CA1038400A - 1-indancarboxylic acids - Google Patents

Abstract

Abstract of the Disclosure 5-Cyclohexyl-1-indancarboxylic acids are useful anti-inflammatory agents in the treatment of inflammatory diseases in animals, including man. An example of a compound of the disclosure is 5-cyclohexyl-1-indancarboxylic acid.

Description

- ?

,_~

~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) ''`. 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.

. ;

. . . .

.. ! ~
. . ..

., ~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 .

~>

., .

. 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 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-, "' ' - : ; '' '~ ' : `';

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 ' ~'''' ), ' ~

!
` 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 . - '.

: 24,!

2S111 ' ', ' " ' ' ' ' ,. " ' ' ~ ' ' '!; ' 26 !i .,, . ~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 24 F) (+)5-Cyclohex~ Loxo-l-indancarboxy}~c-Acid~ !
I -C ~ K

, !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.

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 . " ' ' ' ~., 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 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 . ;

22 ¦¦ . Exam~le 4 ~ j -23 il .

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 -'`' !l ' ' ' .' . ,- ' I

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 ! ~

,.,. : ':' ' ' '' ~

; ' ' ,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 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 '' ' 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.
,!

- !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 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 I~. -29- -, !

Claims (11)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a substantially pure isomer of the compound having the formula (V) (V) in which Y is H, Cl, Br, I or F;
A is hydrogen or (lower)alkyl and pharmaceutically acceptable salts thereof, which comprises resolving the product of formula V occurring in the form of a racemic mixture into a substantially pure isomer by treatment with an optically active resolving agent and recovering the substantially pure isomer so obtained and where required conver-ting said substantially pure isomer into a pharmaceutically acceptable salt thereof.

2. The process as in Claim 1 wherein the substantially pure levorotatory isomer of the compound is obtained by treating the compound with an appropriate optically active resolving agent.

3. The process as in Claim 1 wherein the substantially pure dextrorotatory isomer of the compound is obtained by treating the compound with an appropriate optically active resolving agent.

4. The process as in Claim 1 in which A is hydrogen.

5. The process as in Claim 1 in which Y is chloro.

6. The process as in Claim 1 in which Y is hydrogen.

7. The substantially pure levorotatory isomer of the compound having the formula (V) (V) in which Y is H, Cl, Br, I, or F;
A is hydrogen or (lower)alkyl and pharmaceutically acceptable salts thereof whenever prepared by the process of Claim 2.

8. The substantially pure dextrorotatory isomer of the compound having the formula (V) (V) in which Y is H, Cl, Br, I or F;
A is hydrogen or (lower)alkyl and pharmaceutically acceptable salts thereof whenever prepared by the process of Claim 3.

9. The process of resolving a compound having the formula in which Y is chloro and A is hydrogen or lower alkyl occurring in the form of a racemic mixture into its substantially pure levorotatory (1-) isomer by treatment with an appropriate optically active resolving agent, and recovering the substantially pure levorotatory isomer so obtained.

10. The process of resolving a compound having the formula in which Y is chloro and A is hydrogen or lower alkyl occurring in the form of a racemic mixture into its substantially pure dextrorotatory (d-) isomer by treatment with an appropriate optically active resolving agent, and recovering the substan-tially pure dextrorotatory isomer so obtained.

11. A substantially pure isomer of the compound having the formula (V) in which Y is H, Cl, Br, I or F;
A is hydrogen or (lower)alkyl and pharmaceutically acceptable salts thereof, whenever prepared by the process of Claim 1.