof.
- 3(c)
... . .. . . . ..... . . .
~ i!
Ill 1(138~W~ ~
1 1l The pharm~ceutically-acceptable, nontoxic cations include metallic
j
2 !' cations such as sodium~ potassium, calcium and stluminum and orgs~nic amine
3 ¦I cations of trl~lxylamines~ e.g. triethylamine, procaine, dibenzylamine,
4 il ~-benzyl-~-phenethylE~ine, l-ephenamine, N~'-dibenzylethylenediamine,
S ¦¦ dehydroabietylamine, N,N'-bis-dehydroabietylethylenediamine, ~-(lower)-
¦l alkyl-piperidines, e.g. N-ethylpiperidine, and other amines which ha~e
7 1~ been used tc form salts with medicinally acti~e carboxylic acids.
S 1I me ter~ "tlower)alkyl" as used herein means both straight and
9 ¦I branched chain aliphAtic hydrocarbon r~icals ha~ing from 1 to 6 carbon¦1 atoms such as methyl, ethyl, propyl, isopropyl, butyl, iæobutyl, etc.
11 ¦ Simi~arly, whc~e the term "(lower)~' is used as part of the tescription of
another group~ e.g. "(lower)alkoxy", it refers to the alkyl portion o~
13 1¦ such group whlch is there~ore as described abo~e in connect_on w1th
~t 1l "(lower)aikyl" and thus lncludes such radicals as methoxy, ethoxy, lsopropoxy,
¦ etc.
16 ll me compoun,ds o~ the instant ~n~ention can ~te prepared by the
!l ~oll~wing s~
1, ~C~IO ~ HOAc ~C~ C~C2C2~5)2
~ ~ ~ OH2(C02C2}~5)2
22 j C02~ ~ CN
23 1 ~ *CX~c~~c02~ ~ *CH-Ç~2C02c2x5
24 1 ~ ~HCl
26
28 ~ , AlC13
30 ~¦B ~ ~2 B~l~\ ~ I~HOAO/XC104
1; ~
- :
;: :
10384~0
; wherein R is cyclohex~l.
The optionally Y-substituted 5-cyclohexyl-1-indancarboxy-
lic acids of the present invention can be prepared by one of two
synthetic routes:
1. (a) 6-Halosubstituted-l-Indancarboxylic Acid:
5-Cyclohexyl-l-indancarboxylic acid is halogenated
with N-halosuccinimide to produce 6-halo-5-cyclohexyl-1-indancar-
;~ boxylic acids (see Example 3).
(b) 4 or 6-Nitrosubstituted-l-Indancarboxylic Acids:
5-Cyclohexyl-l-indancarboxylic acid is nitrated
with one equivalent of nitric acid in the presence of sulfuric
:; acid to produce a mixture of 4 and 6-nitro-5-cyclohexyl-1-indan-
carboxylic acids. The mixture can be resolved into pure 4-nitro-
5-cyclohexyl-1-indancarboxylic acid and 6-nitro-5-cyclohexyl-1-
indancarboxylic acid by methods known to the art. These resolved
6-nitrosubstituted compounds are most valuable as intermediates
in the preparation of the other claimed compounds of the present
r'. invention.
(c) 6-Aminosubstituted-l-Indancarboxylic Acids:
; The purified 6-nitrosubstituted indancarboxylic
.
;~ acids obtained in part "(b)" above are reduced by the use of
hydrogen and catalyst (Pd/C, PtO2, etc.) to produce the 6-amino-
substituted indancarboxylic acids of the present invention.
- (d) l-Indancarboxylic Acid Diazonium Salts:
The aminosubstituted compound prepared in step
"(c)" above is placed in a strong mineral acid, i.e., HCl, H2S04,
HBr, etc., at 0 C. Nitrous acid is generated in situ by the
addition of sodium nitrite to produce the diazonium salt of the
amine.
(e) 6-Hydroxy-5-Cyclohexyl-l-Indancarboxylic Acid:
Heating of the 6-diazonium salt obtained in step
~(d) n after the addition of water, will result in the formation
` of the 6-hydroxy-5-
-- 5 --
,
"' ' - : ; '' '~ ' : `';
11 1038~
1 `1 cyclohexyl-l-indancarboxylic acid.
(f) 6-Alkoxy-5-Cyclohexyl-l-Indancarboxylic Acid:
j,
3 ~' Heating of the 6-diazonium salt obtained ln step "(d)" after
the additlon of the appropriate alcohol will result in the formation of the
5 1 6-~lkoxy compound.
6 ,l (g) 6-Halo-5-Cyclohexyl-l-Indancarbox~lic Acid:
; The 6-diazonium salt prepared as in Step "(d)" ~rom the
3 ll 6-sminosubstltuted-l-lndancarboxylic acld obtained in step "(c)" ls
g j, tre~ted with either cooper-bronze (Gattermann Reaction) or cuprous hal~de
~l (Cl, Br~ I) to produce the 6-halosubstituted compound.
(h) 6-Cyano-5 Cyclohexyl-l-Indancarboxyllc Acid:
`' 12 1I The 6-dia~onium salt obtained by the procedure o~ step "(d)"
~ which 18 prepared in ~ S ~ ls treated with base to neutralize the salt
-~ 14 ,li solutlon, followed by the addltion of a solution o~ cuprous cyanide-sodium
` It
:~ 15 Ij cyanlde complex to produce a preclpitate. He~ting Or the prec~pitate
16 !i decomposes it to the cya~osubstituted acid.
7 ¦¦ (i) 6-Fluoro-6-CyclohexYl-l-IndancarboxYlic Acid:
l8 ~¦ The 6-di~zonium salt, as in step "(g)", is treated with
~ Ij fluoroboric acid~ The fluoroborate precipitates and is collected. After
¦ washing and drying~ the precipltate is heated and it d~composes ~o ~hc
~ deslred 6-~luorosubstltuted compound.
22 1l (J ) -Merc~pto-5-~yclohexyl-l-Indancarbox~lic acid: l
23 ll The 6-dia~onlu~ salt prepared in step "(d)" is treated with
24 jl potassium ethyl xanthate which produces an ethyl dlthiocarbonate. Saponiri~ i
2S l¦ cation of the dithiocarbonate produces t~e des~red 6-mercaptosubstituted
26 ¦¦ co~pound
27 ll ~k) 6-Methylthio-5-Cyclohexyl-l-Indancarboxylic acid:
Il Treatment o~ the 6-mercaptosubstituted c~mpound obtained in
29 1 step "(J)" with dimethYlsulfate in the presence of a base~;followed by mild
il hydrolysis, produces the 6-methylthiosub~tituted a¢id.
11 ' ~'''' ), ' ~
-6- I
!
` 10384~0
1 " ~1) 6-Methyl-5-Cyclohexyl-l-Indancarb x~ic Acid:
2 !, The 6-bromo- or iodo~5-cyclohexyl-1-indancarboxylic acid
3 obtained in Step "(g)" is treated with lithium dimethylcopper to produce
6-methyl-5-cyclohexyl-1-indancarboxylic acid [E.J. Corey and G.~. Posner,
S , J. Am. Chem. Soc., 89, p. 3911 (1967)].
6 ,~ me compounds of the instant invention can be prepsred by the
utillzation of one or more o~ the disclosed procedures above and they
,l include among others:
il 6-Chloro-5-cyclohexyl-1-indancarboxylic acid,
10 l,l 6-~romo-5-cyclohexyl-1-indancarboxylic acid,
11 1' 6-Iodo-5-cyclohexyl-1-indancarboxylic acid,
12 jl, 6-Fluoro-5-cyclohexyl-1-indancarboxylic acid,
13 ' 6-Hydroxy-5-cyclohexyl-1-indancarboxylic acid,
14 ! 6-Methoxy-5-cyclohexyl-1-indancarboxyllc acid,
lS I 6-Nitro-5-cyclohexyl-1-indancarboxylic acid,
6-Amino-5-cyclohexyl-1-indancarboxylic acid,
1~ 6-Cyano-5-cyclohexyl-1-indancarboxylic acid,
18 ~l 6-Methy1-5-cyclohexyl-1-indancarboxylic acid,
19 !1 6-Mercapto-5-cyclohexyl-1-lndancarboxylic acld~ and
20 i1 6-Methylthio-5-cyclohexyl-1-indancarboxylic acld.
21 ¦I m e cc~pounds Or the instant invention can be resolved into their
22 l¦ substantially pure dextro- and levorotatory ~somers by ~ethods co = nly
23 1l known ln the art. ~or illustrative purposes, the compound 5-cyclo-
24 1l hexyl-l-indancarboxylic acid wa6 resolved into its respective lsomers by
1 the procedure of ~irst treatlne the mixture with cinchonidine to produce the ¦
26 1 cinchonid1ne salt Or (~)-5-cyclohexyl-1-indancarboxylic acid. The salt
27 ¦I was recrystallized and then decomposed to the Sree ~cid to yield
28 ~! substantially pure (~)-50cyclohexy1-l-indancarboxylic acid.
2g 11 The levorotatory acld enriched mother liquor6 remain~ng above, a~ter
ll the collectlon of the clnc~onldine salt o~ the dextrorotatory acld wss
!1 ~ ; _7_ I ,i
I!
.
., 11 , ., .
,1 1038400
1 1, isolated fro~ it, was concentrated to dryness. The resldue was treated
` ¦¦ with ether and hydrochlorlc acid. A partially resol~ed mixture o~ the
3 ,I dextrorotatory and levorotatory isomers, enriched with the levorotatory
4 ~¦ acid, was obtsined
S 'l me enriched acid was d~issolved in ethanol and treQted with dehydro-
6 ¦I abietyla~ine. The dehydroabietylamine salt of (-)-5-cyclohexyl-1-
~ 7 j~ indancarboxylic acid was collected and purified by crystalllzation. The
- ~ 1l 6alt was treated with hydrochloric acid, and extracted with ether. The
9 ¦~ ethereal solution was concentrated to dryness and substantially pure
1 10 11 levorotatory isomer crystallized from petroleum ether. (See Example 4.)
All the compounds of the instant invention can be resolved into
12 ¦ their component dextrorotatory and levorota~ory isomers by a procedure
13 ¦ similar, if not identical, to that described above. ~xaimination of the
14 ¦ chemic~l literature likewise provides many other methods for the resolution
¦ of racemlc monocarboxylic acid~.
Some racemic mixtures can be precipitated as eutectics instead o~
17 ¦ mixed cr~stals and can thus be ~uickly separated and in such cases can
18 ¦ someti~es be selectiVe~Y precipitated. me more common method o~ chemicsl
~ resolution may be used. ~y this method diastereomers are formed from the
- 20 ¦ racemic mlxture by rew t~on with an opticall~v-active ~e~olYing agent. mus~
21 an optically-actl~e base can be reacted with the carbox~l group. The
22 difrerence i~ solubility between the diastereomer~ ~ormed permits the
23 ¦ selective cryst~llization of one form and regeneration o~ the optically-
24 '¦ active acid ~ro~ the mixture. Ihere ls, however, a third method of
~ resol~ing which shcws great prcmise. This is one of the other ~orms of
26 biochemical procedu~es using selecti~e e~zymatic reaction. Thus, the
27 -racemic acid can be sub~ected to an asym~etric oxidase or decarboxylase
28 whlch w~ by oxldatlon or decarboxylation~ destroy one ~orm, leaving the
29 other form unchanged. EYen more a~tractiYe i8 the use Or hydrolylase on
¦¦ a derivati~e Or the racemic ~ixture to form preferentially one ~orm of
. 11 , , , . ~ , .
'8~
.
.. _. _ _.. _._ .. _,._,_. _ , _ ! '
Ij
the acid. Thus, esters or amides o~ the acids can be sub~ected to an
~ jl esterase which will selectlvely saponify one enantiomorph and leave the
3 11 other unchanged. Amide or salt diastereomers of the free acld may be
4 1l ~ormed with optically-active amines, such as quinine, brucine, cinchonidine,
S 1l cinchonine, dehydroabietylamine, hydroxy-hydrindamlnej menthylamine,
6 l' morphine, ~-phenylethylamine, phenyloxynaphthylmethyla~ine, quinldine,
7 i~ l-renchylamine, strychnine, basic amino acids,-such as ly6ine, arginine,
3 l; amino acid esters, and the like. Similarly, ester diastereomers of the
g !i ~ree acid may be formed with optically- active alcohols, ~uch as borneol,
1~ menthol, 2-octanol and the like. EspeciaIly preferred is the use of
~ cinchonidine to eive the readily decomposable diastereomer salt which
12 ¦I may then be resolved by dissolving in a solvent, such G8 acetone, and
13 ¦¦ d$stll~ng the solvent at atmosphcric ~ressure unt~ cryst~ls begin to
14 ~¦ appear and further crystallization produced Oy allowing the mixture to
l! cool to roo~ temperature, thereby separating the two enantiomorphs.
16 il me acid m~y then be recovered from the s~lt by extractine the s~lt between j
17 ¦1 an organic solvent, such as petroleum ether and dilute hydrochloric acid
18 11 or ~o~e other organlc solvent agueous system. Worhup of the rem~ining
9 li mother liguors and subsequent puri~ica~ion will ueually provide the other
20 ¦¦ isomer. 'I
21 1! It i~ noted~ however, the racemic mixtures themselves are potent
22 !1 anti-inflam~a~orY ugents.
23 1! The compounds o~ tkis in~ention h~ve a high degree o~ anti-~nflamm~tory !
24 ¦¦ actlvity.They are useful in treating arthrit~s, rheum~tism and other
2S 1¦ inflammatory diseases in ma~$als.
26 ~! Anti-inPlamm~tory te3ts o~ the compounds o~ the ~resent invention
27 jl were carried out on rats using the carrageenln-induced ~oot edema test28 ¦ Or Charles A. W~n~er et al., "Carr~geenin-I~duced Edema i~ Xind Paw o~ th~
29 li Rnk a8 an A~say ~or Anti-In~lamm&tory Drug5~ Proceedings of the Soclety
1I for Experi~ental Biology and M~dlcine~ 111, 544 (1962). me co~pound
Il !
. 103~400 .
1 li under inve~tigation W&~ given orally to the rat, and one hour later
2 ¦I c8rrageenin was in~ected subcutaneously into one p8W- Three hours later3 ,I the degree of ede~a was measured volumetrically by fluid displacement, '~
, and compared to that of the control paw to give a result presented
S I in term~ of percentage inhibition of edema. Any result of more than 30
6 i.¦ inhibition was greater than three t~mes the standard deviation of the
result in control animals, and thus clearly indicated anti-i~flammatory
S I activlty.
9 ¦ In the rat paw edem~ test described above, the compounds o~ the
1 instant invention exhibit anti-inflammatory activ$ty deemed use~ul in the
11 ~ treatment of in~lammatory diseases in mammals, including man. The
12 1 co~pounds of the invention are gener~lly use~ul in the dosage range of
13 1 about 0.1 mg./kg. to about 40 mg./kg. three to four ti~es a day.
14 T~ey can be administered orally or parenterally, but preferably
~ 1 or~lly. More specifically, the co~pounds of the inst~nt invention are
16 l preferentialiy adm~nlstered in dosages in the range of about 0.2 mg./kg.
17 1 to about 30 mg./kg. three to four times a day.
18 ll The dosage wlll vary with the particular compound of the in ention.
~ jj For ex~pla~ 5-cyclo~exy~ indancarbcxylic scid produced a 61~ inhibltion
20 ¦ ~ edem~ at a dose of 128 mg./~g. Its minimum effectl~e dose (MED) was
21 ¦ 3,7 mg./Xg. (MED is de~ined as the dose which produces 30% inhibition
22 ¦ o~ ~dema) and its lethal dose in 5 ~ o~ the animal~ (LD50) wa6 287 mg /Xg
23 ¦ m e therapeutlc lndex was 76.
24 ¦ (l)-6-Chloro-5-cyclohexyl-1-lndancarboxylic acid hcwever, was
substantially more potent in producing a 62~ inhibltion oP edema at 128 mg./
26 kg., with an MED of 1.5 mg./kg., and LD50 o~ 41 ~g.jkg. and a th~rspeutic
27 index o~ 27.
28 Resolution o~ 6-chloro-5-cyclohexyl-1-lndancarboxylic scid into
29 ¦ it~ (+) and (-) isomers showed that the dextr~rotatory (1) isomer was the
` re potent haYing an MæD of 0.85 mg./kg. as compared to-the levorotatory
.. ' : '' '' `) ' "
I , . `` -10- ' ` ' `
`: ! . . I
;; , ~' ~ . _ ~ _
~(~3fl400
I 11 isomer which h~d an MED of 16 ~g./kg.
~ 11 In the case of 5 cyclohexy}-l-indancarboxylic acid, it ~ppears the
3 l! m~ority of the anti-lnflammatory activity resides in the levorotatory
1, 1 isomer, (-)-5-cyclohexyl~l-indancar~,oxylic acid, as compared to little
S ,~ or none in the dextrorotatory isomer. The unresolved racemic mixture
Il 16 ~cti~e a6 ouch however and is useful as an anti-inflammatory agent.
7 t,l The oral dosage in humans o~ the comFounds of the present $nventio~8 is in the range o~ about 0.2 mg./kg. to about 25 mg./kg. administered
9 three or four times a day. The preferred human dosage is in the range
0.2 ~g.tkg. to about 10 mg./Xg. three to four times a day.
11 j The carboxylic acids I of the present in~ention have also ~hown
12 11 actl~ity in Dice, rats and dogs when administered in the ~orm of their
(lower)alkyl esters or terti~ry-amino (lower)alXyl esters. mese compounds
14 ¦ are also considered an integral part of the present in~ention.
~ I Ihere~ore, a preferred embodim~,nt o~ the present ln~e~tion are the
16 ¦ compounds havin~ the r~rmula
17 y~
23 Y iB hydroger., chloro, bromo, ~luoro, hydroxy, (lower)alkyl, (lower)~lXoxy,24 mercapto, cyano~ nitro~ amino or (lower)~lkyithio, ~5 is (lower)alkyl or
2S a (lower)alkyl posses6ing a ~amine function; or a pharmaceutically
2~ scceptRble salt thereof.
Another pre~erred embod$ment are the compounds ha~ing the ~ormula
28.! .. , I
29 11, . ' . ' ' I
30 1l ~
... ... . ... . ....... .. . ... ..
.. , . . , . .... ..... , .. , ., . . ... . , . ., , = . .... .
_ ._ . ~ .. _ . _ _. . __ _ _~.. . ~ . _ . . .~ ._~ ___ _ _ _ ._ : ~ ' . : . .~ :.. ___A _ _ _ ' _ . _ _ _:_ _ . . _ .
,
_- .
'I ' ' _
: , ~038400
1 ' - Y O R5
2 , - ~
. ., ', , , lJ . ' , .
S
6 '' in wh1ch
Y i~ hydrogen, chloro, ~luoro, hydroxy, (lower)alXyl, (lower)alkoxy, n~tro
8 ll or amino, R5 i6 (lower) alkyl or a (lower3alkyl group possesi3ing a t-amine9 ~i ~unctlon; or a phArmaceutically acceptable ~alt thereo~. I
,, Another preferred e~bodiment are the co~pounds ha~ing the formula
11 i1
2 ~ C02~5
lS !l
!l in which
; 17 1~ Y is hydrogen or chloro ~nd R~ is (lower)alkyl.
8 !i A more preferred embodi~ent are the compounds h~ing the ~or~ula
. 19 ii '
~o ~ c5~5
24 j~ in whieh
25 li Y i8 hydrogen or chloro and R5 is methyl, ethyl or prop~l.
For the purpo~e of thi3 disclosure~ the term "(lcwer)alkyl po9sess$ng
27 ¦ -a t a~ine runctlon" shail mean a group consisting of up to 8 c~rbon atoms,
28 j which ~roup conta~n~ a t-~mlne funct~on, i.e., NjN-dimethylaminoethyl~,
29 j N,N-diethylsninoethyl-, N-methyl-4-piperidyl-, N-et~yl-4-pyrrolidyl-,
30 ¦¦ N-mRthyl-3-pyrrolidyl-, ~,N-dimethylaminoprop~l-, or the like.
!l !
..
.j ~
- 103~400
.. ,, . i .
1 ~ ~en the compounds of the present invention contain an ester function
2 ,I possessing a tertiary amine ~unction, the compounds are capable o~ forming3 ~cid addition salts such as the hydrochloride, hydrobromide, hydroiodide,
.
- 4 j sulf~te, sulf3mate, and phosphate~ and the organic acid additlon salts
- S ~I such as the maleate, acetate, citrate, succinate, benzoate, tartrate,
., . ,; . , .
6 . malate,.~andelate, ascorbate and the like. All o~ these salts and their
7 1l equivslents sre a part o~ the invention.
jl , , ., ' ' .. i,
:~ . 9 '
.~ " 1' ,
10i'
: 11 !i - '... .- I `
.. 12 ,!
13 Ij
14. ' .
' ~ 1 1 . . , . . , , - . ,
` lS,i " ,......... . ...
.. 16., . :
~ . 17 1i - ~ '
19 )~
;; . 20 !1
-~ 211 ' . .
.. ~ ; , ,, , : . . .
221 . - '.
23
: 24,!
2S111 ' ', ' " ' ' ' ' ,. " ' ' ~ ' '
'!; ' 26 !i
27
.,, . ~l . .
28 ,~
29 ll
30 !1 -
1~ , . ...
!
~ 3-
',1 , ' . , .
- - -
.` .
.. ~ '.~ ,. . .
.. 1l , '. ' 1031B400
1 1IDescriPtion of The Preferred Em odiments
2 . i
' 'l( ample 1
3 li '~
4 ~ A) p-Cyclohexylbenzaldeh~de: ~D. Bodroux and R. Thomassin, ComPt. 'i
R~ 205, 991 (1937
. S ,~
6 Il Titænium tetrachloride ~A. Rieche, X. Gross, and E. Hoft, Organic
7 ¦I Syntheses, 4I, 1 (1967)] (183 ml., 316 grams, 1.67 moles) was added
~ 8 ~1 ~lcwly o~er a period of ten minutes and with constant stirring to a
: 9' ¦I cooled'(ice-water) solution of cyclohexylbenzene (160 grams, 1.0 mole)
! ~ in methylene chloride (650 ml.). With continued stirriag and cooling,
~ dichloromethyl methyi ether (96 gra~s, 0.833 mole) was added dropwise '
-- 12 1 over ~ period o~ 45 mi~utes. After the addition was complete, the mixture
was ~tirred for thirty minutes with cooling, ~ol}owed by 130 mlnutes at
14 ¦¦ room temperature. The reaction ~ixture was poured onto ice. The orga~ic
lS ! layer W~8 separated and the aqueous layer extracted with methylene chloride ~,
16 il ~3 x 250 ml.). me comb~ned methyler.e chloride solution was washed with
17 ¦I water (2 x 400 ml.) and drled (sodium sul~ate). The dried solution was
reduced to dryness in a rotary e~porator to lea~e a brcwn oil (209 grams).
me oil ~as di~tilled under reduced pressu~e. ~-Cyclohexylbenzaldehyde
l (81.3 grams~ 52%) was collected ag the fraction with bp 9ô - 100/0.2 ~m
' 21 ~lit. D. Bodroux and B. mo~ass1n~ ~ .'Rend.~ ?05, 9g~ (1937) ~ bp 159
'' 22 10 ~.] ' ' , ' ' : ' 1'
23 ~
"...................................... : ' : ' ' ., 1,
' 24 3) Diethyl ~ clohex~lbenzylidenemalonate.
"'' 2S . , '" ': . I
' ' 26 A solution o~ ~-cyclohexylbenzaldehyde (9.4 grams, 0.05 mole)9
27 dlethyl malonate (8.01 gra~s, 0.05 mole)~ piperidina (0.5 gram), ~nd
~ 28 glacial acetlc acid (0.33 gram) in benzene (25 ml.) was heated under reflux
- ¦ for 18 hours ~C.F.H. Allen ~nd F.W. Spangler~ "Organ1c 8yntheses~" Coll.
30 j Vo~. III, John W11 y and Sons, I~c.~ New York~ ~ew Yor~ 1963, p. 377].
" ' ' -14~
Il ' , ,,'' ' ' ' I
The liberated water was removed from the reaction mixture as it was ~ormed.
The cooled reaction mixture was diluted with benzene (25 ml.), washed with
wa~er (2 x 25 ml.) followed by 1 N hydrochloric acid (25 ml.), water
(25 ml.),saturated sodium bicarbonate solution (25 ml.), and water (25 ml.).
The solution wa~ dried (sodium sulfate) and concentrated in a rotary evspora-
tor to leave a yellow oil (17.7 g.). The product was distilled under
~acuum. Diethyl ~-cyclohexylben~ylidenemalona~e (11.7 grams, 71%) was
collected as the fraction with b.p. 172 - 174°/0.01 mm.
nal. calc'd. ~or C2oH2604: C, 72-70; H~ 7.93.
Found: C, 72.62; H, 7.94.
C) Eth~l 3-Cyano-3~ c~clohex~l~henyl ~roPionate
A solution Or potas6ium cyanide (l.ô grams, 0.0277 mole) in water
(4.5 ml.) wa6 added quickly to a solution of diethyl ~-cyclohexylbenzyli-
denemalonate (9.0 grsms. O.oe72 mole) in 10~ ethanol (90 ml.). The
stlrred mixture was heated by means of an oil bath maintained ~t about
70° ~or twenty hours tC.F.H. Allen and H.B. Johnson, "Crganic Syntheses,"
Coll, VR1~ IV, John Wiley and Sons, Inc., ~ew York, New York, 1963,
p. 804]. The reactlon ~ixture was nlio~led to cool to roo~ tem~erature.
$he preclpitated solid was removed by filtratlon. The ~iltrate w2s
acidi~ied with 10% hydrochlorlc acid (1.5 ml.) and then concentr~ted ln a
rotary eYapor~tor. The residue was ~artit~oned between chloro~`~rm
(150 ml.) snd water (50 ml.). me chloro~orm layer was separ~ted, dried
(~odlu~ ~ul~ate) snd concentrated to l~a~e a pale yellow oil (8.1 gr~ms)
which was distilled under reduced pressure. Etbyl 3-cy~no-3-(~-cyclo-
hexylphenyl)propionate (4.2 gran~, 54%) was collected as the ~rsction
w~th b.p. 160 - 161-¦0.15 mm.
An~l. Calc'd ~or C18H23N02:~C, 75-75; H~ 8.12
Found: C~ ?5~77; H, 8.28
l i
49~
1 1' D) P-cyclohexylphenylsuccinic Acid
2 !l .
3 1~ A mixture o~ ethyl 3-cyano-3-(~-cyclohexylphenyl)-propionate ~3.0
I¦ grams), gl&CiBl acetic acid (10 ml.) and concentrated hydrochloric acid
S i¦ (10 ml.) was heated under reflux for three hours. A cry~talline solid
; ,, separated ~rom the re~ction mixture which W85 allowed to cool 810wl~.
1¦ The solid (1.95 grams, 67~), with m.p. 178 - 182, was recrystallized from
- I! aqueous eth~nol ~ollowed by ethyl scetate to gi~e the p-cyclohexylphenyl-
i! succinic acid as colorless crystals, m.p. 188 - 189~C.
1¦ - 16 20 4 ' 9 ; ~ 7 3
11 I Found: C, 6g.54; ~, 7.36
12 !i ~
il E) p-Cyclohexylphenylsuccinic Anhydride -
: 13 ~l -
.' !! . . I
14 ll A mixture of ~-cyclohexylphenylsuccinic acid (10~0 grams) and acetic
` 15 ~! anhydride t50 ~1.) was heated under re~lux for 1.25 hours. The cooled
16 ~¦ solution was reduced to dryness in a rotary evaporator and the solid
17 ¦¦ resldue rec7ystallized from cyclohexane to giYe ~-cyclohexylphenylsuccin~c
18 1¦ ~nhydrlde (8.8 grams, 94%) as colorless crystal6, m.p. 116.5 - 118C. The
~ ¦I product was recrystallized fro~ cyclohexane to gi~e colorlees crystals,
lm.~ 118.5C. I
21 ¦Anal. Cal¢ d- ~or C16H1803 C, 74.39; H~ 7-oe
!~Found: C~ 74.58; H, 7.24
23
24 F) (+)5-Cyclohex~ Loxo-l-indancarboxy}~c-Acid~ !
I -
26
C ~ K
-16-
, !l
,
l i
I1 1038gOO
'! A solu-tlon of ~-cyclohexylphenylsuccinic anhydride (33.0 grams,
2 ll 0.128 mole) ~n dry methylene chloride (400 ml.) was added dropwise to a
; 1i stirred, cooled (ice-water) suspension of aluminum chloride (37.4 grams,
4 ~l 0.281 ~ole) in methylene chloride (400 ml.) ~H.O. House, F.J. S~uter,
S ¦¦ W.G. Xenyon~ and J. J. Riehl, J. Org. Chem., 33,'957 tl968)].
6 Il, The mixture was stirred with cooling for one hour, and was then
7 ¦I sti~red at roo~ temperature for twenty-Pour hours. The'reaction mixture
¦, was reduced to dryness and the residue triturated with ice-water (500 ml.)
9 1¦ and concentrated hydrochloric acid (30 ml.). ~he resulting'gummy
'i suspension was stirred for thirty~six hours at room te~per~ture. The
mixture was Piltered asd the collected of~-white solid dried under
12 !¦ ~acuum. me solid was recrystallized from cyclohexane to give (~ 5-cyclo-
!I hexyl-3-oxo-1-indancarboxylic acid (30.4 g.,92%) as o~-white crystals,
14 !j m.p. 117-118C. A portion of the product was recrystallized (with
charcoal tre~tment) Prom cyclohexane to gi~e colorless crystals, m.p.
16 11 117 - 118C. 'l, '
7 1! Ana1- Calc'd- for C16~83 C~ 74-39; H~ 7-02 I ;'
18 ~1 Found:' C~ 74.29; H, 7.23 '
:9 !¦
G) (~)5-C~clohexyl-l-indanc~rboxylic Acid.
21
D I ~
17 ~ A solut~ Or (~)-S-oyclc~xyl-3-cxo-1-i~d~co~rooxyllc ~cic (9.0 e~G~s) i~
28 glaclal acetic acid (150 ml.) containlng 6 ~ perchloric acld (2 ml.) and
29 10~ pslladium on csrbon (2.0 grams) was shaken with hydrogen ~Parr' I
Il hydro~enator~ 3 atmo8 ) unti} no further hydrogen was ~bso~ed me
! ' ' . I
I -17- ' I
, I . " ' ' ' ~.,
1400
mixture was filtered and anhydrous sodium acetate (2.5 grams) was added
2 !~ to the filtrate. The resultin~ solution was reduced to dryness. Several
3 i~ portionæ of toluene were added to the residue and a~ter each ~ddition
. ,j , .
4 1i t~e mixture was evaporated. The residue was partitioned between diethyl
S 1~ ether (200 ml.) and water (~0 ml.). The ether layer was washed with
6 ll water (40 ml.) followed by saturated aqueous sodium chloride (40 ml.),
7 !1 and dried (sodium sulfate). The solution was ~educed to dryness to yield
Il a buff solld which was recrystallized fro~ Skellysolve ~ to give(t)-5-cyclo-
9 1I hexyl-l-indancarboxylic acid (8.4 grams, 98.5~) as bufD cxystals, m.p.
'I 145 - 147C. A portion of the product was recrystalli~ed ~rom ~kellysol~e R,
(essentially n-hexane, b.p. 60 - 68C), with cbarcoal treatment, to gi~e , -
2 ¦¦ colorless crystals, m.p. 147 - 148C.
13 ~¦ nal. Calc'd. for C16H2002: C, 78-65; X, 8-25
: 14 i~ Found: C, 78.58; H, 8.34
,., lS 111 ' '' ' '' " ' ' I
16 !
17 1 anrple 2
. , jl . !
2~ !~ Sodium 5-CYclohexyl~l-indancarbo~ylate (-) racemic mixture
21
22 ¦1 A solution o~ sodium 2-etkylhexanoate (6.15 grams, 0.037 mole) in
23 ¦ acetone (30 ml.) was add~d to a ~olution of(~)-5-cyclohexyl-1-indancarboxyli4
24 ¦ acid (9.0 grams, 0.03~3 mole) in warm acetone (70 ml.). me mixture
I was allowed to stand ~nd cool to room temperature. me crystalline solid
26 I (7.25 grams, 74%) that formed was collected, washed with acetone and I -
27 I recrystall~zed from methanol-acetone to giYe sodlum 5-cyclohexyl~
28 I indancarboxylate as colorless çrystals.
l Anal. Calo'd. for C16~ g~a02: C, 72.16; H, 7-19
-~ 30 Found: C, 72.11; ~, 7.40
* "Skellysolve B" is a trademark designating.a highly refined petroleum
. I hydrocarbon fraction with IQW evaporat.ion residue and having a specific
~ I gravity(60F) of 0. 683; a flash point of -25F; an aniline point Of 142. 5FI
: .......... ¦ and a boiling range of from 146 F to 156F.
. I . -18- i - _
.. . . . . .. . . . ..
~ l i
~l ~038l~0
!~
.'.' ' lj ' ' ' . ' ' .
Exismple ~
2 !~
; . ~
4 1 ~+)-6-Chloro-5-cyclohexyl-1-indanc~rbox~lic acid
~j
6 il N-Chlorosuccinimide (8.2 grams, 0.0614 mole) was added to a stirred,
!i cooled (ice-w~ter) solution of (f)-5-cyclohexyl-1-indancarboxylic acid (10.0
grams 0 0409 le) in dimethylformamide (82 ml ) ~he solution was
¦¦ st~rred f~r fi~teen minutes at 0C., thirty mlnutes at 25C., nine hours
il at 50C. ~ollowed by eight hours at 25C. The solution was diluted with
11 cold water (400 ml.) and stirred until the precipitated product turned
12 1I granular (fifteen minute)- The crude produc~ was collected, washed with3 ¦I cold water, and dried. Crystallization fram SXéllyæol~e B witA chQrco,~l j
14 ~¦ treatment ga~e colorless crystPls (6.65 grams, 58%), m.p. 149 - 150C. ~ ;
I . ~.
The product ~a~c recrystallized twice from Skellysol~e B to gi~e (+)-6-chloro-~
16 i 5-cyclohexyl-1-indancarboxylic acid &æ colorle6s crystals, m.p. 150.5 -
1~ 1 152.5C.
18 ~Anal. Calc'd. for C16~ 9C102: C, 68.94; ~, 6-87; Cl, 12-72
Found: C, 69.19; ~, 7.04; Cl, 12.97
20 li . ;
21
22 ¦¦ . Exam~le 4 ~ j -
23 il .
24
2S !I Resolutlion of (+)-5~Cyclohexyl-l-indancarboxylic Acid: -
26 1¦ A) (+~-5-CyclOhexy~ nd,3~ ~rbo~s~lic Acid:
27 1 ' . ~
28 ¦ A solution of (+)-5-cyclohe~yl-1-indancarboxyllc acid (15.0 grams,
¦ 0.0614 mole) and cinchonidine (9.05 granLC, 0.0307 molej in abæolute
ethL~ol (700 ~ ~ 09 boiled do;* to ~ volume Or Lbout 300 al Dhe
. I . '-19- ',
. ., . ,. I
: ~ f . i
`:
i,
03~400
1 ~ mixture was allowed to cool slowly and was left ~or twenty hours at 25C.
2 il The colorless crystals were collected and washed with cold ethanol to gi~e
3 ~! the cinchonidine sAlt o~ 5-cyclohexyl-l-indancarboxylic acid (13.0
~ ~I gram~), m.p. 212 - 212.5C. Additional cinchonidine (1.0 grsm, 0.0034
S ~ ~ole) was added to the mother liquors and thelr ~olume reduced to about
6 l, 165 ~1. by bo~ing. The hot solution was seeded w~th the salt o~ the (i)
7 1¦ scid ~nd stored at 5C. ~or sixty-fi~e hours, when an sddition~l crop
8 Ij (2.4 grams) of theicinchonidine salt of the (~) aGid, m.p. 211 - 215DC.
9 ¦1 was obtained. Th~ mother liguors were retained for isoltation of the (-)
1l isomer.
Ihe sPlt with m.p. 212 - 212.5C. was recrystallized ~rom ethanol to
12 l gi~e colorless crystnls (11.8 grams), m.p. 217.5 - 219C. The product was
partitioned between ether (500 ml.) and 10% aqueous hydrochloric acid
14 l (250 ml.). The ethereul layer was washed succes6i~ely with 10~ aqu~ous
~ 1~ hydrochloric acld (250 ml.) w~ter (2 x 250 ml.) and water saturated with
16 ~¦ sodium chloride (250 ml.). The ethereal solution W&s dried (Na2S04),
17 l¦ ~iltered, and the ~iltrate reduced to dryness to giYe (+)-5-cyclohexyl~
18 ¦ $ndancarboxylic acid (5.5 grams), m.p. 108 - llO~C. T~o recryst ~ l~ations
~ ~om petroleu~ ethor (~-p. 39 ~ 50~C-~,gave colorlass needles, m.~. 108 -
20lOg.gC~ C~]D5 ~ 9.60 (ethanol)~ and E~365 1 44.8 (cthanol).
21_ ~1. Calc'd. ~or C16~ 002: C~ 78.65; H~ ô- 5- ¦
22~ Found: C~ 78.40; H, 8.27.
23 1 ~
2S l B) (-)-5-CYclohQxYl-l-indancnrboxylic Acid:
26 The mother liguors from the ~alt ~ormation in 2art A, were reduced to
27 ~ dryness and the re~idue treated with ether and 10% aqueou3 hydrochloric
28 ¦ acid as ~re~iously de~cribed ~or the salt of the ~) lscmer and from the
29- ethereal l~yer wa~ obtained a partially resolved mixture o~ acids (7.6
gr~mu)~ enriched in~the (-) is er, ~a~D - 7.69' lethanol) and ~o~365 -
I -20-
'`' !l ' ' ' .' . ,- ' I
1038400
1 jl 35.4 (ethanol). m is mixture WQS extracted with boiling petroleum ether
(b.p. 39 - 50C., 3 x 35 ml.) and the combined extracts were reduced in
1,
3 l~ volume ~50 ml.) and cooled in an ice bath. The crystalline solid (5.1
~ ,, grams), m.p. 105 - 108~C., C~]D - 8.91- (ethanol) and [~]365 - 41.5
S ~! (eth~3nol)~ was collected.
6 1~ me solution of this acid (5.02 grams, 0.0205 mole) and dehydroabietyl-
7 ~I amine (5.85 grams, 0.0205 mole) in ethanol (500 ml.) was boiled down to a
~ olume of about 175~ml. and cooled to 25C. during two hours. me
9 !I dehydroabietylamine æalt of (-)-5-cyclohexyl-1-indancarboxylic acid (8.7
1I grams), m.p. 179 - 181C., was collected and recrystallized from ethanol
11 ¦I to giYe colorless crystals (8.o grams), m.p. 184 - 185C. me mother
12 !¦ llquors from the product with m.p. 179 - 181C., were reduced in Yol~me
13 1l and an addition~l crop of salt (0.95 gram), m.p. 178.5 - 180.5C., was I -
14 l~ isol~ted. This latter material was recrystPllized fro~ ethanol and the
product (o.78 gram), m.p. 182 - 183~C., w, combined with the main crop.
16 ¦i Ihe dehydroabietylamine salt (ô.78 grams) was partitioned between ether
17 !l (400 ml. ) and 10% aqueous hydrochloric acid. The ethereal solution was
18 ¦I washed with water (3 x 150 ml.) followed by water saturated with sodium
chlo~ide (2 x 100 ml.), dried (Na2S04j, and reduced to ~ryne3s to leave
I! the (-) isomer (4.0 grams). Recrysta~lization from petroleum ether
21 11 (b.p. 39 - 50C~ gave calorlesæ needle~ (3.41 grams) of (-)-5-cyclohexyl- ¦
22 ¦¦ l-indancarboxylic acid: m.p. 108 - ~09.5C., ~]D5 9.66 (ethanol) and
I ~]365 44 70 (ethanol)-
Anal. Calc d for CI6H2002: C, 78.65, ~, 8.25
D 1~ ~ Fcund: C, 78.B5~ H, 8 31
29 ! ~
,.,. : ':' ' ' '' ~
I -21- I
; ' ' ,1
.. . . . .
~ . . . .. ... . .. .. . ... . . . .
i
~oo `
3 l, Resolution of(+)-6-Chloro-5-Cyclohexyl~ dancarboxYlic Acid:
4 l'
S j, A) t+)-6-Chloro-5-cyclohexyl-1-indancarboxylic Acld
6 'I A solution 4~ (~)-6-chloro~5-cyclohexyl-1-indancarboxylic acid (20.0 g,
, 0.0719 ~ole) and dehydroabietylamine (10.22 g, 0.03595 mole~ in absolute
i ethanol (700 ml.) wa~ boiled down to a volume of about 380 ml. The mixture
- 9 'I was allowed to cool sloway a~d was left for 20 hours at sbout 25. The
1 10 !I resulting cryst~lline 301id (16.3 g.), m.p. 188 - 190C, *ns collected and I -
11 !! recrystallized ~rom methanol:water (20:1) to give colorless cryst ls (11.0 g.),
12 1! m.p. lg2 - 194C. ~ecrysta~l1zation from methanol gave colorless crystals
¦¦ (7.4 g.), m.p. 194 - 195.5C. The salt was partitioned between diethyl
~` 14 !¦ ether and 1 N hydrochloric acid. The ethereal layer was washed successi~ely
lS 1I with 1 N hydrochloric acid (twice), w~ter (twice), and water saturated with
16 1! sodium chloride. The ethereal solution was dried (Na2S ~ ) and concentrated
~ 1, 1! to give (+)-6-chloro-5-cyclohexyl-1-indancarboxylic acid (3.5 g.) as
¦ 18 1I colorless cryst~ls, m.p. 133 - 134C. Recryst~llization f~om Skelly~olve
19 ¦¦ ga~e colorless needles (3.0 g-), m.p. 135 - 136C, ~]D5 + 28.7 (ethanol)
¦l and ~vq365 + 88.7 (ethanol)-
¦ A~Sa1. CB1CId. for C16~19C102s C, 68.94; ~, 6.~7; Cl, 12.72
, Found: C, 68.94; H, 6.81; Cl, 12.64
23
24 B) (-)-6-Chloro-5-cyclohexyl-1-indancarboxylic Acid
2S ¦ A solution ~ (+)-5-cyclohexyl-1-indancarboxylic acid (8.o g., 0.0328
mole) and N-chlorosuccinimide (6.52 g., 0.049 ~ole) in dimethylformo~ide
1 27 I (66 ml.) wns hested, with stirring, by means o~ an oil bath maintained ~t
28 ~ 52 - 55C for 9 hours, ~ollcwed by 32 for 10 hour~. me solutlon WBS
¦ poured into water (280 ml.) and the mixture triturated w~th ~ce cooling.
30 1~
~i i
il -22-
~1 I
: . 't
'~ , .
--'~ ~ .
.' 1 `
i03B400
.
1 i The resulting solid was collected, dried, and recrystallized from
2 Skellysol~e B ~Norit) to gi~e colorless crystals (3.12 g., 34%), m.p. 127 -
3 ~ 130C. The product was recrystallized twice from petroleum ether (b.p. 30
4 I 60C) to giYe (-)-6-chloro-5-cyclohexyl-1-indancarboxylic acid as colorless
S ~i crystals, m.p. ~34 - 135C, ~c]D - 28.2 (ethanol) and ['J365 - 87.5
6 'I (ethanol).
7 Anal. Calc d. ~or C16HlgC102: C, 68-94; H, 6-87; Cl~ 12-72
8 ' ~ Found: C, 68.82; H, 6.86; Cl, 12.68
10 ~, Example 6
11 ii I
12 ~, (+~5 ~ ro-1-ind~ncarboxylic Acid
A mixture of concentrated sulfuric acid (670 g.) and concentrated
il nitric acid (~2.0 g. o~ 70~, o.466 le HN03) was added, dropwise with
stirring, to a cooled (ice-water) mixture of (~)-5-cyclohexyl-1-indancarboxylic
16 !¦ acid (100.0 g., 0.409 mole) in nitromethane (12So ml.) oYer a period of
17 11 70 minutes. The solution was then stirred for two hours with cooling,
18 I follcwed by 2.5 hours at 25. The reaction mixture was poured ~nto ice.
19 1! me resulting mixture wa~ extracted with diethyl ether. me ether extract
~¦ was washed with water, followed by aqueous sodium acetate, water, and
21 ~I saturatad aqueous sodium chloride. Ihe ether solution was then dried
22 ¦ (Na2S ~ ) and concentrated. Ihe residue was crystallized from nitromethane
23 ¦~ to giYe a tsn solid (48.7 g.), m.p. loe - 112C. Recrystallization ~rom
24 1l benzene:SkellysolYe B gave tan crystals`, m.p. 112 - 115C.
¦¦ A portion of the product was purif,~ed by chromatography on silicic
26 ll acid (Mallinckrodt CC-4, 100-200 mesh) ~ith toluene:acetone (30:1). The
27 'I product was finally recryst~l~ized fro~jbenzene:Skellysol~e ~ to giYe
28 ~ )5-cyclohexyl-6-nitro-1-indancsrboxylic acid ~s pale ye Uow crystal6,
29 11 m.p. 118 - 120C, resolidifying and rem~lting at 150 - 151C.
30 1~* "Norit" i8 a trade mark for activatej adsorptlon carbons of vegetable
'~ brigin.
j - -23- ~ `
~r '.
Ij
` !
'I 1038400
!l
1 1~Anal. Calc'd. ~or C16~ 9N04: C, 66-42;-H, 6-62; N~ 4-84 .!
2 ~ound: C, 66.75; H, 6.72; N, 4.67
, 3 ',
., ~; . .
4 I Example 7
I,
6 ~ Amino-5-cyclohexyl-indancarboxylic Acid
7 il- ~ solution o~ t~)5-cyclohexyl,6-nitro-1-indancarboxylic acid (14.0 g.)
in 95~ ethanol (200 ml.) containing Raney ~ickel was shaken with hydrogen
9 11 at room temperature and an initial pressure of 3.5 ~g./cm2 for 2.5 hours.
¦l The catalyst WAS removed by filtration and the filtrate concentratet to
11 I; about half ~olume by boiling. After addition of a small volume of water
12 !¦ to the hot solution, the (+)-6-amino-5-cyclohexyl-1-inda~carboxylic acid (8.9 8?
13 ¦I crystallized as light green crystals, m.p. 103 - 114C.
14
lS ¦l : . ExamPle 8
16 ,~
17 l¦ (* ~-Cyclohexyl-6-hydroxy-1-indancarboxylic Acid
18 I A mixture (~)6-amino-5-cyclohexyl-1-indancarhoxylic acid (5.80 g.,
19 1, o.oz24 mole), water (50 ml.) and concentrated hydrochloric acid (50 ml.)
¦ was cooled to 0 and treated, with stirring7 over a period o~ 45 minutes
21 !¦ with sodium nitrite (1.70 g., 0.0246 mole) in water (5 ml.). Stirring was
l; continued for 15 minu,tes at 25, followed by 8 minutes at 80 - 90. The
24 ! mixture was cooled and extracted with diethyl ether. The ether solution
¦ was washed twice w~th water ~ollowed by saturated aqueous sodi~m chloride~
~ a~d concentrated in ~ rotary evaporator. The residual gum was purified by
~¦ chromatography on silicic acid (110 g. of Mallinckrodt CC-4, 100-200 mesh)
¦ with toluene:acetone (20:1). The product was recrystallized from benze~e:
11 Skellysolve B to giYe tan cryst~ls (2.0 g.) m.p. 159 - 160. The product
¦¦ wa~ recrystallizea twice from benzene:SXellysol~e B to give (+)5-cyclohexyl-
6-hydroxy-1-indanc~rb~xylic acid a~ tan crystals, m.p. 159.5 - 161.
1~ ' 1
-24- -
'' ' 1~ ' , . ,
;,
,, ' '' I~'' ' ' , ', ~
~ . 1038400
i, Anal. Calc'd for C16H2003: C, 73-82; ~, 7-74
2 li Found: C9 74.00; ~H, 7.99
ample 9
~ s !i .
6 '' (+)~-Cyclohexyl-6-metho~ 1ndancarboxyllc Acid
Ii
7 'I A mixture Or (+)-5-cyclohexy1-6-hydroxy-1-indancarbox;ylic acid (~.oe g.,
8 Il 0.0154 mole), dimethyl sulfate (4.29 g., 0.034 mole), and potassium carbonate
9 li (8.55 g., 0.0618 mole) in acetone (45 ml.) containing 10,~ potassium hydroxide
!1 in methanol (1 ml.) was heated under reflux for four hours and was then ,
11 ~i a~lowed to stand at 25 for 17 hours. The mixture was filtered and 'che
12 ~l ~iltrate concentrated in a rotary evaporator. me resldual red oll (5.6 g.)
U ¦! was purified by chromatography on silicic acid (160 g. of Ma~linckrodt CC-7,
14 ¦~ 100-200 mesh~ with toluene.
I¦ A mixture of the yellow oil (3.3 g.) obtained ~rom chromatography, 1
16 1¦ NaOH (25 ml-)? and 95% ethanol (6 ml.) was heated under reflux ~or 35
17 ~ inutes. The cooled solution was acidi~ied with dilute hydrochloric acid. I
18 ! The precipitated crystalline solid (2.93 g.) m.p. 162 ~ 1~4, was recrystall-, ;;-
19 ¦! ized from cyclobexane to give (~)5-cyclohexyl-6-methoxy-1-indancarboxylic j
20 1¦ acid (2.72 g.) as ~ale yellow crystals~ m.p. 167.5 - 16go.
21 liAnal. C~c'd. ror C17H2203 C, 74-42; H, 8.08
I! ~otmd: C, 74.63; H, 8.28
23 1~ i
24 1 . ' ~ le 10
,- 2S j . " ' '. -
26 l (+~ rclohexyl-6-fluoro-1-indancarbox~rlic Acid
,
27 ¦ A suspension of (~6-amino-5-cyclohexyl-1-indanc~boxylic acid
28 1¦ (lO.0 g.~ o.o386 le) in dieth~l ether (70 ml.) wa~ treated with an excess
29 ¦¦ of ethereal diazomethalle. me solution was filtered and t~e filtrate
30 1! concentrated on a steam bath to ~ilre the meth~rl ester as an oil.
,!
25-
- !l
.
'~~ 103~3400
1 Fluoroboric acid (21.0 g., 0.116 mole) was added to a solution of the2 , ester in ethanol (10 ml.). To the cooled (ice-water) solution was added,3 I with stirring, isoamyl nitrite (5.0 g., 0.0~25 mole) over a period of two
4 1I minutes. me ~ixkure was allowed to stand at 0 for 0.5 hours. The
S `I solution was then diluted with diethyl 2ther (150 ml.) and kept at -10~ for
6 ,, 20 hours. The solid diazonium fluoroborate (9.0 g.) was collected and dried.
7 ,, A suspension of the diszonium salt in Skellysol~e C~(100 ml.) was heated
1' under reflux for 0.5 hours. The mixture was ~iltered while still wsrm and the1l ;
9 !¦ ~iltrate concentrated to give methyl (~)5-cyclohexyl-6-fluoro-1-indancarboxy- !
¦I late (6.2 g.),
11 li A mixture of the crude ester (6.2 g.), 1 N sodium hydroxide (50 ml.),
12 !~ and 95~ ethanol (20 ml.) was heated under reflux for 0.5 hour. The hot
solution was treated with Norit and filtered. The cooled filtrate was ~,
14 ~ scidified with 1 N- hydrochloric acid and the precipitated material extrscted j
1! into diethyl ether. The ether solution was washed twice with water followed
16 ' by saturated aqueous sodium chloride, and dried (Na2S04). The dried solution !
17 I~ was reduced to dryness and the residue recrystallized from Skellysol~e B to
il
gi~e pale yellow crystals (4.4 g.), m.p. 137 - 141. The product was purified1
by chromatography on silicic acid (Mallinckrodt CC-4, 100-200 mesh) with
~ toluene:acetone (25:1), and finslly recrystallized from aqueous ethanol to
21 ~¦ give (_)5-cyclohexy1-6-fluoro-1-indancarboxylic acid (3.5 g.) as pale yellow
22 1I crystals, m.p. 143 -,145.5 .
23'! Anal. Calc'd. for C~6HlgF42 C, 73.26; H, 7.30
241¦ Found: C, 72.99; H, 7.40
25 i!
26 1!
27 li
: 28
:-. ij ' ' ''
2g 1,
!
-26- - ,
. I .1
! , . . .
1l l03s~ao~ I
1 5 Example 11
' 2 ~i ,
3 l,
4 l, (+)-Methyl 5-Cyclohexyl-l-indancarboxylate
S ,I Excess diazomethane in diethyl ether was added to a su3pension of
i; 6 ~l (+)-5-cyclohexyl-1-indancarboxylic acid (lô.0 g) in diethyl ether (100 ml.).
7 i¦ qhe resulting solution was concentrated to an oil which slowly crystallized
1 8 1i¦ on standing'to g$ve a buff solid (19.5 g.), m.p. 44.5 - 46.5. The product
'; 9 ¦I was recrystallized from'methanol (Norit) to gi~e colorless crystals (18.2 g.) '
l¦ m.p. 46.5 - 48. ,
, 11 '1l Anal. Calc'd. ror C17~22 C, 79.03; H, ô-58
12 1¦ ~ound: C, 78.ôô; N, 8.74
' .13 11 " , , I
.~ 14 1i j :
., lS 11 ,, . 1., .
,,' 16 ~3 ` Ex~mple 12,
' 17
, ~, 18 !¦ ! -
,-' ll (-)-Methyl 5-Cyclohexyl-l-indancarboxylate
~I Excess diazomethane in diethyl ether was added to an ~ce-cold sol~t~on
- 1~ Or (-)-5-cyclohexyl~1-indancarboxylic acid (6.o g.) in diethyl ether
Il (50 ml.). me solution was filtered snd concentrated to 75 ~1. The
24 ¦ solution wa6 ~ashed with saturated aqueous sodium bicarbonate follcwed by
2S water and saturated ~ueous 60dium chloride, dried ,(Na2S04), and concentrated
26 '~ in a rotary evaporator. The residual oil wa6 di~tilled to gi~e (-)-methyl
¦ 5-cyclohexyl-1-indancsrboxylate (5.6 g.) as a colorle6s oil~ b.p. 14p - 150
28 1 (0.1 m~), [~]D ~ -93 (benzene), and ~365'- 12.4- (benzene).
29 1 A~ 1. Calc'd ~or C17H2202 C~ 79 ,3;
¦ Found: C, 78.97; H, 8.ô5
, 11 ' , . .. I
~ 27- 1
~ !'
-~ .
-~r~, . . . ...
' . ' .
!! . ,
.~
i' . . 1038~00 ,
l iI Example 13
. . .
3 ~;
Ethyl 5-Cyclohexyl-l-indancarboxylate ~ -
~ .
, 1
: 5 ;' A solution of(~)-5-cyclohexyl-1-indancarbcxylic acid (6.o g. ) in ethanol I
6 '1 (30 ml.) containing hydrogen chloride (9.0 g.) was heated under reflux for
; 1l 4.5 hours. 'I'he cooled solution was diluted with water, and the ethanol
3 ~~ re ved in a rotary e~aporator. me residual aqueous mixture was extracted
9 1, with diethyl ether. ~'he ether extract was washed with aqueous sodium
,! bicarbonate followed by water and saturated aqueous sodium chloride, dried
(Na2S04), and concentrated. The residual oil was distilled to gi~e (+)-ethyl ~
12 ¦l 5-cyclohexyl-1-indancarboxylate (5.1 g.) as a colorless oil, b.p. 141.5 - ¦
13 il 142 (O.oe mm).
i 1~ 1!An~l. Calc'd rOr C18~ 402: C, 79-37; H, 8-88
~` lS 1l Found: C, 79.67; H, 8.94
16 ll
j
17 !1
!i
~. 18 11 !
" . ..
19 ! ample l4
20 il j
21
22 ~ )-N-Methyl-4-piperidyl 5-Cyclohexyl-l-indancarboxylate Hydrochloride
23 1!A solution o~ (~)-5-cyclohexyl-1-indancarboxylic acid (7.0 g., 0.0284
24 1¦mole), thionyl chloride (3.5 g., 0.0294 mole), ~nd dimet4ylformamide (3 drops)j
2S i in methylene chloride (75 ml.) was heated under reflux Por one hour. me
26 solution was concentrated in a rotary evaporator. A solution of the residual ¦
27 l¦ oil in benzene (20 ml.) was ~dded dropwise, with cooling, to a solution of -
28 l¦ 4-hydroxy-N-mRthylpiperidine (6.6 B., 0.0573 mole) ~n benzene (30 ml.) o~er
¦ a period of ten minut~s. The mixture was stirred at room temperature for
i an add~tlonal 15 mlnutes. Water (25 ml.) ~ollowed by catura~ed aqueou3
. '-
¦ -2a-
!
.
.j ~
- 10384()0
1 ~i sodium bicarbonate (50 ml.) was added to the mixture, which was stirred for
15 minutes. me ~enzene layer was separated, wsshed twice with water~
3 ~ dried (Na~S~ ), and concentrated to an orange oil ~9.4 g.). Hydrogen chloride,
4 ,j gas was p~ssed into a solution of the oil in diethyl ether tlOO mi.) until
S 1I no further material precipitated from solution. The supernatant ether was
6 ,I decanted, and the residual gum washed with fresh ether and then triturated
7 l) with ether acetate to give a crystalline solid (8.5 g.), m.p. 203 - 206.
8 !j me product was recrystallized from nitromethane (Norit) to give (~)-N-
9 ¦¦ methyl-4-piperidyl 5-cyclohexyl-l~indancarboxylate hydrochloride as an off-
. ~
~ I0 llwhite solid, m.p. 207 - 210.
; 11 ilAnP~. Calc'd ~or C22H31N02 HCl: C, 69-90; H~ 8-54; Cl~ 9-38; N~ 3-71
12 ¦¦~ound: C~ 69.93; H, 8.65; Cl, 9.25; N, 3.88
. 13
ls 11 I
16 ¦ Exam~le 15
17
18
19 11 (+) ~ Dimethylaminoethyl 5-Cy~lohexyl-l-indancarboxylate ~drochloride20 ¦ In a manner 8imi1&r t~ that described in Example 14~ dimethylsmino~
21 j ethyl 5-cyclohexyl~l-lndancsrbcxylate hydroc,~loride was prepared from
22 ~ 5-cyclohexyl-1-indancarboxylic acld (r.o g., 0.~284 mole), thionyl
23 ¦ chloride (3.5 g., o.oes4 mole), ~-dimethylaminoethanol (5.1 g., 0.0573 mole) i
24 ¦¦ and hydrogen chlorlde. The crude hydrochloride (8.7 ~.) was recry8tal11zed
2S !¦ ~rom ethyl ~cetate to gi~e off-white crystals, m.p. 14~3 - 150.
26 llAn 1. Calc'd ~or C20~29N02 HCl: C, 68.25; H~ 8.59; N, 3.63
27 l. Found: C~ 67.90; H, 8.76; N~ 3.85
28
I~. -29- -
, !
