CA1122985A - Substituted 1,3-dihydrospiro(benzo(c)thiophene)s - Google Patents
Substituted 1,3-dihydrospiro(benzo(c)thiophene)sInfo
- Publication number
- CA1122985A CA1122985A CA317,255A CA317255A CA1122985A CA 1122985 A CA1122985 A CA 1122985A CA 317255 A CA317255 A CA 317255A CA 1122985 A CA1122985 A CA 1122985A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- compound
- ether
- thiophene
- benzo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/54—Sulfur atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Abstract of the Disclosure Novel substituted 1,3-dihydrospiro[benzo(c)thiophen]s and methods of preparing the same are described. These compounds are useful as antidepressants and tranquilizers and intermediates therefor.
Description
3L12;~ 35 d~r~ r?r -~ t, _~ . Y'?~qu~ '`7 ~ ? ~ a~ t r~ r~
rn ~-? t ~ `, o f ~ ~ r i r ~ ~ -F
r~ h. ?~ ~r~ . c ~? ut l C ? l ~ ~ ' ? f :f ^~ ~ t -L l,r -? '. ~ - ^. '? '` `~ -l r; ?~ r~ . rn`
t`?~lti t`~l ~`t~ ~n~ c~rlt.~- ~ r'-; r ~ 'T~'~,' ~'3 ~; -': -?~l t,i.v(? in~r~lipnt~
T ~ t, ~ r' h ~ rl ~ ~ - r ~ ~ "
~nv-~nt~ n ~ J" r~ ?r~^t-.~lfr r ~ .^? - ~ ?~
,t;~ t~ t; ~ ; r ~ [l J~ t~ f~ ]
R
Rm ~CH2 ) :i rl lA,~ ?~ r, ; ', i"~
F~ ` . P ~ , (' r; ' ' l~ ' r~ ,? r~ r; ~
l:lZ~8~
- ?~
Sri ~ [~ sf~'r~?r!A.ofllr~n-~ ~ 3~T `~ ? !, 7 ~ r ~r idi n ~c ~ S-`; "'~` [', ;
f ~ 3 -T ) 7 ,'` - ? ~ ~ ~ r i cl i i ~ , " T
( 1 97 5 ~, ~?scri 1~ c~s ~r ~ri ^~ h?r~ r~ r ~ ~ h" t,-~
fc~rm~ o i~
' ~ i 2 ~ ~ ~
: and ~ ;
O R' R' R"
in ~hich ,~ is hydro~en, halogen or methoxy, R is methyl or benzyl, R' is phenyl, substituted phenyl, al~yl, phenylalkyl, diphenylalky~
or thienyl and R" is alkyl, phenyl, benzyl, 3-methyl-5-isoxazolyl or pyridyl. However, in this article no pharmaceutical activity is described for the disclosed isobenzofurans.
Ileither of these two references describes or sug~ests the instantly claimed compounds. Each discloses isobenzofurans, not benzo(c~thiophenes. Also, the co~npounds of this invention cannot be prepared by the syntheses described in the above-mentioned prior art.
This invention relates to novel su~stituted 1,3-dihydrospiro[benzo(c)thiophene]s of the forrlula:
R
~ N ~
(CH~,CH2)n ' (R )~ ~ S
, ~ (R )m and to the op~ical antipodes and pharmaceutically acceptablesalts thereo~, in ~hich R is hydrogen, hydroxy, benzoyloxy, lo~erall;yl, cycloalkylloweralI;yl or cycloalkylloweralkanoyl in which the cycloalkyl portion contains from 3 to 6 carbon ~- atons, loweralkenyl, phenylalkyl, diphenylalkyl, diphenylmethoxyal~
~ 5 phenoxyalkyl, loweralkanoyl, phenylalkanoyl, benzoyl, benzoylallyl, phenylhydro,~yalkyl, all~yloxycarbonvl of ? to 6 carbon atoms, phenyloxycarbonyl, cycloal~ylcarbonyl o 4 to 8 carbon atoms or I
-(C~l2)m - C-~hRlR2 in which Ph is phenyl; Rl and R2 are the sal~e S or different and each can be hydrogen, loweralkyl, loweralkoxy, trifluoromethvl, halogen, hydroxy, methylenedioxy or loweralkylthio;
m, n and n' are integers from 1 to 3; and the sum of n and n' is 3 or 4. In the above, the modifier "lower" ~leans up to 6 carbon atoms.
Acids useful for preparing the phanmaceutically acceptable acid addition salts of the invention include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as well as organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric and oxalic acids.
Some coMpounds within the scope of this invention have p,reater pharmaceutical activity than others. The latter compounds are neverthelesfi desirable and useful as intermediates in the preparation of the more active compounds. Preferred compounds are those in which R is hydrogen, alkyl of 1 to 3 carbon atoms, especially methyl, or substituted benzoylpropyl with optimum com~ounds bein~ further limited in that the n and n' are both 2.
The compounds of the invention mav be prepared by any of several methods of preparation described below. In this description, R, Rl, R2, n, n' and m are, w th the exceptions noted as defined previously.
;~85 . , d A
A ? .." ¢? '~ ¢~ 5 ~ Q~ T, ~ ' d r~ .7 ?r~ ¢~ ¢~ ; ;r'-' ~ r T ~ ~ ~` '~ r- - -c ¢~ r ~,~ i !~3, ~ }'~ d, ~ h~ ? ~~ ~' t ' ~`~3~ - ?~ ~ ` " '`' ~ ^ ' ,~ i `~ ": ::r-t ~?r~ r~ ¢ f~ rr _1 ¢ ~¢
~,h, '~ 3~n? ¢~r~ t ~?t.r~.~?f~ d~¢~fl!.r~l . A ~ ~ 3~~''`'~ '' ` .~' ~'~ ~.'i~7?~ ~?--~_ r~ r~ _7!' ~n 1 -¢~¢` ¢ ~
(R~m ~ _~ (R )m ~Li I II
~ .r~ r ~ ¢~ ` ~' i V '~ r ~? ~~
r!or~ f ~ r~rn~
(C~ 2)n' ~ - T ` ~ '' ` ` ' i !'~:' type oE reaction, e.g., at a temperature of -80 to 20C., pre-ferably -80 to -40C., in a solvent such as ether, tetrahydro~
furan or hexane to provide a phenylcycloazalkanol (III).
I
~N~
(CH~)n (CH2)n, (R )m ~ OH III
8~
1~?~ J~,r.-~?-~f~ q~l ~f ~?~ ? ~ r~ ~~'q ~H2SH
(~ (R )m ~-,d ~ cl ~ ,t ('~ q~ m ~ ?t r~ f~
f~r.,d(~ t;~ ~f~at~ t ~ rf-r~ f fr~T ?~ f C - t, l~r~ 2 tr:i ~ f -~r ~ r ~; n~ `r ~ j f r~ f~_ q~lk,~ " ( -, ~r~ . l (CH ~CH2)n (Rl~n~ ~
~ (R )m T~ n~;J `! t ~ r~
rl~f,v~ ? t;h,~ c"-r ? r~-n.d~ ? ~
nk~r~ c~!cl o ~ l 't,q~ ] (~r ~ ~R ~ r~ r ~ ?
CH~N~
rn ~-? t ~ `, o f ~ ~ r i r ~ ~ -F
r~ h. ?~ ~r~ . c ~? ut l C ? l ~ ~ ' ? f :f ^~ ~ t -L l,r -? '. ~ - ^. '? '` `~ -l r; ?~ r~ . rn`
t`?~lti t`~l ~`t~ ~n~ c~rlt.~- ~ r'-; r ~ 'T~'~,' ~'3 ~; -': -?~l t,i.v(? in~r~lipnt~
T ~ t, ~ r' h ~ rl ~ ~ - r ~ ~ "
~nv-~nt~ n ~ J" r~ ?r~^t-.~lfr r ~ .^? - ~ ?~
,t;~ t~ t; ~ ; r ~ [l J~ t~ f~ ]
R
Rm ~CH2 ) :i rl lA,~ ?~ r, ; ', i"~
F~ ` . P ~ , (' r; ' ' l~ ' r~ ,? r~ r; ~
l:lZ~8~
- ?~
Sri ~ [~ sf~'r~?r!A.ofllr~n-~ ~ 3~T `~ ? !, 7 ~ r ~r idi n ~c ~ S-`; "'~` [', ;
f ~ 3 -T ) 7 ,'` - ? ~ ~ ~ r i cl i i ~ , " T
( 1 97 5 ~, ~?scri 1~ c~s ~r ~ri ^~ h?r~ r~ r ~ ~ h" t,-~
fc~rm~ o i~
' ~ i 2 ~ ~ ~
: and ~ ;
O R' R' R"
in ~hich ,~ is hydro~en, halogen or methoxy, R is methyl or benzyl, R' is phenyl, substituted phenyl, al~yl, phenylalkyl, diphenylalky~
or thienyl and R" is alkyl, phenyl, benzyl, 3-methyl-5-isoxazolyl or pyridyl. However, in this article no pharmaceutical activity is described for the disclosed isobenzofurans.
Ileither of these two references describes or sug~ests the instantly claimed compounds. Each discloses isobenzofurans, not benzo(c~thiophenes. Also, the co~npounds of this invention cannot be prepared by the syntheses described in the above-mentioned prior art.
This invention relates to novel su~stituted 1,3-dihydrospiro[benzo(c)thiophene]s of the forrlula:
R
~ N ~
(CH~,CH2)n ' (R )~ ~ S
, ~ (R )m and to the op~ical antipodes and pharmaceutically acceptablesalts thereo~, in ~hich R is hydrogen, hydroxy, benzoyloxy, lo~erall;yl, cycloalkylloweralI;yl or cycloalkylloweralkanoyl in which the cycloalkyl portion contains from 3 to 6 carbon ~- atons, loweralkenyl, phenylalkyl, diphenylalkyl, diphenylmethoxyal~
~ 5 phenoxyalkyl, loweralkanoyl, phenylalkanoyl, benzoyl, benzoylallyl, phenylhydro,~yalkyl, all~yloxycarbonvl of ? to 6 carbon atoms, phenyloxycarbonyl, cycloal~ylcarbonyl o 4 to 8 carbon atoms or I
-(C~l2)m - C-~hRlR2 in which Ph is phenyl; Rl and R2 are the sal~e S or different and each can be hydrogen, loweralkyl, loweralkoxy, trifluoromethvl, halogen, hydroxy, methylenedioxy or loweralkylthio;
m, n and n' are integers from 1 to 3; and the sum of n and n' is 3 or 4. In the above, the modifier "lower" ~leans up to 6 carbon atoms.
Acids useful for preparing the phanmaceutically acceptable acid addition salts of the invention include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as well as organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric and oxalic acids.
Some coMpounds within the scope of this invention have p,reater pharmaceutical activity than others. The latter compounds are neverthelesfi desirable and useful as intermediates in the preparation of the more active compounds. Preferred compounds are those in which R is hydrogen, alkyl of 1 to 3 carbon atoms, especially methyl, or substituted benzoylpropyl with optimum com~ounds bein~ further limited in that the n and n' are both 2.
The compounds of the invention mav be prepared by any of several methods of preparation described below. In this description, R, Rl, R2, n, n' and m are, w th the exceptions noted as defined previously.
;~85 . , d A
A ? .." ¢? '~ ¢~ 5 ~ Q~ T, ~ ' d r~ .7 ?r~ ¢~ ¢~ ; ;r'-' ~ r T ~ ~ ~` '~ r- - -c ¢~ r ~,~ i !~3, ~ }'~ d, ~ h~ ? ~~ ~' t ' ~`~3~ - ?~ ~ ` " '`' ~ ^ ' ,~ i `~ ": ::r-t ~?r~ r~ ¢ f~ rr _1 ¢ ~¢
~,h, '~ 3~n? ¢~r~ t ~?t.r~.~?f~ d~¢~fl!.r~l . A ~ ~ 3~~''`'~ '' ` .~' ~'~ ~.'i~7?~ ~?--~_ r~ r~ _7!' ~n 1 -¢~¢` ¢ ~
(R~m ~ _~ (R )m ~Li I II
~ .r~ r ~ ¢~ ` ~' i V '~ r ~? ~~
r!or~ f ~ r~rn~
(C~ 2)n' ~ - T ` ~ '' ` ` ' i !'~:' type oE reaction, e.g., at a temperature of -80 to 20C., pre-ferably -80 to -40C., in a solvent such as ether, tetrahydro~
furan or hexane to provide a phenylcycloazalkanol (III).
I
~N~
(CH~)n (CH2)n, (R )m ~ OH III
8~
1~?~ J~,r.-~?-~f~ q~l ~f ~?~ ? ~ r~ ~~'q ~H2SH
(~ (R )m ~-,d ~ cl ~ ,t ('~ q~ m ~ ?t r~ f~
f~r.,d(~ t;~ ~f~at~ t ~ rf-r~ f fr~T ?~ f C - t, l~r~ 2 tr:i ~ f -~r ~ r ~; n~ `r ~ j f r~ f~_ q~lk,~ " ( -, ~r~ . l (CH ~CH2)n (Rl~n~ ~
~ (R )m T~ n~;J `! t ~ r~
rl~f,v~ ? t;h,~ c"-r ? r~-n.d~ ? ~
nk~r~ c~!cl o ~ l 't,q~ ] (~r ~ ~R ~ r~ r ~ ?
CH~N~
2~CH2)n (R )m{~S
[~ (R )m r.~(~ t.~
.. . . .. . ... .
A ~ r~ ; r~ [l~ ; o?!lhen 2 - ~ ~ ' f 1 ~ lr.
( 'J ) !~ - r~? (~ t;~ ~,1 A ~ ; + r- ~ r r-~
1 k ~ y ~ f ~ rr) ~ + ? ~ ? r î ~ I '` f? ~ f f r s b i c ~ ? ~ ~, ? 1~ t ~ c~ r o r r~ ?7t~ o xy ^ a rb )~ ? [~
?~ .r--? r~ V. ) ~ j-? C Om~ C~ i s 1 ~?'~f - `'' a ? ~ J l ?--' r~
I{) R
(CH~n ~H2 ) n (R )m~S
[~ (R )m ~, '' t;l,l t ! '~l C
~!L ~ r~!ul~3 f,f '~
vl~r~ .lL(~i .? ~ r, ,~t `~ ;, ' .. "' J "`~ 'i '~' ,-~
t1~?~ t,~ ! r r~
[~ (R )m r.~(~ t.~
.. . . .. . ... .
A ~ r~ ; r~ [l~ ; o?!lhen 2 - ~ ~ ' f 1 ~ lr.
( 'J ) !~ - r~? (~ t;~ ~,1 A ~ ; + r- ~ r r-~
1 k ~ y ~ f ~ rr) ~ + ? ~ ? r î ~ I '` f? ~ f f r s b i c ~ ? ~ ~, ? 1~ t ~ c~ r o r r~ ?7t~ o xy ^ a rb )~ ? [~
?~ .r--? r~ V. ) ~ j-? C Om~ C~ i s 1 ~?'~f - `'' a ? ~ J l ?--' r~
I{) R
(CH~n ~H2 ) n (R )m~S
[~ (R )m ~, '' t;l,l t ! '~l C
~!L ~ r~!ul~3 f,f '~
vl~r~ .lL(~i .? ~ r, ,~t `~ ;, ' .. "' J "`~ 'i '~' ,-~
t1~?~ t,~ ! r r~
3`` (~-3 ~ ': i (~J? !;~ " 1~ t l ,~l r ~'1 (c~f~n ~E12)n~
(R )m ~
~ (R )m 112'Z63BS
Method D
A compound of the invention prepared in Method C can be treated with a compound of the formula ~I(CH~)m _ C ~ 2 in which R1 is as defined initially, under normal reaction conditions to provide the corresponding compound of the in-(~;H2) ~ ;L
~J~l)m - ~ ~ S
A preferred method includes the use of potassium iodide as a reaction initiator, sodium bicarbonate as an acid sca-venger and dimethylformamide as a solvent at a reaction tem-perature of about 75C.
Method E
The compound prepared in Method D is subjected to hydro-lysis to provide the corresponding compound of the invention in which R is (CH2)m-CO ~ wherein m and R1, R2 are as defined initially. A preferred method involves the use of a strong acid such as 3N HCl in a solvent such as water or ethanol.
1122~3S
Method F
~ n N-unsubstituted-i,3-dihvdrospiro[benzo(c)thiophene-cycloazal~ane] (VII3 prepared in Method C can be reacted in a kno~m manner with an alkanoyl chloride or anhydride, benzoyl chloride or anhydride, aralkanoyl chloride~ alkyl halide, alkenyl halide, cycloalkanoyl halide or arall;yl halide to provide the corresponding compound of the invention in which R
is alkanoyl, benzoyl, phenylall~anoyl, alkvl, alkenyl, cycloalkyl-carbonvl., phenylalkyl or cycloall;ylalkyl.
10 Method t~
A compound prepared in ~ethod B, E.or F in which R
is all;oxycarbonyl, phenoxycarbonyl, all;anovl, benzoyl, phenylalkan~
cycloalkylcarbonyl or benzoylalkyl can be reduced in a l;nown ~anner with a reap,ent such a lithiun aluminun hvdride or diborane to the corresponding compound if the invention in which R is alkyl, cycloalkyl, phenylalkyl or phenylhydro~cyal~yl.
Method H
A compound of the invention prepared in ~Iethod C can be treàted Wit}l a peroxide of the formula R1~3 C-O-O-~Rl , in whic~l Rl is as defined initially, under nor~al reaction conditions to provide the correspondin~, compound of the invention llZZ~85 o -- 10 N OC ~
(C}I2)n(C~l2)n' R1 (IX) (R~
~ (R2) A preferred method includes the use of sodium carbonate, ben-zene solvent and a temperature of about 65-70C.
Method I
A compound of the invention prepared in Method H can be treated with a base, such as NaOH, under normal hydrolyzing conditions, to provide the corresponding compound of the in-vention (X) OH
~N
CH2) (R )m~S
~3 (R2)m Method J
A compound of the invention prepared in Method A,B,C,E,F,G,H or I which contains an alkoxy group on a phenyl ring can be heated with an acid, such as hydrobromic acid or aluminum tribromide, under the normal conditi.ons of hydrolyzing reac-tions to provide the corresponding hydroxy (phenolic) compound, a compound of the present invention.
The compounds of the present invention are useful in the treatment of depression in mammals, as demonstrated by their ability to inhibit tetrabenazine-induced depression in mice /~International Journal of Neuropharmacology, 8, 73 ~lZ~ 5 l. ? ~ i. S ~ ? ~ 7 ~?--` ? r ~ ? ~ ;, 'j ?
3'` ~sr~ c t i~ 3 -r~ J~ r~ ` ' J~ [~
~L ~--7~ x ~ di -1~?J ?~ 3~ t1~
?:n~ ? 7il-~-?1~ ~pir ~~'' i¢1 ~;1~}? ~? f~c+ ?
o ~t~ 1- ?r e ~ 3 S i a O f t, ~ ? ~ r ~ -? ~ 3 ~; 7 _ r, ?--~1 1, ? J ~ ~ ? ~i d ~ r~ r ~? ;~ S ' T r~ .? .5 ~ -~ da ~ -? ~ s ~, r~a t, ~? tt7A~ ~ t ~ c ~ ? ~ r~ ~ s a ~ ~ ? -~
i~.? nt,i ¢~ e S 5,q.. !lt s i n r~ ?!nr~la .~ .!t~ d V~
r~rl~in~, f?-~or~ t¢J 5(,~ In~ O ~ AJ ~ ?~.
C o~rl r~ n t,? ~ r~r ? ~ .. r, ~
ll s G ful ~? ,'; t;~r~ 9u i. ~ ¢' /~ ? ~ r~
tll~? ¢~I~nt;r~l r~r -~?~ -q.! .~ ` r"' i - '-d~?morls~;,r~t.,~l ;r~ ~?';':? S ~ tn A~ '?'`'''' '~ q li~ [.,`~
1 5 7--'~ ( 1 9 5 3 ) ~ , ? ~t,r~ r!~ l rr. ~ ~ l J . . ' ~ rt ~ rl i v t;o W?.~ t, (~¢~:?!~r~oUI~r~ ? r ~ t, 7':', t~ rlglli ] i.'.!,"?`'~ ,'lr?.l``it;.i, t, ~ ? b ~ rr ~ '?
,?l~r (~!n~r~ r ~ ;
I t,3 -t~ J~ ~17~ y1-~ J !~ - L`-~
( ~ ) t,~ l 3. (! ?`~ J ~t~ i r~ r '.i ~? .i ~
1, 3 11?~J~r?rO- ! ~ t(~ i ?~ ; ] ~
~})~ S~? ;r; :t~ ?~ t ~ t i 3 ~ r.~ !`t~ [1~ ~?~ ) t ! ~ rl ? ~ . 7 r~ r~ ~? l l r y ~ 3--~ ` ` 3 r [b '~! Z J ( c ) ~ r~ ?r~ r~
1, 3 ~tli l.~,~d:ro- l ~ -t-?.~ ' r~ , ' Y~
Ll~ rL ~ o ( c ) ~Jh~ c r~ t?n~ tli~
11'~;Z~8S
l'-allyl-1,3~dihydro-3-phenylspiro[~enzo(c)thlophene-1,4'-piperidine];
1,3-dihydro-1'-methyl-3-(4-metho,cyphenyl)spiro-[benzo(c)tlliophene-1,4'-piperidine];
6-fluoro-3-(4-fluorophenyl)-1,3-di~lydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine];
1,3-dihydro-3-~4-methoxyphenyl)spiro[benzo(c)-thiophene-1,4'-piperidine];
1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-(4-methoxyphenyl)spiro~benzo(c)thiophene-1,4'-piperidine];
6-fluoro-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine];
(R )m ~
~ (R )m 112'Z63BS
Method D
A compound of the invention prepared in Method C can be treated with a compound of the formula ~I(CH~)m _ C ~ 2 in which R1 is as defined initially, under normal reaction conditions to provide the corresponding compound of the in-(~;H2) ~ ;L
~J~l)m - ~ ~ S
A preferred method includes the use of potassium iodide as a reaction initiator, sodium bicarbonate as an acid sca-venger and dimethylformamide as a solvent at a reaction tem-perature of about 75C.
Method E
The compound prepared in Method D is subjected to hydro-lysis to provide the corresponding compound of the invention in which R is (CH2)m-CO ~ wherein m and R1, R2 are as defined initially. A preferred method involves the use of a strong acid such as 3N HCl in a solvent such as water or ethanol.
1122~3S
Method F
~ n N-unsubstituted-i,3-dihvdrospiro[benzo(c)thiophene-cycloazal~ane] (VII3 prepared in Method C can be reacted in a kno~m manner with an alkanoyl chloride or anhydride, benzoyl chloride or anhydride, aralkanoyl chloride~ alkyl halide, alkenyl halide, cycloalkanoyl halide or arall;yl halide to provide the corresponding compound of the invention in which R
is alkanoyl, benzoyl, phenylall~anoyl, alkvl, alkenyl, cycloalkyl-carbonvl., phenylalkyl or cycloall;ylalkyl.
10 Method t~
A compound prepared in ~ethod B, E.or F in which R
is all;oxycarbonyl, phenoxycarbonyl, all;anovl, benzoyl, phenylalkan~
cycloalkylcarbonyl or benzoylalkyl can be reduced in a l;nown ~anner with a reap,ent such a lithiun aluminun hvdride or diborane to the corresponding compound if the invention in which R is alkyl, cycloalkyl, phenylalkyl or phenylhydro~cyal~yl.
Method H
A compound of the invention prepared in ~Iethod C can be treàted Wit}l a peroxide of the formula R1~3 C-O-O-~Rl , in whic~l Rl is as defined initially, under nor~al reaction conditions to provide the correspondin~, compound of the invention llZZ~85 o -- 10 N OC ~
(C}I2)n(C~l2)n' R1 (IX) (R~
~ (R2) A preferred method includes the use of sodium carbonate, ben-zene solvent and a temperature of about 65-70C.
Method I
A compound of the invention prepared in Method H can be treated with a base, such as NaOH, under normal hydrolyzing conditions, to provide the corresponding compound of the in-vention (X) OH
~N
CH2) (R )m~S
~3 (R2)m Method J
A compound of the invention prepared in Method A,B,C,E,F,G,H or I which contains an alkoxy group on a phenyl ring can be heated with an acid, such as hydrobromic acid or aluminum tribromide, under the normal conditi.ons of hydrolyzing reac-tions to provide the corresponding hydroxy (phenolic) compound, a compound of the present invention.
The compounds of the present invention are useful in the treatment of depression in mammals, as demonstrated by their ability to inhibit tetrabenazine-induced depression in mice /~International Journal of Neuropharmacology, 8, 73 ~lZ~ 5 l. ? ~ i. S ~ ? ~ 7 ~?--` ? r ~ ? ~ ;, 'j ?
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11'~;Z~8S
l'-allyl-1,3~dihydro-3-phenylspiro[~enzo(c)thlophene-1,4'-piperidine];
1,3-dihydro-1'-methyl-3-(4-metho,cyphenyl)spiro-[benzo(c)tlliophene-1,4'-piperidine];
6-fluoro-3-(4-fluorophenyl)-1,3-di~lydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine];
1,3-dihydro-3-~4-methoxyphenyl)spiro[benzo(c)-thiophene-1,4'-piperidine];
1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-(4-methoxyphenyl)spiro~benzo(c)thiophene-1,4'-piperidine];
6-fluoro-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine];
4,6-difluoro-1,3-dihydro-3-phenylspiro[benzo(c~
thiophene-1,4'-piperidine];
6-fluoro-1'-[3-(4-fluorobenzoyl)propyl]-3-(4-fluorophenyl)-1,3-dihydro-spiro[benzo(c)thiophene-1,4'-piperidine];
1,3-dihydro-1'-(4,4-diphenylbutyl)-3-(4-trifluoromethyl-phenyl)-spiro~benzo(c)thiophene-1,4'-piperidine];
3-(3-bromophenyl)-1,3-dihydro-1'-(3-phenoxypropyl)-spiro~ben20(c)thiophene-1,4'-piperidine];
l'-benzoyl-1,3-dihydro-3-(4-hydroxyphenyl)spiro~berlzo-(c)thiophene-1,4'-piperidine];
1,3-dihydro-3-phenyl-1'-phenylacetylspiro[benzo(c)-thiophene-1,4'-piperidine];
1,3-dihydro-3-(3,4-methylenedioxyphenyl)-1'-methylspiro-[benzo(c)thiophene-1,4'-piperidine];
1,3-dihydro-1'-hvdroxy-3-(4-metho,cvphenv')spiro-[benzo(c)thiophene-1,4'-piperidine];
3-(3,4-dichlorophenyl)-1,3-dihvdro-1'-methylspiro-~benzo(c)thiophene-1,3'-pyrrolidine];
112~2~85 1,3-dihvdro~ ethyl-3~ methvlthiophenyl)spiro-~benzo(c)thiophene-1,4'-piperidine];
1,3-dihydro-1'-methyl-6-methylthio-3-?henylspiro[benzo-(c)thiophene-1,3'-pyr.olidine];
1'-cyclopropylacetyl-1,3-dihydro-3-phenylspiro[benzo-(c)thiophene-1,4'-pi.peridine];
6-methyl-1,3-dihydro-1'-methyl-3-phenylspiro[benzo(c)-thiophene-1,4'-piperidine];
7-metho~y-1,3-dihydro-1'-methyl-3-phenylspiro[benæo(c)-thiophene-1,4'-piperidine];
! S-trifluoromethyl-1,3-dihydro-1'-raethyl-3-phenylspiro-[benzo(c)thiophene-1,4'-piperidine];
4-hydroxy-1,3-dihydro-1'-~ethyl-3-phenylspiro[benzo(c)-thiophene-1,4'-piperidine~;
thiophene-1,4'-piperidine];
6-fluoro-1'-[3-(4-fluorobenzoyl)propyl]-3-(4-fluorophenyl)-1,3-dihydro-spiro[benzo(c)thiophene-1,4'-piperidine];
1,3-dihydro-1'-(4,4-diphenylbutyl)-3-(4-trifluoromethyl-phenyl)-spiro~benzo(c)thiophene-1,4'-piperidine];
3-(3-bromophenyl)-1,3-dihydro-1'-(3-phenoxypropyl)-spiro~ben20(c)thiophene-1,4'-piperidine];
l'-benzoyl-1,3-dihydro-3-(4-hydroxyphenyl)spiro~berlzo-(c)thiophene-1,4'-piperidine];
1,3-dihydro-3-phenyl-1'-phenylacetylspiro[benzo(c)-thiophene-1,4'-piperidine];
1,3-dihydro-3-(3,4-methylenedioxyphenyl)-1'-methylspiro-[benzo(c)thiophene-1,4'-piperidine];
1,3-dihydro-1'-hvdroxy-3-(4-metho,cvphenv')spiro-[benzo(c)thiophene-1,4'-piperidine];
3-(3,4-dichlorophenyl)-1,3-dihvdro-1'-methylspiro-~benzo(c)thiophene-1,3'-pyrrolidine];
112~2~85 1,3-dihvdro~ ethyl-3~ methvlthiophenyl)spiro-~benzo(c)thiophene-1,4'-piperidine];
1,3-dihydro-1'-methyl-6-methylthio-3-?henylspiro[benzo-(c)thiophene-1,3'-pyr.olidine];
1'-cyclopropylacetyl-1,3-dihydro-3-phenylspiro[benzo-(c)thiophene-1,4'-pi.peridine];
6-methyl-1,3-dihydro-1'-methyl-3-phenylspiro[benzo(c)-thiophene-1,4'-piperidine];
7-metho~y-1,3-dihydro-1'-methyl-3-phenylspiro[benæo(c)-thiophene-1,4'-piperidine];
! S-trifluoromethyl-1,3-dihydro-1'-raethyl-3-phenylspiro-[benzo(c)thiophene-1,4'-piperidine];
4-hydroxy-1,3-dihydro-1'-~ethyl-3-phenylspiro[benzo(c)-thiophene-1,4'-piperidine~;
5,fi-methylenedioxy-1,3-dihYdro-l'-r,~e~hvl-3-phenvlspiro-~benzo(c)thiophene-1,4'-piperidine];
1,3-dihydro-1'-methyl-3-(2-r.~ethoxyphenyl)spiro[benzo-(c)thiophene-1,4'-piperidine];
l'-benzoylpropyl-1,3-dihydro-3-phenylspiro[benzo-(c)thiophene-1,4'-piperidine];
l'-benzoylpropyl-1,3-dihydro-3-phenylspiro[benzo(c)-thiophene-1,4'-piperidine]ethylene ~;etal;
1'-(4-fluorophenethyl)-1,3-dihydro-3-phenylspiro-~ben20(c)thiophene-1,4'-piperidine]; and 1,3-dihydro-1'-(3,4-dimethoxyphenyl)propyl-3-phenyl-spiro~benzo(c)thiophene-1,4'-piperidine].
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112;~85 ether-21~ hydrochloric acid mixture and then permitted to stand at a lowered temperature for two hours. The cooled mixutre is filtered to collect its crystalline product. The product is recrystallized from an acetone-ether ni~cture to ~,ive colorless S prisms, mp 182-1~4C. of 4-benzylthio-4-(7-fluorophenyl)l-methylpiperidine hydrochloride.
c. A ~ixture of 0.9 g of 50% ~sodium hydride in 20 ml of dimethvlsulfoxide is heated at ~0-35C. in a nitrogen atmosphere for 30 minutes to produce a solution of sodiu~ methylsulfinvl-methide. This solution is permitted to cool to ambient tem~erature. ~ solution of 4.9 g of 4-benzvlthio-4-(2-fluorophenyl)-l-methylpiperidine, free base of b, in 10 ml of dimethylsulfoxide is added over a 5 ~inute span. After total addition, the mixture is stirred at ambient temperature for one hour and then poured onto ice-water. The resulting solid, collected by filtration, is recrystallized from an ether-hexane mixture to r,ive colorless prisms, mp 120-121c., of 1,3~dihydro-l'-methyl-3-phenylspiro[benzo(c)thiophene-1,~'-piperidine].
Analysis:
Calculated for C191~21~1S: 77.24%C; 7.17%~ -74%~ 0.35%S.
Found: 77.31%C; 7.20%11; L.59'l~; 10.71V,/S.
d. IJith the suhstit~ltion of l-methyl-3-pyrrolidone for l-methyl-4-piperidone into the manipulative procedure of Method ~, 3-(7-fluorophenyl)-3-hydroxv-l-metllylpyrrolidine may be obtained. , e. Starting with 3-(2-fluorophenvl(-3-hydroxy-1-methylpyrrolidine, the manipulative procedures of Method A may be implemented to provide 1,3-dihydro-1'-me~hyl-3-phenylspiro-[benzo(c)thiophene-1,3'-pyrrolidine].
. -- ~8 - f. lhe substitution of l-benzyl-3-pyrrolidone for l-methyl-3-pyrrolidone into the manipulative procedures of E~cample ld and le may provide l'-benzvl-1,3-dihydro-3-phenyl-spiro~benzo(c)thiophene-1,3'-pyrrolidine], g. I~i.h the substitution of l'-~ethyl-3-piperidone for l-methyl-4-piperidone into the manipulative procedure of Example la, 3-(2--luorophenyl)-3-hydroxy-1-nethylpiperidine may be obtained.
h. Starting with 3-(2-fluorophenyl)-3-hydroxy-1-methylpiperidine, the ~anipulative procedures of Example lb and lc may be i~plemented to provide 1,3-dihydro-1'-~ethyl-3-phenylspirolbenzo~c)thiophene-1,3'-piperidine].
Example 2 a. 9.9 ~1 (11.~ g~ of 4-chloroben7,yl mercaptan and 11.1 ml of boron trifluoride etherate are added sequentially to 5.00 g of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine.
ExAmple la, in 11.1 ml of glacial acetic acid. The reaction is stirred at 55-fi~C. for 48 hours. The e~ccess rea~,ents are remoYed at 80C. in vacuo and the residue is tal;en up with a 1:1 ether-21~ hydrochloride acid mixture. This biphasic mixture is stirred for 2.5 hours and then for an ~dditional ten minutes a~ter 50 ~1 of ice are added. The ether layer is decanted off. The aqueous layer is sequentially washed with ether and filtered to collect a crude product. The product is washed with a small portion of water and then a large portion of ether to give a white powder. The powder is recrystallized from acetone to give white crystals, mp 164-166C.
of 4-(4-chlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine ,9 hydrochloride.
Analysis:
Calculated for ClgH21NClFS HCl: 59~08%C; 5~74~H; 3~63~; 4~92%E
Found: 59~04ZC; 5~56%H; 3~68~o~; 4~78%E
b, A solution of sodium methylsulfinylmethide is produced from 0.7 g of (50%) sodium hydride and 15 ml of dimethylsulfoxide as in Example lc. A solution of 4.2 g of 4-(4-chlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine, free base of a, in 15 ml of dimethylsulfoxide is added to tiliS
solution over a three m,inute span. After total addition, the ~ixture is stirred at ambient temperature for one hour and thcn poured onto 70 ml of ice-water. The mixture is diluted with water to 1~0 ml total volume before being filtered to collect the crude product. The product is washed with water and then dissolved with ether. The ethereal solution is sequentially washed thrice with water and once Wit]l a saturated sodium chloride solution and dried to give yellow-white crystals. Tlle crystals are chromato~raphed with ether ~lrough an alumilla column to give white crystals, mp 121-123C of 3-(4-chlorophellyl~
1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine~.
Analysis:
Calculated for ClgH20Cl~S: 69.19,.C; 6.11%ll; 4.25Y.N; 10.75~Cl.
Found: 69.24%C; 6.21%~; 3.96~; 10.74~Cl Example 3 ~ A mi~ture of 2.3 g of 1,3-dihydro-1'-methyl-3-pilenyl-spirotbenzotc)thiophene-1,4'-piperidine], Example 1, 1.4 g of phenyl chloroformate and 0.5 g of sodium bicarbonate in 40 ml of methylene chloride is stirred at ambient temperature for 4 hours before being filtered. The filtrate is sequentially washed with a dilute sodium hydroxide solution and water a~ld 112'~5 dried. The solvent is removed in vacuo, leaving a solid residue which is recrystallized from a benzene-hexane mixture to give rosettes, mp 171-173C, of 1,3-dihydro-1'-phenoxycarbonyl-3-phenylspiro~ benzo(c)thiophene-1,4'-piperidine 7.
Analysis:
Caluclated for C25H23N02S: 74.78 % C; 5.77 % H; 3.49 % N.
Found: 75.04 % C; 5.84 % H; 3.43 % N.
a. A mixture of 3.0 g of 1,3-dihydro-1'-phenoxycar-bonyl-3-phenylspiro/ benzo(c)thiophene-1,4'-piperidine 7, Example 3, 8.0 g of potassium hydroxide pellets in 50 ml of ethylene glycol is stirred at 155C until a clear solu-tion results. The solution is permitted to cool, diluted with water and the biphasic mixture extracted thrice with chloroform. The combined chloroform extracts are washed carefully with water and dried and the chloroform removed leaving a solid residue. The residue is recryQtallized from an acetone-hexane to ~ive prisms, mp 142-144C of 1,3-dihydro-3-phenylspiro/ benzo(c)thiophene-1,4'-pipe-ridine 7.
Analysis:
Calculated for Cl8HlgNS:
76.83 % C; 6.80 % H; 4.98 % N; 11.39 g S.
Found: 77.05 ~ C; 6.84 % H; 4.68 % N; 11.26 % S.
1~2Z985 A mixture of 2.8 g of 1,3-dihydro-3-phenylspiro/ ben-zo(c)thiophene 7, Example 4a, 1.4 g of benzyl chloride and 3.5 g of sodiu~. bicarbonate in 50 ml of dimethylform-amide is stirred at 70C for two hours. Water is added to the cooled mixture and the biphasic mixture is extract-ed four times with methylene chloride. The methylene chlo ride extracts are dried and concentrated in vacuo leaving an oily residue which crystallizes in standing. The product is recrystallized from an ether-hexane mixture to give fine needles, mp 144-145C of 1'-benzyl-1,3-dihydro-3-phenyl-spiro/ benzo(c)thiophene-1,4'-piperidine 7.
Analysis:
Calculated for C25H25NS:
80.82 % C; 6.78 % H; 3.78 % N; 8.63 % S.
Found: 60.81 % C; 6.68 % H; 3.65 % N; 8.76 % S.
EXAMPL~ 6 A mixture of 3.9 g of 1,3-dihydro-3-phenylspiro~ benzo (c)thiophene-1,4'-piperidine 7, Example 4, 3.4 g of diben-zoyl peroxide, 4.0 g of potassium carbonate in 60 ml of benzene is stirred at a temperature of 65-70C for 16 hours before being filtered. The filtrate is washed and dried and the solvent removed in vacuo, leaving a crude oily product. The product is chromatographed through a silica gel column with a methylene chloride eluant to provide l'-benzoyloxy-1,3-dihydro-3-phenylspiro/~benzo(c)thiophene-1,4'-piperidine 7.
Analysis:
Calculated for C25H23N02S: 74.7& ~ C; 5-77 ~ ~; 3-48 g ~-29 Found: 74.67 ~ C; 5.82 % H; 3~33 ~ N.
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1~L2Z~85 a. A salllple of 2-brano-1 ,4-difluor~benzLne is tredted according to the multi-step procedure of Exdm~le 1~ to ultimdtely obtain 4-(2,5-difluorophenyl)-4-hydroxy-1-methylpiperidine, which is converted to its mdleic acid salt which is recryst211ized from an acetone-eth-er mixture to obtain the pure salt, m.p. 163-165~C.
b. A mixture of 4-(2,5-difluorophenyl)-4-hydroxy-l-methyl-piperidine, free base of a, 4 ml of boron trifluoride etherateJ 5 ml of benzyl mercaptan dnd 5 ml of glaci~l dcetic ~cid is stirred at 65C for 16 hours. Excess acid is removed under reduc~d pressure with the residue equilibrated with 0.5N hydrochloric dCid and ether and the resulting solution is stirred dt 10-20C tor four hours. The resulting crystalline precipitdte is sequentidlly collected by filtrdtion, bdsified and ~xtrdcted with ether l)rovidiny the desired product as an oil. The oil is converted to itS IlldleiC
acid sdlt which is recrystdllized from dn acetone-ether mixture tu provide prisms, m.p. 164-166C of 4-benzyl thio-4-(2 ,S-difluoro-phenyl)-l-methylpiperidine maledte.
c. A solution of sodiunl nle~hylsulfinylll~t;hidL which u,as prepared by hedting 250 mg of sodium hydride (50~ dis~ersion, wdshed with pentdne) in 10 ml of dimethylsulfoxide 3t ~0C fùr 30 minu~es is added o~er a five-minute spdn dt dmbient temperdture to d mixture of 4-benzylthio-4-(2,5-difluorophenyl)-1-methylpiperidine, fr~e bdse of b, in 5 ml of dilnethylsulfoxide. After totdl dddition, the mixture is stirred dt ambient temperdture for 30 minutes before being poured onto 50 g of ice water. The mixture is extracted thrice with methylene chloride and the combined extracts are washed with water and dried. The methylene chloride is re~oved under vacuum, leaving a solid residue. The residue is recrystallized fron an ether-pentane mixture to give granular crystals, m.p.
136-317C. of 6-fluoro-1,3-dihydro-1'-methyl-3-phenylspiro-~benzo~c)thiophene-1,4'-pi~eridine].
Analysis:
Calculated for C19H20FtlS: 72.81%C; 6.42~/~11; 4.47~ ; 6.06%F; 10.23C/~S
Found: 72.52%C; 6.46%H; 4.27V/~; 5.88%~; 10.49%S
, Example ~1 A mixture of 0.3 ~ of 6-fluoro-1,3-dihydro-1'-rnethyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidin~] and 0.3 g of phenyl chloroformate in 10 ml of meth~lene c~lloride which was ~reviously stirred at ambient temperature for 16 hours is sequentially ~uenclled ~ith ~tater, washed with 10% sodium hydroxide and dried. The reaction mixture is concentrated under vacuu~
leaving a viscous oii ~hich crvstallized wi~h standing. The solid product is recrystallized from an ether-pentane mixture to ~ive prisms, m.p. 156-15~C. of 6-~luoro-1,3-dihydro-3-phenyl-l'-phenoxycarbonyl~.piro[benzo(c)thiopllene-1,4'-piperidine].
Analysis:
Calculated for C25H22F~IO~S: 71.57%C; 5.?9~ ; 3.34~/~.
Found: ~ 71.65%C; 5.33~,'H; 3.15 ~xample 22 A solution of 2.5 ~, of 3-(3,4-dichlorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine], free base of Example 19, and 1.3 g of phenyl chloroformate in 30 ml of methylene chloride is stirred at ambient tem~erature for 16 hours. The wel stirred solution is washed successively ~ith dilute sodium hydroxide and water and then dried, effecting a crystallin~ product. The product is recrystallized from an acetone-pentane mixture to give fine needles, m.p. 200-202C.
of 3-(3,4-dichlorophenyl)-1,3-dihydro-1'-phenoxycarbonyls~iro-! [benzo(c)t~iophene-1,4'-piperidine].
Analysis:
Calculated for C2s~I21C12~02S
Found:63~ 71%C; 4.56,'I~; 2. 93%N~
Example 23 a. ~2 ml of boron trifluoride etherate are added to a mixture of 30~ 0 g of 4-(2-fluorophenyl)-4-hvdroxy-1-methvl-piperidine of ~xample la and ~2 ~1 of ~.-methylbenæyl mercaptan.
The resultin~, solution is stirred and heated at 75C. for six hours and then the excess reagents sre distilled at 80-100C.
The oil re~ainin~, in the flasl; is stirred with 250 ml of 2~1 HCl and 500 ml of ether for one hour after which 1500 ml of ice is added to form a slurry. The slurry is stirred an additional hour a~d filtered to yield a white solid which is washed with ether and air dried. The material is recrystallized fro~ methanol-acetone-ether to give the ~r,oduct, 4-( -fluorophenyl)-l-methvl-4-(2-methvlbenzylthio)piperidine 1 1 Z25~8S
hydrochloride. An elemental analysis sample was further recrystallized from acetone-ether to give a sample with constant melting point of 206 - 208C.
Analysis:
Calculated for C20H24FNS HCl: 65.64 % C; 6.89 % H; 3.83 % N
Found: 65.46 % C; 6.82 % H; 3.55 % N.
b. A 0.73 g sample of sodium hydride, 50 % in mine-ral oil, is cleaned by triturating with hexane. To the cleaned sodium hydride, is added 20 ml of dimethylsulfoxide and the solution heated in an oil bath at 80 - 90C for 30 minutes. The solution is cooled to room temperature and 4.05 g of 4-(2-fluorophenyl)-1-methyl-4-(2-methylbenzyl-thio)piperidine of Example 23a in 15 ml of dimethylsulf-oxide is added over a 5-minute period. The reaction is stirred for thirty minutes, poured into 100 ml of ice-wa-ter, and filtered. The resulting tan solid i9 dissolved in dichloromethane and chromatographed on an A12C3/ether column (eluting with ether) m.p. 132 - 143C. The sample is recrystallized from ether-hexane to obtain 1,3-dihydro-1'-methyl-3-(2-methylphenyl)spiro! benzo(c)thiophene-1,4'-piperidine 7, m.p. 132 - 134C.
Analys i9:
Calculated for C20H23NS: 77.62 % C; 7.49 Z H; 4.53 % N.
Found: 77.63 Z C; 7.67 % H; 4.35 % N.
A suspension of 3-(3,4-dichlorophenyl)-1,3-dihydro-~l'-phenoxycarbonylspiro/ benzo(c)thiophene-1,4'-piperidine 7 (2.35 g), 7.0 g of potassium hydroxide (85 %) in 30 ml of 29 ethylene glycol is stirred at 160C for 30 minutes. The 112~85 mixture is cooled, diluted with water and extracted with 3 portions (tO0 ml) of dichloromethane. Following drying (MgS04) and evaporation in vacuo, the crude amine is con-verted to a crystalline maleate in ether. Recrystalliza-5 tion from methanol-ether gives rhombic crystals of 3-(3,4-dichlorophenyl)-1,3-dihydrospiro/ benzo(c)thiophene-1,4'-piperidine 7maleate m.p. 192 - 193C.
Analysis:
d for C1gH~7Cl2NS C4H404 56.65 % C; 4.54 % H7 3.00 % N; 15.20 % Cl.
Found: 56.75 Z C; 4.51 % H; 2.88 % N; 14.91 % Cl.
A mixture of 1.5 g of the free base 3-(3,4-dichloro-phenyl)-1,3-dihydrospiro/ benzo(c)thiophene-1,4'-piperi-15 dine 7 of Example 24, 1.3 g of ~chlorobutyrophenone ethy-lene ketal, 0.9 g of potassium iodide, 0.9 g of sodium bi-carbonate in 15 ml of anhydrous dimethylformamide is stir-red at 80C for 16 hours. The mixture is diluted with ice-water and extracted three times with CH2Cl2. The CH2Cl2 20 solution is dried (K2C03) and concentrated in vacuo to an oily residue. Purification is carried out by column chro-matography (alumina-ether) and upon treatment with ethere-al-HBr, a crystalline hydrobromide is obtained with simul-taneous cleavage of the ketal ring. Recrystallization of 25 the granular hydrobromide from methanol ether gives color-less crystals of 3-(3,4-dichlorophenyl)-~'-/ 3-(4-fluoro-benzoyl)propyl 7-1,3-dihydrospiro/ benzo(c)thiophene-- 1,4'-piperidine 7hydrobromide.
:1~122~85 Analysis:
for C28H26cl2FNos HBr:
56.47 % C; 4.57 % H; 2.23 % N
Found:56.43 % C; 4.59 % H; 2.31 % N.
A mixture of the free base 3-(3,4-dichlorophenyl)-1,3-dihydrospiro/ benzo(c)thiophene-1,4'-piperidin~ 7 of Ex-ample 24 (2.0 g), of ~-chloro-4-fluorobutyrophenone ethy-lene ketal, 0.9 g of sodium bicarbonate, 0.9 g of potassium iodide in 15 ml of anhydrous DMF is stirred at 80C for 16 hours. The cooled mixture is diluted with water and ether and the layers are separated. The organic solution is washed with water, dried (MgS04) and concentrated to an oily residue in vacuo. Purification of the crude product is accompli~hed by passing through a short alumina-ether column. Elution with ether gives a pale yellowish oil which is converted to a crystalline maleate in ether. Re-crystallization from acetone-ether gives granulars, m.p.
116 - 119C of 3-(3,4-dichlorophenyl)-1'-! 3-(4-fluoroben-zoyl)propyl 7-1,3-dihydrospiro/ benzotc)thiophene-1,4'-piperidine 7 ethylene ketal maleate.
Analysis:
60.5~ % C; 5.08 % H; 2.08 % N.
Found:60.53 % C; 5.05 % H; 1.86 % N.
a. A mixture of 4-(-2-fluorophenyl)-4-hydroxy-1-me-thylpiperidine of Example la (10.5 g), 10 g of p-fluoroben-29 zyl mercaptan, 18 ml of boron trifluoride etherate and 10 llZZ~?85 ml of glacial acetic acid is stirred at 60 - 65C for 16 hours. The excess reagents are removed under reduced pressure at 100C and the oily residue is triturated with an exces, of 0.5 N hydrochloric acid and 200 ml of ether.
A white precipitate is filtered after 2 hours at 5 - 10C
and is basified to give the desired product. The oily amine is converted to a crystalline maleate in ether, re-crystallized from methanol-ether gives colorless prisms, m.p. 123 - 125C of 4-(4-fluorobenzylthio)-4-(2~fluorophe-nyl)-l-methylpiperidine maleate.
Analysis:
19 21 2NS 4H404:
61.45 % C; 5.61 % H; 3.12 % N.
Found: 61.71 % C; 5.75 % H; 3.15 % N.
b. A solution of sodium methylsulfinyl methide is prepared by heating 0.87 g of sodium hydride in 80 ml of dimethylsulfoxide at 80OC for 30 minutes. The solution is then treated with 8.9 g of the free base 4-(4-fluorobenzyl-thio)-4-(2-~luorophenyl)-1-methylpiperidine of Example 27a in 20 ml of DMS0 over 2 minutes and stirring continued for 15 minutes at 80C before quenching with ice-water. The mixture is extracted 3 times with CH2C12, the combined CH2C12 solution washed with water and dried, and concen-trated to an oily residue. Purification of the crude product is carried out by column chromatography (alumina-ether) and concentration of the combined effluent affords a heavy oil which crystallizes on cooling. Recrystalliza-tion from ether-pentane gives long needles, m.p. 109 -29 110C, of 3-(4-fluorophenyl)-1,3-dihydro~ methylspiro-112~9~3~
/ benzo(c)thiophene-1,4'-piperidine 7.
Analysis:
Calculated for ClgH20FNS
72.81 ~ C; 6.43 ~ H; 4.47 % N; 6.38 % F.
Found: 73.05 % C; 6.31 % H; 4.58 ~ N; 6.23 % F.
A mixture of 3-(4-fluorophenyl)-1,3-dihydro-1'-me-thylspiro/ benzo(c)thiophene-1,4'-piperidine 7 of Ex-ample 27 (3.6 g), 2.1 g of phenyl chloroformate in 100 ml of CH2C12 is stirred at room temperature for 64 hours.
The solution i9 washed with 10 % aqueous NaOH, water, and dried over MgSO4. Evaporation under reduced pressure affords a crystalline residue, m.p. 198 - 200C. Recry-stallization of the crude product from acetone-pentane gives granular crystals, m.p. 200 - 201C of 3-(4-fluoro-phenyl)-1,3-dihydro-1'-phenoxycarbonylspiro /benzo(c)thio-phene-1,4'-piperidine 7.
Analysis:
Calculated for C25H22FN~2S: 71.57 % C; 5.28 % H; 3.34 % N.
Found: 71.73 % C; 5.25 % H; 3.20 % N.
__ A mixture of 3-(4-fluorophenyl)-1,3-dihydro-1'-phen-oxycarbonylspiro/ benzo(c)thiophene-1,4'-piperidine 7 of Example 28 (4 3 g), 1.4 g of potassium hydroxide in 50 ml of ethylene glycol is stirred at 160C for 30 minutes.
The cooled mixture is diluted with water and extracted three - times with 150 ml portions of ether. The combined ether extract is washed with water (3 - 4 times), dried, and con-29 centrated to an oily residue of secondary amine. The se-1122~1~5 condary amine is converted to its hydrochloride in a con-ventional manner by stirring without heating with hydro-chloric acid for several hours. Recrystallization from methanol-acetone-ether gives crys~als, m.p. 259 - 260C of 3-(4-fluorophenyl)-1,3-dihydrosplro /benzo(c)thiophene-1,4'-piperidine 7 hydrochloride.
Analysis:
Calculated for C18H18FNS HCl:
64.36 % C; 5.70 % H; 4.17 % N; 5.65 % F.
Found: 64.09 % C; 5.55 % H; 4.28 % N; 5.78 % F.
EXA~PLE 30 A mixture of 3-(4-fluorophenyl)-1,3-dihydrospiro-/ benzo(c)thiophene-1,4'-piperidine 7 (2.2 g of the free base of Example 29) 2.2 g of 3~-chloro-4-fluorobutyro-phenone ethylene ketal, 1.5 g of sodium bicarbonate, 1.5 gof potassium iodide in 25 ml of DMF is stirred at 80C for 16 hours. The cooled mixture is quenched with water, ex-tracted 3 times with ether and dried. Removal of the sol-vent in vacuo at 80C leaves a reddish oil which is puri-fied by passing through a short column of alumina packed inether. Elution with ether gives a pure tertiary amine which is converted into a crystalline maleate. Recrystal-lization from acetone-ether affords colorless prisms, m.p.
175 - 177C of 1'-/ 3-(4-fluorobenzoyl)-propyl 7-3-(4-fluorophenyl)-1,3-dihydrospiro ~enzo(c)thiophene-1,4'-piperidine 7 ethylene ketal maleate.
Analysis:
ated for C30H31F2No2s C4H404:
65.46 % C; 5.64 % H; 2.24 ~ N.
Found: 65.28 % C; 5.71 ~ H; 2.21 % N.
~:lZZ~85 Example 31 A solution of 1'-[3-(p-fluorobenzoyl)l~ropyl]-3-(4-fluorophenyl)-1,3-dihydro-spiro[benzo(c~tlliophene-1,4'-piperidine] ethylene l;etal of Example 30 (2.3 g of the free 5 base) in 200 ml of ether and 10 ml of methanol is saturated with anhydrous hydro~,en bromide. After standing at room temperature for 2 hours, the mixture is carefully neutraliæed with 1~l ammonia and the ether solu~ion is washed 3 times with water, dried and concentrated to an oily residue. The free 10 base is con~Terted to a crystalline maleate in ether and recrystalli7.ation from acetone-ether gives off-white prisr.ls, m.p. 149-150C., of 1'-~3-(4-fluorobenæoyl)~ropyl]-3-(4-fluoroph~nyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4~-piperidine maleate.
15Analysis:
C28H27F2~0S.Cl~H4O4: ~;~.31r/~,; 5.40~/~; 2-42V~ 55~F
Found: ~)6~41%C; 5.22~H; 2.36~ .64 ~.xample 32 a. 59.7 g of 2-chlorobenzylmercaptan, followed by 55 ml of boron trifluoride etherate are added to ?.5 ~, of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine of ~ample la in 55 ml of acetic acid. The reaction is stirred at 55-fi5C. for 20 hours.
The excess acid is removed under reduced pressllre at 80-100C.
The oily residue is then equilibrated ~Jith 200 ml of 2I~
25 hydrochloric acid and 200 ml of ether. The etiler, and two more 125 ml portions of ether, is decanted off. The oil and water mixture i~
112Z~85 diluted to 650 ml volume with water and is stored at 0C
for about three days to produce crystals. The mixture is diluted and filtered. The precipitate is washed with water and ether, and dried. The solld is recrystallized (acetone:ether) to a broad melting (122 - 129C) solid.
A portion of the solid is placed in water, basified with 10 % aqueous NaOH, extracted into ether, washed,dried and treated with ethereal hydrogen chloride to give a white powder. The powder is recrystallized from acetone-ether to give a white crystalline solid, m.p. 173 - 175C of 4-(2-chlorobenzylthio)-4-(2-fluorophenyl)-t-methylpiperi-dine hydrochloride.
Analysis:
Calculated for C19H2lClFNS:
59.08 % C; 5.74 % H; 3.63 % N; 4.92 % F.
Found: 58.81 % C; 5.63 % H; 3.37 % N; 5.03 % F.
b. A 0.2 g sample of sodium hydride, (prepared by washing a 50 % oil dispersion) is heated at 80C with stir-ring in 15 ml of dimethylsulfoxide for 30 minutes. Then 2.1 g of the free base 4-(2-chlorobenzylthio)-4-(2-fluoro-phenyl)-l-methylpiperidine of Example 32a in 10 ml of dry DMS0 is added in one portion and the oil bath is removed.
The reaction is allowed to stir without heating for 40 mi-nutes, then is poured onto 250 cc of ice with 250 ml of ether. The layers are shaken and separated and the aque-ous portion extracted again with 150 ml of ether. The com-bined ether is washed with two 100 ml portions of water and one 10 ml portion of saturated sodium chloride solu-~ 29 tion, and is dried over magnesium sulfate to give an oil.
2~85 The oil is chromatographed on a column of alumina with ether to a material (free base) showing one spot (Rf û.54;
25 % MeOH: CH2Cl2, silica) by tlc. The product in ether is treated with excess e.hereal maleic acid, washed witn 5 ether, and dried to give a white powder, m.p. 173 - 176C, of 3-(2-chlorophenyl)-1,3-dihydro-1'-methylspiro/ benzo(c)-thiophene-1,4'-piperidine 7maleate.
A small portion of the salt is recrystallized twice from acetone to give crystals melting at 178 - 178.5C.
Analysis:
Calculated for C19H20ClNS-C4H4O4:
~1.95 % C; 5.43 % H; 3.14 % N; 7.95 % Cl.
Found: 62.03 % C; 5.46 % H; 3.10 % N; 7.94 % Cl.
a. A mixture of 4-(2-fluorophenyl)-4-hydroxy-1-me-thylpiperidine of Example la (15.8 g), 12 ml of 2-fluoro-benzyl mercaptan and 20 ml of boron trifluoride etherate in 15 ml of glacial acetic acid is stirred at 65 - 70C
for 16 hours. The excess reagents are removed under re-20 duced pressure, the residue is triturated with 300 ml of 0.5 N HCl and 100 ml of ether. After standing at 5 - 10C
for 30 minutes, a crystalline precipitate is filtered, air driea and made basic with lO % aqueous NH40H. The liberat-ed amine is taken up in ether, dried and concentrated to a 25 yellowish oil which is then converted to its maleate in ether, recrystallization of the crude salt from methanol-ether gives colorless prisms, m.p. 153 - 154C of 4-(2-fluorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine - 29 maleate.
112Z~85 Analysls:
Calculated for C~gH21F2NS-C4H404 61.45 % C; 5.61 % H; 3.12 % N.
Found: 61.28 % C; 5.57 % ~; 2.98 % N.
b. A solution of sodium methylsulfinyl methide is prepared by heating 1.2 g of sodium hydride in 100 ml of DMS0 at 80C for 30 minutes. The mixture is cooled to room temperature and to it is added 12 g of the free base 4-(2-fluorobenzylthio)-4-(2-f'uorophenyl)-1-methylpiperi-dine in 40 ml of DMS0 over a period of 5 minutes. Follow-ing the addition is stirred at 70 - 80C for an additional 30 minutes, The mixture is d~luted with ice-water, ex-tracted 3 times with ether. lhe combined ether solution is washed 4 times with water, dried and concentrated to a thick oil. Chromatography over Al203-ether removes a small amount of impurities and the purified amine is con-verted to a crystalline hydrobromide in ether. Recrystal-lization from methanol-ether gives colorless crystals, m.p. 263 - 265C (dec.) of 3-(2-fiuorophenyl)-1,3-dihydro-l'-methylspiro-/ benzo(c)thiophene-1,4'-piperidine 7 hydrobromide.
Analysis:
Calculated for ClgH20FNS'HBr:
57,86 % C; 5.37 % H; 3.55 % N; 4.82 % F.
Found: 57.67 ~ C; 5.47 % H; 3.58 % N; 4.80 % F.
A mixture of the free amine 3-(2-fluorophenyl)-1,3-dihydro-l'-methylspiro/ benzo(c)thiophene-1,4'-piperidine 7 ~ ~ ~ .
112~85 Example 33 (6.3 g), 3.9 g of phenyl chloroformate in 100 ml of anhydrous CH2C12 is stirred at room temperature for 4 hours. The reaction mixture is washed with 10 %
aqu*ous sodium hydride and dried over MgS04 for 2 hours.
Removal of solvent under reduced pressure leads to a thi~k oil which is purified through a short silica gel column packed in CH2C12. Elution with a large excess of CH2C12 gave, after concentration, a colorless oil which solidified on standing, to yield 3-(2-fluorophenyl)-1,3-di-hydro-l'-phenoxycarbonylspiro/ benzo(c)thiophene-1,4'-pi-peridine 7 m.p. 122 - 123C.
Analysis:
Calculated for C25H22FN02S:
71.57 % C; 5.28 % H; 3.34 % N.
Found: 71.49 % C; 5.23 % H; 3.27 % N.
A mixture of 3-(2-fluorphenyl)-1,3-dihydro-1'-phenoxy-carbonylspiro/ benzo(c)thiophene-1,4'-piperidine 7 of Example 34 (5.6 g), 18 g of potassium hydroxide in 100 ml of ethylene glycol is stirred at 170C for 30 minutes.
The mixture is poured into water and extracted 3 times with ether. The ether solution is washed with water, dried and concentrated in vacuo to give a viscous oil of free amine.
A crystalline maleate is prepared and recrystallized from methanol-acetone-ether to give a white powder of 3-(2-fluo-- rophenyl)-1,3-dihydrospiro/~benzo(c)thiophene-1,4'-piperi-dine 7 maleate.
Analysis:
29 Calculated for C1gH1gFNs;c4~4o4 ll~Z~85 - 44 _ 63.5~ % C; 5.34 % H; 3.37 % N; 4.57 % F.
Found:63.55 % C; 5.33 % H; 3.10 % N; 4.52 % F.
A mixture of 3-(2-fluorophenyl)-1,3-dihydrospiro/ ben-zo(c)thiophene-1,4'-piperidine 7 of Example 35 (2.2 g), 2.2 g of ~-chloro-4-fluorobutyrophenone ethylene ketal compound, 1.5 g of potassium iodide, 1.5 g of sodium bicarbonate in 25 ml of DMF is stirred at 70-75C for 16 hours. The cooled mixture is diluted with water and the mixture ex-tracted 3 times with ether. The ether solution, after washing with water and drying, is concentrated in vacuo to an oily residue which is purified through a short column of alumina, elution with ether gives a colorless oil which is converted to a crystalline maleate, m.p. 105-151C of 15 1'-/ 3-(4-fluorobenzoyl)propyl 7-3-(2-fluorophenyl)-1,3-di-hydrospiro/ benzo(c)thiophene-1,4'-piperidine 7 ethylene ketal maleate.
Analysis:
Calculated for C30H30F2N02S C4 4 4 65.46 % C; 5.64 % H; 2.24 % N.
Found: 65.46 % C; 5.37 % H; 2.12 % N.
A solution of 1'-/ 3-(4-fluorobenzoyl)propyl 7-3-(2-fluorophenyl~-1,3-dihydrospiro/ benzo(c)thiophene-1,4'-25 piperidine 7 ethylene ketal of Example 36 (2.0 g) in 20 ml - of ethanol and 20 ml of 3N hydrochloric acid is heated on a steam bath for 30 minutes. The cooled solution is basifi-ed with 40 % aqueous sodium hydroxide and extracted 3 : ~ 29 times with ether. The combined ether solution is washed 2~ ~ 5 thoroughly with water, dried and treated with an excess of ethereal maleic acid. A crystalline maleate is recrystal-lized from acetone-ether to give all-white prisms, m.p.
137-138.5C, of 1'-/ 3-(4-fluorobenzoyl)propyl 7-3-(2-fluorophenyl)-1,3-dihydrospiro/ benzo(c)thiophene-1,4'-piperidine 7 maleate.
Analysis:
Calculated for C2gH27F2N C4H404 66.31 % C; 5.40 ~ H; 2.42 % N; 6.55 % F.
Found: 66.18 % C; 5.34 % H; 2.42 % N; 6.49 % F.
A 4.5 g sample of phenyl chloroformate in 150 ml of dichloromethane is stirred at 25C while 7.5 g of 1.3-di-hydro-l'-methyl-3-(2-methylphenyl)spiro/ benzo(c)thiophene-1,4'-piperidine 7 of Example 23 in 75 ml of dichloromethane is rapidly added. The reaction is stirred a total of 24 hours at 25C and quenched with 225 ml of 10 % aqueous NaOH solution. The organic layer is separated, washed with water, dried over MgS04, filtered and evaporated to an oil. The oil is column chromatographed on a silica gel/
CH2C12 column with CH2C12 being used for elution.
The isolated product is a pale yellow oil of 1,3-dihydro-3-(2-methylphenyl)-1'phenoxycarbonylspiro/ benzo(c)thiophene-1,4'-piperidine 7.
25 Analysis:
26H25N02S: 75.15 % C; 6.06 % H.
Found:74.90 % C; 6.05 % H.
- ~12Z~85 Example 39 A solution of 16 g of potassiu~ hydro~ide dissolved in 100 ~1 of ethylene glycol is added tc 6.~ g of 1,3-dihydro-3-(2-methylphenyl)~ phenoxycarbonyls~iro[benzo(c)thiophene-1,4'-piperidine] of Exa~.ple 38. ~he re~ult ng solution is stirred and heated at 160C. for one hour. The solution is poured into 300 ml of ice water and extracted with ether. The ether fractions are combined, washed with water, dried over MgSO4, filtered, and evaporated to a residue which is converted to a white, granular, ~aleate salt, 1,3-dihvdro-3-(2-methylphenyl~s~iro[benzo(c)thiophene-1,4'-pi~eridine] maleate, which is recrvstallized from methanol-ether and has a ~.p.
178-179C.
Analysis:
ClgH21~S-C4H404: 67.13%C; 6.12%H; 3 40V~I
Found: 67.10%C; ~. 96~/oH; 3 ~14~/oN
~xample 40 A nixture of 6.0 g of 1,3-dihydro-3-(4-methylphenyl)-l'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-pi~eridine] of Exa~ple 13, 16.0 g of potassium hydroxide and 100 ml of ethylene glycol is stirred and heated at 160C. for one hour. The reaction mixture is quenched with ice water and e~tracted with ether. The ether extracts are combined, washed with water, dried over ~IgS04, and evaporated to an oil. The oil is converted to 1,3~dihydro-3-(4-methylphenyl)spiro[benzo(c)-thiophene-1,4'-piperidine] maleate. m.~. 214-215C.
.
Analysis:
Calculated for C19H21NS-C4H404~ 67.13 % C; 6.12 % H; 3.40 % N.
Found: 67.05 % C; 6.20 % H; 3.21 % N.
a. To 25 g of 4-(2-fluorophenyl)-4-hydroxyl-1-me-thylpiperidine of Example 1a is added 50 g of m-methylbenzyl mercaptan. To this mixture is added 68 ml of boron tri-fluoride etherate. The reaction is stirred at 65-70C
for about three days. Excess reagent is then removed under aspirator pressure at 60-100C. The mixture is poured into 360 ml of 0.5 N hydrochlorid acid with 300 ml of ether. An oil falls out, from which the water and ether are decanted. The oil is placed under 250 ml of 0.5 N
hydrochloric acid and 200 ml of ether. The oil is again separated from the solutions and is placed under 150 ml of water with 20 ml of lO % aqueous sodium hydroxide solution.
The suspension is diluted further with 200 ml of water and is extracted with two 200 ml portions and one 100 ml por-tion of ether. The combined amine ether extracts are added to a solution of l2.5 ml of 4O ~ aqueous hydrogen bromide in 300 ml of water to glve a white salt. The mixture is allowed to stand 16 hours, then the ether is decanted off. The aqueous mixture is washed again by adding and decanting 200 ml of ether. The salt is then filtered off, washed with water and ether, and dried to a white powder, m.p. 143-145C, of 4-(2-fluorophenyl)-4-(3-methylbenzylthio)-l-methylpiperidine hydrobromide. A
thrice recrystallized (acetone-ether) sample melts at 29- 145-146C.
112~985 Analysis:
Calculated for C20H24FNS HBr: 58.54 % C; 6.14 % H; 3.4 % N.
Found: 58.45 % C; 6.16 ~ H; 3.16 % N.
b. A 3.43 g portion o~ 50 % sodium hydride dispersion is washed with hexane under dry nitrogen and then heated with 100 ml of sieve dried dimethylsulfoxide at 80-85C
for 40 minutes. Then 18.48 g of the free base of 4-(2-fluorophenyl)-4-(3-methylbenzylthio)-1-methylpiperidine of Example 4la in 70 ml of dry DMS0 is added over 60 seconds.
The red mixture is stirred, cooled to room temperature over one hour, and poured into 500 cc of ice water. The aqueous mixture is extracted with three 200 ml portions of dichlo-romethane. Combined dichloromethane extracts are washed with four 200 ml portions of water and one 100 ml portion of saturated aqueous sodium chloride solution, and dried over magnesium sulfate to yield an oil. The oil is dissolv-ed in ether, filtered, evaporated, and chromatographed on 400 ml of alumina with ether to give an oil which is dis-solved in ether and treated with ethereal hydrogen bromide to give a salt. The salt is washed with ether and recry-stallized from methanol-acetone-ether to give a white, crystalline powder, m.p. 258-260C of 1,3-dihydro-1'-methyl-3-(3-methylphenyl)spiro/ benzo(c)thiophene-1,4'-piperidine 7 hydrobromide.
25 Analysis:
Calculated for C20H23NS-HBr 61.54 % C; 6.20 ~ H; 3.59 % N.
Found: 61.27 % C; 6.24 % H; 3.45 % N.
~ ~, .
_ 49 ~ Z985 ~xample 42 A solution of 0~70 g of the a~ine 1,3-dihydro-3-(2-nethylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine] of Examp~e 3~, 0.76 g of y-chloro-p-fluorobut~rophenone ethylene ketal, 0.3~ g of sodium bicarbonate, 0.3~ g of ~', and 10 ml of anhydrous DMF is stirred and heated at 70-80C for 24 hours.
The reaction is ~orked up by pouring it into water and extracting with ether. The ether fractions are combined, washed with water, and dried over ~qgS04~ The solution is iltered, evaporated and the resulting oil colu~n chromatographed on a A1203/ether colu~n (eluted with ether). The isolated product is converted to a maleate salt of 1'-[3-(4-fluorobenæoyl)propyl]-1,3-dihydro-3-(2-methylphenylspiro[benzo(c)thiophene-1,4'-piperidine] ethylene ketal maleate, m.p. 157-159C.
16 Anal~sis:
Calculated for C31H34~lO2S-C4H40~ 67.~3C,'C; 6-18%H; 2-26%N-Found: 67.7~C,'C; 6.02%H. 2.24%N.
Example ~3 To 3.33 ~ of phenyl chlorofo~ate in 850 ml of dichloromethane is added a solution of 6.73 ~, of the free base 3-(2-chlorophenyl)-1,3-dihydro-1'-methvlspiro[benzo(c)thiopllene-1,4'-piperidine] of Example 32 in 75 ml of dichloromethane over two minutes. The reaction is stirred at ambient temperature for 64 hours, then diluted with 200 ml of dichloronethane and washed~th t~ 3~0 ~a ~orti~ls of 57 a~ueous sodium hvdroxide solution, th~ 200 112~85 ml portions of water and one 75 ml portion of brine. The solution is dried over magnesium sulfate and evaporated to an oil. The oil is chromatographed on a silica gel with dichloromethane to give an oil of 3-(2-chlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro-/ benzo(c)thiophene-1,4'-piperidine 7.
Analysis:
Calculated for C25H22ClN02S: 68.88 % C; 5.09 % H; 3.21 % N.
Found: 69.36 % C; 4.94 % H; 3.33 % N.
To 1.81 g of phenyl chloroformate in 40 ml of dichlo-romethane is added a solution of 2.9~ g of the free base 1,3-dihydr-o-1'-methyl-3-(3-methylphenyl)spiro/ benzo(c) thiophene-1,4'-piperidine 7 of Example 41 in 35 ml of di-chloromethane over 5 minutes. The reaction is stirred at ambient temperature for 21 hours. The reaction is then diluted with 100 ml of dichloromethane; wahsed with two 150 ml portions of 5 % aqueous sodium hydroxide solution, two 100 ml portions of water and one 50 ml portion of brine;
and dried over magnesium sulfate to an oil. The oil is chromatographed on silica gel with dichloromethane to yield 1,3-dihydro-3-(3-methylphenyl)-1'-phenoxycarbonylspiro/ ben-zo(c)-thiophene-1,4'-piperidine 7, m.p. 154-157C. A por-tion is recrystallized from toluene-hexane, m.p. 157-160C.
Analysis:
Calculated for C26H25N02S: 75.16 % C; 6.07 ~ H; 3.37 % N.
29 Found: 75.28 % C; 6.12 % H; 3.17 % N.
llZZ~?8S
To 6.19 g of 3-(-2-chlorophenyl)-1,3-dihydro-1'-phen-oxycarbonylspiro/ benzo(c)thic,phene-1,4'-piperidine 7 of E~ample 43 in 95 ml of ethylene glycol at 150C is added 15.1 g of 85 % potassium hydroxide pellets. The reaction is stirred in a 160-165C bath for 40 minutes, then cooled to room temperature and poured into 250 ml of water.
The mixture is diluted to 500 ml with water and extracted with three 150 ml portions of water and one 40 ml portion of saturated sodium chloride ~solution and dried over magne-sium sulfate to an oil. The oil is dissolved in ether, filtered, and treated with etihereal maleic acid. The crude salt is washed with ether and recrystallized from methanol-acetone-ether to give a white salt of 3-(2-chlorophenyl)-1,3-dihydrospiro/ benzo(c)thiophene-1,4'-piperidine 7 maleate, 15 m.p. 172-173C.
Analysiq:
Calculated for C18Hl8ClNS:
61,18 % C; 5.14 % H; 3.24 % N; 8.21 % Cl.
Found: 61.47 % C; 5.22 % ~; 3.18 % N; 7.85 % Cl.
To 2.48 g of the free ba~e, 3-(2-chlorophenyl)-1,3-dihydro-spiro/ benzo(c)thiophene-1,4'-piperidine 7 of Example 45, in 28 ml of sieve-dried dimethylformamide with 2.78 g of ~ -chloro-p-fluorophenylbutyrophenone ethylene 25 ketal is added 2.02 g of sodium bicarbonate and 2.02 g of potassium iodide. The reaction is then heated in an 85-50 C bath for 17 hours. The mixture is diluted with 90 ml - of chloroform and fultered through paper. The solution is 29 evaporated and the oil partit~oned between 140 ml of di-.
chloromethane and 75 ml of water. The dichloromethane is washed with 75 ml of water and one 25 ml portion of saturat-ed sodium chloride solution and dried over magnesium sulfa-te. The oil is chro~latographed on alumina with ether and treated with ethereal oxalic acid to give a salt. The salt is washed with ether and recrystallized from methanol-acetone-ether (m.p. 200-201C) to give a white solid of 3-(2-chlorophenyl)-1'-/ 3-(4-fluorobenzoyl)propyl 7-1,3-di-hydrospiro/ benzo(c)thiophene-1,4'-piperidine 7ethylene ketal oxalate, m.p. 200-201C.
Analysis:
62.59 ~ C; 5.42 % H; 2.28 % N.
Found:62.53 % C; 5.44 % H; 2.26 % N.
a.To 14.45 g of 4-(2-fluorophenyl)-4-hydroxy-l-methylpiperidine of Example la is added 39.45 g of 2,4-di-chlorobenzyl mercaptan followed by 40 ml of boron trifluori-de etherate. The reaction is stirred at 80-85C for about 4 days. The excess reagent is removed under aspira-tor pressure to 110C and the residual oil poured into 200 ml of 0.5 N hydrochloric acid and 200 ml of ether. The mixture is allowed to stand 18 hours, the ether decanted off and two more 200 ml portions of ether are added and decanted. The crude precipitate is filtered, washed with 75 ml of water and three 125 ml portions of ether, and dried to an apparently mixed salt. A portion of the salt is basified in aqueous ammonium hydroxide, extracted with 29 ether, washed with water and brine, and dried over magne-~12'~85 sium sulfate. The ethereal solution is treated with ethe-real hydrogen bromide to give a salt. The salt is washed with ether and dried to give a white powder of 4-(2,4-dichlorobenzylthio)-4-(2-fluorophenyl)-l-methylpi-peridine hydrobromide, m.p. 208.5-210C.
Analysis:
Calculated for C19H20Cl2FNS HBr: 49.05 % C; 4.55 % H; 3.01 % N.
Found: 48.87 % C; 4.52 % H; 2.96 % N.
b. A 0,3 g of sodium hydride (50 %) is washed with hexane under nitrogen and heated at 80C with 11 ml of dry dimethylsulfoxide for 30 minutes. Then 1.6~ g of the free base, 4~(2,4-dichlorobenzylthio)-4-(2-fluorophenyl)-1-me-thylpiperidine of Example 47a in 7.3 ml of dry DMS0 is added at once and the heating removed. The reaction is stirred under nitrogen, while cooling to room temperature over 45 minutes, then poured onto ice and extracted with 50 ml of ether and 150 ml of dichloromethane. Co~.bined orga-nic phases are washed with two lO0 ml portions of water and one 25 ml portion of brine, and dried over magnesium sulfate to an oil. The oil is chromatographed on alumina with ether to give an oil. The oil, in ether, is treated with ethereal hydrogen bromide to form a salt. The salt is washed with ether and recrystallized from acetone-ether to give a yellowish-white salt of 3-~2,4-dichlorophenyl)-1,3-dihydro-l'-methyl-spiro(benzo(c)thiophene-1,4'-piperidine) hydrobromide, m.p. 259.5-261C. A portion of the crude salt is recrystallized thrice from methanol-acetone ether to give a m.p. 260-261C.
- 29 Analysis:
Calculated for C19H19Cl2NS HBr:
51.26 % C; 4.53 % H; 3.15 % N; 15.93 % Cl.
Found: 51.43 % C; '~.56 % H; 3.15 % N; 15.65 % Cl.
To 1.34 g of 1,3-dihydro-3-(3-methylphenyl)-1'-phen-oxycarbonylspiro/ benzo(c)thiophene-1,4'-piperidine 7 of Example 44 in 22 ml of ethylene glycol, under nitrogen, at 150C is added 3,44 g of 85 % aqueous potassium hydroxide.
The rection is stirred at 160C for 40 minutes, then is poured into 50 ml of ice water, diluted to 120 ml and extracted with two 50 ml portions of dichloromethane. The combined dichloromethane extract is washed with two 50 ml portions of water and one 20 ml portion of saturated sodium chloride solution, and dried over magnesium sulfate to an oil. The oil is purified by swirling and decanting one 50 ml portion and two 25 ml portions of boiling hexane. The evaporated hexane gives an oil (free base) which is dissolv-ed in ether, treated with ethereal maleic acid, and recry-stallized from acetone to a white powder of l,3-dihydro-3-(3-methylphenyl)spiro! benzo(c)thiophene-1,4'-piperidine 7 maleate, m.p. 175-176C.
Analys i9:
Calculated for ClgH21SN~C4H404 67.14 % C; 6.12 % H; 3.41 % N.
25 Found: 67.29 % C; 6.13 % H; 3.30 % N.
To 4.02 g of the free base 3-(2-chlorophenyl)-l'-/ 3-I4-fluorobenzoyl)propyl 7-1,3-dihydrospiro/ benzo(c) : ~- 29 thiophene-1,4-piperidine 7 ethylene ketal of Example 46 in liZ;~3S
250 ml of ether with 15 ml of methanol is added 120 ml of an ethereal hydrogen bromide solution. The reaction is allowed to stir for two hours, then 120 ml of 1:4, 58 %
ammonium hydroxide: water is added with stirring to dissolve all material. The layers are separated and the ether washed with three 100 ml portions of water and one 25 ml portion of saturated aqueous sodium chloride solution and dried over magnesium sulfate to yield a solid. The solid is stirred in a mixture of 125 ml of ether and 64 ml of 15:1, water: 58 % ammonium hydroxide for one hour. The layers are separated and the aqueous layer washed with two 50 ml por-tions of ether, and then filtered and dried to a solid. The combined ether solutions are washed with water and brine, dried, evaporated, and the solids recrystallized from ethyl acetate and combined to give a solid of 3-(2-chlorophenyl)-1'-/ 3-(4-fluorobenzoylpropyl 7dihydrospiro / benzo(c)thiophene-1,4'-piperidine 7, melting at 144-148C.
Analysis:
Calculated for C28H27ClFNOS:
70.07 % C; 5.67 % H; 2.92 % N; 7.39 % Cl.
Found: 69,81 % C; 5.54 % H; 2.79 % N; 7.29 % Cl.
To 5.25 g of the free base, 1.3-dihydro-3-(3-methyl-phenyl)spiro! benzo(c)thlophene-1,4'-piperidine 7 of Example 48 in 65 ml of sieve-dried dimethylformamide is added 5.43 g of ~-chloro-p-fluorobutyrophenone ethylene ketal, followed by 3.6 g of sodium bicarbonate and 3.6 g of potassium iodide. The reaction is stirred in an 85C
29 bath for 24 hours, then diluted with 130 ml of chloroform and filtered. The solvent is removed and the residual oil is partitioned between 250 ml of dichloromethane and 150 ml portion of water and one 35 ml portion of saturated sodium chloride solution and dried over magnesium sulfate to an oil. The oil is chromatographed on alumina with ether and is converted to the maleate salt by treatment with ethereal maleic acid. Recrystallization from acetone-ether yield l'-/ 3-(4-fluorobenzoyl)propyl 7-1,3-dihydro-3-(3-methyl-phenyl)spir~/ benæo(c)thiophene-1,4'-piperidine 7ethylene ketal maleate, m.p. 155-157C.
Analysis:
Calculated for C31H34FN02S C4H404:
67.84 % C; 6.18 g H; 2.26 % N.
Found: 67.76 % C; 6.19 % H; 2.15 % N.
To 8.5 g of phenyl chloroformate in 130 ml of dry dichloromethane under nitrogen is added a solution of 15.56 g of the fr~e base of 3-(2,4-dichlorobenzylthio)-1,3-dihy-dro-l'-methylspiro~ benzo(c)thiophene-1,4'-piperidine 7 of Example 47 in lO0 ml of dry dichloromethane over 15 minutes.
The reaction is stirred at ambient temperature for 21 hours, then diluted with 450 ml of dichloromethane, washed with two 300 ml portions of 10 % aqueous sodium hydroxide solu-tion, two 300 ml portions of water and one 100 ml portion of brine and dried over magnesium sulfate to an oil. The oil is chromatographed on silica gel with dichloromethane to give a clear oil of 3-(2,4-dichlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro/ benzo(c)thiophene-1,4'-piperidine 7 29 A:nalysis:
Calculated for C25H21C12N2S 63-84 % C; 4-50 % H; 2-98 % N-Found: 63.71 % C; 4.52 % H; 2.79 % N.
A solution of 2.85 g of the free base 1'-/ 3-(4-fluoro-benzoyl)propyl 7-1,3-dihydro-3-(2-methylphenyl)spiro/ benzo (c)thiophene-1,4'-piperidine 7 ethylene ketal of Example 42, 30 ml of absolute ethanol, and 30 ml of 3N HCl solution is refluxed for 45 minutes. The reaction is cooled, made basic with 40 % aqueous NaOH solution, and extracted with CH2C12. The CH2C12 fractions are combined, washed with water, and dried over MgS04. The solution is filter-ed and evaporated to a solid which is recrystallized from ethyl acetate to give a pure product of 1'-/ 3-(4-fluoro-benzoyl)propyl 7-1,3-dihydro-3-(2-methylphenyl)spiro/ benzo (c)thiophene-1,4'-piperidine 7, m.p. 143-145C.
Analysis:
Calculated for C29H30FNOS: 75.78 % C; 6.58 % H; 3.05 % N.
Found: 75.51 % C; 6.70 % H; 2.85 % N.
To 15.12 g of 3-(2,4-dichlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro! benzo(c)thiophene-1,4'-piperidine 7 of Example 51 in 216 ml of ethylene glycol at 150C, un-der nitrogen, is added 34,2 g of 85 % potassium hydroxide pellets. The reaction is stirred at 160C for 45 minutes, then poured into 1.4 1 of water and extracted with three 350 ml portions of dichloromethane. The combined dichloro-methane extract is washed with two 400 ml portions of water and one 100 ml portion of saturated aqueous sodium chloride 29 solution and dried over magnesium sulfate to an oil. The `
.
1~2~985 oil is purified by decanting with three 225 ml portions of boiling hexane to yield a solid. A portion of the solid is dissolved in ether and treated with ethereal maleic ac~d to give a salt. The salt is washed with ether and recrystallized from methanol-acetone-ether to a white powder of 3-(2,4-dichlorophenyl)-1,3-dihydrospiro / benzo (c)thiophene-1,4'-piperidine 7 maleate, m.p. 171-172.5C.
Analysis:
Calculated for C18Hl7C12NS C4H404:
56.66 % C; 4.54 % H; 3.00 % N; 15.20 % Cl.
Found: 56.49 % C; 4.54 % H; 2.81 % N; 14.99 % Cl.
To 3.0 g of the free base 3-(2,4-dichlorophenyl)-1,3-dihydrospiro/ benzo(c)thiophene-1,4'-piperidine 7 of Example 53 in 35 ml of sieve-dried dimethylformamide is added 2.62 g of ~-chloro-p-fluorobutyrophenone ethylene ketal, followed by 1.7 g of sodium bicarbonate and 1.7 g of potassium iodide. The reaction is stirred at 80-90C for 20 hours.
The mixture is diluted with 75 ml of chloroform, filtered, and rotary evaporated at 75C to an oil. The oil is partitioned between 125 ml of dichloromethane and 85 ml of water. The mixture is diluted with 10 ml of saturated aqueous sodium bicarbonate solution, and the organic layer separated and washed with one 80 ml portion of water and one 30 ml portion of saturated sodium chloride solution.
The dichlorornethane solution is dried and evaporated to an oil~ The oil is chromatographed on alumina with ether and a portion of the resultant oil is placed in ether and 29 treated with ethereal oxalic acid to give a salt.
The salt is washed with ether and recrystallized from methanol-acetone-ether to yield a white powder of 3-(2,4-dichlorophenyl)-1'-/ 3-(4-fluorobenzoyl)-propyl 7-1,3-dihydrospiro/ benzo~c)thiophene-1,4'-piperidine 7 5 ethylene ketal oxalate, m.p. 164-165C.
Analysis:
59.26 % C; 4.97 % H; 2.16 % N.
Found:59.15 % C; 4.81 % H; 2.11 % N.
a.To 26.33 g of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine of Example 1a with 20 ml (approximately 23.3 g) of m-fluorobenzylmercaptan in 25 ml of glacial acetic acid is added 33 ml of boron trifluoride ethane.
The reaction is stirred at 65-68C for 44 hours, then an additional 17 ml of boron trifluoride etherate is added and stirring at 65-68C is resumed for about three more days.
Excess solvent is removed under reduced pressure to 110C.
The residue is mixed with 450 ml of 0.5 N HCl and 175 ml of ether to form an oil. The oil and water layer is washed by decanting with ether, then the aqueous acid is carefully decanted from the oil. The oil is placed under water, treated to pH=9-lO with ammonium hydroxide and extracted with ether. The ethereal solution is washed with water until neutral, then is poured into a solution of 30 ml of 48 % hydrogen bromide diluted to 350 ml to form a salt.
The salt is filtered off, washed with a small amount of water and a generous amount of ether to give a white salt 29 of 4-(3-fluorobenzylthio-)-4-(2-fluorophenyl)-1-methylpipe-liZZ~85 ridine hydrobromide, m.p. 176-178.5C. A thrice recrystal-lized (methanol-acetone-ether) sample melts at 178-179C.
Analysis:
Calculated for C19H21F2NS HBr:
55.08 % C; 5.35 % H; 3.38 % N.
Found: 55.05 % C; 5.38 % H; 3.38 % N.
b. To 1.404 g of sodium hydride (from 2.87 g of a 50 % dispersion), under nitrogen, is added 120 ml of sieve-dried dimethylsulfoxid. The mixture is stirred in an 80 -85C bath for 35 minutes, then cooled to room ~empera-ture. A solution of 14.0 g of the free base 4-(3-fluoro-benzylthio)-4-(2-fluorophenyl)-1-methylpiperidine of Ex-ample 55a in 47 ml of DMS0 is added over 60 seconds and the solution stirred for one hour. The reacti~n is then poured into 700 ml of ice water and extracted with three 200 ml portions of dichloromethane. The combined dichloro-methane extracts are washed with three 300 ml ~ortions of water and one 75 ml portion of saturated sodium chlo-ride solution, and dried over magnesium - 61 - l i 2~'~85 sulfate to an oil. The oil is chromatogr2phed on alumina with ether to give crystals. A portion of ~his, in ether is treated with ethereal maleic acid. The resulting salt is washed with ether and dried to give a powder of 3-(3-fluorophenyl)-1,3-S dihydro-l'-methylspiro[benzo(c)thiophene-1,4'-piperidine~ maleate, m.p. 137-140C. A twice recrystallized portion melts at 138.5-140.5~C. Upon continued heating, a new crvstalline form develops which collapses in the 175-180C. rang~.
Analysis:
Calculated for ClgH2~JS-C4H4O4: 64.32%C; 5.637~; 3.26~/~J; 4.42%F.
Found:64.26%C; 5.5~,'DH; 2.95V/oIl; 4.58%F.
~xample 56 To 3.26 ~, of the free base 3-(2,4-dichlorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine] ethylene ketal of Example 54 in 30 rnl of warm ethanol is slo~ly added 30 ml of 3N hydrochloric acid. The mixture is heated over a steam bath for 45 minutes. 10 ml of additional ethanol is added and heatin~ is resu~ed for 45 minutes.
The reaction is then cooled to room temperature and basified with 40% aqueous sodium hydroxide solu~ion. The mixuture is diluted with 200 ml of water and extracted with three ~0 r.ll portions of dichlorothane, The combined dichlorometh~ne extracts are washed with two lOOr~
portions of water, one 50 ml portion of saturated aqueous sodiu~
chloride solution and dried over magnesium sulfate to an oil. The oil is 11~298S
dissolved in ether, filtered through celite, and treated with ethereal maleic acid to form a salt. The salt is washed well with ether and recrystallized from acetone-ether to give a white powder of 3-(2,4-dichlorophenyl)~
/ 3-(4-fluorobenzoyl)propyl 7-1,3-dihydrospiro/ benzo(c) thiophene-1,4'-piperidine 7 maleate, m.p. 124-127C.
A thrice recrystallized sample melts at 127-129C.
Analysis:
Calculated for C28H26Cl2FN~S C4H404:
60.96 % C; 4.80 % H; 2.22 % N; 11.25 % C1.
Found: 61.13 % C; 4.78 % H; 2.06 ~ N; 11.02 % Cl~
To 5.0 g of phenyl chloroformate in 80 ml of dichlo-romethane added 7.89 g of the free base, 3-(3-fluorophe-nyl)-1,3-dihydro-l'-methylspiro/ benzo(c)thiophene-1,4'-piperidine 7 of Example 55, in lO ml of dichloromethane over 20 minutes. The reaction mixture is stirred at room temperature for 21 hours, then diluted with 200 ml of dichloromethane. The resultant mixture is washed with two 175 ml portions of lO % aqueous sodium hydroxide solution, two 150 ml portions of water and one 70 ml portion of saturated aqueous sodium chloride solution, and dried over magnesium sulfate to give an oil. The oil is chromatograph ed on silica gel with dichloromethane to give an oil, which crystallizes to yield 3-(3-fluorophenyl)-1,3-dihydro-l'-phenoxycarbonylspiro/ benzo(c)thiophene-1,4'-piperidine 7, m.p. 134-142C. A portion is recrystallized twice from toluene: hexane, m.p. 144-146C.
29 -Analysis:
~12Z~85 Calculated for C2~H22FN02S: 71.58 % C; 5.29 % H; 3.34 % N.
Found: 71.60 % C, 5.33 % H, 3.22 % N.
To 6.97 g of 3-(3-fluorophenyl)-1,3-dihydro-1'-phen-oxycarbonylspiro/ benzo(c)thiophene-1,4'-piperidine 7 of Example 57 in 100 ml of ethylene glycol, under nitrogen, at 150C is added 16 g of 85 % potassium hydroxide pellets.
The reaction is stirred in a 160C bath for 45 minutes.
The solution is then poured into 225 ml of ice-water, diluted to 500 ml and extracted with three 175 ml portions of dichloromethane. The combined dichloromethane extracts are washed with ~00 ml portions of water and one 50 ml portion of saturated aqueous sodium chloride solution, and dried over magnesium sulfate to give a solid free base.
The free base in ether is treated with ethereal maleic acid to give a salt. The salt is washed with ether and recry-stallized from methanol-acetone-ether to give a white powder of 3-(3-fluorophenyl)-1,3-dihydrospiro/ ~enzo(c) thiophene-1,4'-piperidine 7 maleate, m.p. 188-188.5C.
Analysis:
Calculated for C18Hl8FNS:
63.61 % C, 5.34 ~ H; 3.37 % N; 4.57 % F.
Found: 63.53 % C; 5.37 % H; 3.31 % N; 4.45 % F.
To 2.75 g (9.19 mmols) of free base 3-(3-fluorophenyl)-1,3-dihydrospiro/~benzo(c)thiophene-1,4'-piperidine 7 of Example 58 in 47 ml of sieve-dried dimethylformamide is added 2.81 g of ~-chloro-p-fluorobutyrophenone ethylene ke-29 tal with 1.~2 g of potassium iodide and 1.82 g of sodium 11225~85 bicarbonate. The reaction is stirred at 65-90C for 20 hours; then diluted with 75 ml of chloroform, filtered and rotary evaporated at 75C to an oil. The oil is parti-tioned between 125 ml of dichloromethane and 85 ml of water. A lO ml portion of saturated aqueous sodium bicar-bonate is added and the solutions separated. The organic layer is washed with one 80 ml portion of water and one 30 ml portion of saturated aqueous sodium chloride solution and dried over magnesium sulfate to an oil. The oil is chromato~raphed on alumina with ether to give 3-(3-fluoro-phenyl)-1l~/ 3-(4-fluorobenzoyl)propyl 7-1,3-dihydro-spiro/ benzo(c)thiophene-1,4'-piperidine 7 ehtylene ketal.
Recrystallization from cyclohexane-pentane yields a sample which melts at 121.5-123C.
15 Analysis:
or C30H31F2N02S: 70.98 % C; 6.17 % H; 2-76 % N-Found:70.97 % C; 6.20 % H; 2.43 % N.
To 3.75 6 Of 3-(3-fluorophenyl)-l'-/ 3-(4-fluoroben-zoyl)propyl 7-1,3-dihydrospiro~ benzo(c)thiophene-1,4'-pi-peridine 7 ethylene ketal of Exampie 59 in 38 ml of ethanol is added 38 ml of 3N hydrochlorid acid. The reaction is refluxed for two hours and allowed to stand at room tempe-rature for 16 hours. The solution is diluted with lO0 ml of water and a few ml of 40 % aqueous sodium hydroxide solution are added to achieve a pH of ll. The mixture is then diluted with 175 ml of water and extracted with three 175 ml portions Qf dichloromethane solution. The combined 29 dichloromethane extract is washed with two 125 ml portions l~.Z~85 of water and one 60 ml portion of saturated aqueous sodium chloride solution and dried over magnesium sulfate to an oil. The oil, in ether, is treated with ethereal maleic acid, and the resulting salt washed with ether and recry-stallized from acetone ether to a white, crystalline powderof 1'-/ 3-(4-fluorobenzoyl)propyl 7-3-(3-fluorophenyl)-1,3-dihydrospiro-! benzo(c)thiophene-1,4'piperidine 7 maleate, m.p. 149-150.5C.
Analysis:
Calculated for C28H27F2NOS C4H404 66.31 % C; 5.39 % H; 2.42 % N; 6.56 % Fo Four.d: 66.35 % C; 5.54 ~ H; 2.14 % N; 6.61 ~ F.
To a solution of 3.10 g of the free base 1,3-dihydro-3-(4-methylphenyl)spiro/ benzo(c)thiophene-1,4'-piperidine 7 of Example 40 in 54 ml of dimethylformamide is added 3.21 g of the ~-chloro-p-fluorobutyrophenone ethylene ketal, 2.07 g of potassium iodide and 2.07 g of sodium bicarbonate.
The reaction mixture is stirred and heated at 65-90C 18 hours. The reaction mixture is diluted with 75 ml of chlo-roform, filtered, and evaporated to an oil. The oil is par-titioned between 150 ml of dichloromethane and 125 ml of water. The organic layer is washed with water and an aque-OU9 sodium chloride solution and then dried over MgS04:
The solution is filtered and evaporated to an oil which is column chromatographed on an Al203/Et2O. A sample of the resultant free base is converted to the oxalate salt of 1'-/ 3-(4-fluorobenzoyl)propyl 7-3-(4-methyl-phenyl)-1,3-29 dihydrospiro/ benzo(c)thiophene-1,4'-piperidine ~ eth l ~i2~85 ketal oxalate.
Analysis:
Calculated for C31H34FNO2S C2H24 66.76 % C; 6.11 % H; 2.36 % N.
Found: 66.85 % C; 6.12 % H; 2.32 % N.
A solution of 2.57 g of 1'-/ 3-(4-fluorobenzoyl)pro-pyl 7-1,3-dihydro-3-(4-methylphenyl)spiro/ benzo(c)thio-phene-1,4'-piperidine 7 ethylene ketal of Example 61, 27 ml 'O of absolute ethanol, and 27 ml of 3N HCl is heated on a steam bath for 45 minutes. The reaction is cooled, diluted with 75 ml of water, and taken to pH 11 using a 40 % aque-ous NaOH solution. The solution is diluted with 150 ml of water and extracted with dichloromethane. The CH2C12 fractions are combined, washed with water and brine, and dried over MgSO4. The dried CH2C12 solution is fi'ltered and evaporated to an oil which solidifies under pentane. The filtered product is recrystallized from ethyl acetate to give l '-! 3-(4-fluorobenzoyl)propyl 7-1,3-dihy-dro-3-(4-methylphenyl)spiro/ benzo(c)thiophene-1,4'-piperi-dine 7, m.p. 134-135C.
Ana lys is:
Calculated for C29H30FNOS: 75.78 % C; 6.58 % H; 3.05 % N.
Found: 75.61 % C; 6.67 % H; 3.07 % N.
To 6.87 g of 3~(4-chlorophenyl)-1)3-dihydrospiro/ ben-zo(c)thiophene-1,4'-piperidine 7 of Example 15 in a solu-tion of 33 ml of 2-butanone with 33 ml of dimethylformamide 29 is added 6.04 g of ~ -chloro-2,4-difluorobutyrophenone ethylene ketal followed by 6.5 g of sodium bicarbonate and 4.08 g of potassium iodide. The reaction is stirred at 75-80C for 18 hours, then 400 ml of ice-water is added and the mixture extracted with three 125 ml portions of ether. The combined ether extracts are washed with two 150 ml portions of water and one 30 ml portion of brine and dried over magnesium sulfate to yield an oil. The oil is chromatographed on 300 ml of alumina with ether to give an oil which eventually crystallizes to a product. A portion of the product is diluted with ether, treated with ethereal maleic acid to form the salt. The salt is recrystallized once from methanol-ether and once from acetone-ethyl aceta-te pentane to give 3-(4-chlorophenyl)-l'-/ 3-(2,4-difluoro-benzoyl)propyl 7-1 ,3-dihydrospiro! benzo(c)thiophene-1,4'-15 piperidine 7 ethylene ketal maleate, melting at 148-149C.
Analysis:
62.05 % C; 5.21 % H; 2.13 % N.
Found:61.94 % C; 5.01 % H; 2.16 % N.
To 8.21 g (15.15 mmols) of free base 3-(4-chlorophe-nyl)-l-! 3-(2,4-difluorobenzoyl)propyl 7-1 ,3-dihydrospiro ~ benzo(c)thiophene-1,4'-piperidine 7 ethylene ketal of Example 63 in 62 ml of warm 95 % ethanol is added 31 ml of 3N hydrochloric acid, slowly, to give a SUQpenSiOn. The reaction is stirred at room temperature for 3 hours and on a steam bath for 45 minutes. The reaction is then diluted with 400 ml of water and basified with ammonium hydroxide.
. 29 The aqueous mixture is extracted with two 150 ml portions 9~3S
of ether and two 250 ml portions of 1:1, ether: toluene.
Combined organic layers are washed with water and saturated aqueous sodium chloride solution and dried over magneQiUm sulfate to a brown oil. The oil is chro~tographed on silica gel with ether to give a solid. A portion of the product is recrystallized thrice from ether-pentane to give 3-(4-chlorophenyl)-1'-/ 3-(2,4-difluorobenzoyl)propyl 7-1,3-dihydrospiro/ benzo(c)thiophene-1,'~'-piperidine 7, melting at 98-100C.
Analysis:
Calculated for C28H26ClF2NOS: 67.52 % C; 5.26 % H; 2.81 % N.
Found: 67.25 g C; 5.4~ % H; 2.69 % N.
A mixture of l,3-dihydro-3-phenylspiro/ benzo(c)thio-phene-1,4'-piperidine 7 of Example 4 (3.75 g), 3.7 g of ~ -chloro-2,4-difluorobutyrophenone ethylene ketal, 2.5 g of Kl, 4.0 ~ of sodium bicarbonate in a mixture of 20 ml DMF
and 20 ml of 2-butanone is refluxed for 3 hours. The cooled mixture i9 diluted with water, extracted three times with ether and the washed, dried ether solution concentrat-ed to an oily residue. The residual is purified by passing through an alumina column. Elution with ether affords the tertiary amine which is converted to a crystalline maleate of l'-/ 3-(2,4-difluorobenzoyl)propyl 7-1,3-dihydro-3~phe-nylspiro/ benzo(c)thiophene-1,4'-piperidine 7 ethylene ketal maleate, m.p. 171-172.5C.
Analysis:
- 30H31F2N02S 4H404:
29 65.47 % C; 5.66 % H; 5.14 % S.
112~g85 Found: 65.21 % C; 5.68 % H; 5.36 % S.
A solution of 5.0 g of the free base 1'-/ 3-(2,4-di-~luorobenzoyl)propyl 7-1,3-dihydro-3-phenylspiro/ benzo(c) thiophene-1,4'-piperidine 7 ethylene ketal of Example 65 in 20 ml of 3N HCl and 20 ml of water is allowed to stand at room temperature for 3 hours. The excess acid and solvents are removed under pressure at 60C, the residue is basifi-ed with concentrated NH40H. The liberated oil is taken up in ether, washed and dried. Removal of solvents yields a clear oil which is converted to a crystalline maleate in ether of l'-/ 3-(2,4-difluorobenzoyl)propyl 7-1,3-dihydro-3-phenylspiro/ benzo(c)thiophene-1,4'-piperidine 7 maleate, m.p. 134-135C.
15 Analysis:
or C2gH27F2N0s C4H404 66.67 % C; 5.39 % H; 5.53 % S.
Found: 66.21 % C; 5.36 % H; 5.79 % S.
EX~MPLE 67 To 5.60 ~ of the free base 1'-/ 3-(4-fluorobenzoyl)-propyl 7-3-t3-methylphenyl)-1,3-dihydrospiro/ benzo(c)thio-phene-1,4'-piperidine 7 ethylene ketal of Example 50 in 56 ml of warm ethanol is slowly added 56 ml of 3N hydro-chloric acid. The reaction is refluxed for 45 minutes, then cooled to room temperature, basified with a small amount of 40 % aqueous sodium hydroxide, and diluted with 350 ml of water. The solution is extracted with three 15Q ml portions of dichloromethane. The combined dichloro-- 29 methane extract is washed with two 2ao ml portions of w~ter, -- 7~ --one 75 ml portion of brine and dried over magnesium sulfate to give an oil. The oil is dissolved in ether, filtered, and treated with ethereal hydrogen bromide to form a salt.
The salt is washed with ether and recrysta'lized from me-thanol-acetone-ether to give a powder o. 1'-/' 3-(4-fluoro-benzoyl)propyl-1,3-dihydro-3-(3-methylphenyl)spiro/ benzo (c)thiophene-1,4'-piperidine 7 hydrobromide which shrinks to a gel at 190-195C and melts to a dark fluid at 217-218C.
Analysis:
Calculated for C29H30FNOS HBr 64.44 % C; 5.78 % H; 2.59 % N; 3.52 % F.
Found: 64.30 % C; 5.79 % H; 2.48 % N; 3.56 % F.
.
1,3-dihydro-1'-methyl-3-(2-r.~ethoxyphenyl)spiro[benzo-(c)thiophene-1,4'-piperidine];
l'-benzoylpropyl-1,3-dihydro-3-phenylspiro[benzo-(c)thiophene-1,4'-piperidine];
l'-benzoylpropyl-1,3-dihydro-3-phenylspiro[benzo(c)-thiophene-1,4'-piperidine]ethylene ~;etal;
1'-(4-fluorophenethyl)-1,3-dihydro-3-phenylspiro-~ben20(c)thiophene-1,4'-piperidine]; and 1,3-dihydro-1'-(3,4-dimethoxyphenyl)propyl-3-phenyl-spiro~benzo(c)thiophene-1,4'-piperidine].
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112;~85 ether-21~ hydrochloric acid mixture and then permitted to stand at a lowered temperature for two hours. The cooled mixutre is filtered to collect its crystalline product. The product is recrystallized from an acetone-ether ni~cture to ~,ive colorless S prisms, mp 182-1~4C. of 4-benzylthio-4-(7-fluorophenyl)l-methylpiperidine hydrochloride.
c. A ~ixture of 0.9 g of 50% ~sodium hydride in 20 ml of dimethvlsulfoxide is heated at ~0-35C. in a nitrogen atmosphere for 30 minutes to produce a solution of sodiu~ methylsulfinvl-methide. This solution is permitted to cool to ambient tem~erature. ~ solution of 4.9 g of 4-benzvlthio-4-(2-fluorophenyl)-l-methylpiperidine, free base of b, in 10 ml of dimethylsulfoxide is added over a 5 ~inute span. After total addition, the mixture is stirred at ambient temperature for one hour and then poured onto ice-water. The resulting solid, collected by filtration, is recrystallized from an ether-hexane mixture to r,ive colorless prisms, mp 120-121c., of 1,3~dihydro-l'-methyl-3-phenylspiro[benzo(c)thiophene-1,~'-piperidine].
Analysis:
Calculated for C191~21~1S: 77.24%C; 7.17%~ -74%~ 0.35%S.
Found: 77.31%C; 7.20%11; L.59'l~; 10.71V,/S.
d. IJith the suhstit~ltion of l-methyl-3-pyrrolidone for l-methyl-4-piperidone into the manipulative procedure of Method ~, 3-(7-fluorophenyl)-3-hydroxv-l-metllylpyrrolidine may be obtained. , e. Starting with 3-(2-fluorophenvl(-3-hydroxy-1-methylpyrrolidine, the manipulative procedures of Method A may be implemented to provide 1,3-dihydro-1'-me~hyl-3-phenylspiro-[benzo(c)thiophene-1,3'-pyrrolidine].
. -- ~8 - f. lhe substitution of l-benzyl-3-pyrrolidone for l-methyl-3-pyrrolidone into the manipulative procedures of E~cample ld and le may provide l'-benzvl-1,3-dihydro-3-phenyl-spiro~benzo(c)thiophene-1,3'-pyrrolidine], g. I~i.h the substitution of l'-~ethyl-3-piperidone for l-methyl-4-piperidone into the manipulative procedure of Example la, 3-(2--luorophenyl)-3-hydroxy-1-nethylpiperidine may be obtained.
h. Starting with 3-(2-fluorophenyl)-3-hydroxy-1-methylpiperidine, the ~anipulative procedures of Example lb and lc may be i~plemented to provide 1,3-dihydro-1'-~ethyl-3-phenylspirolbenzo~c)thiophene-1,3'-piperidine].
Example 2 a. 9.9 ~1 (11.~ g~ of 4-chloroben7,yl mercaptan and 11.1 ml of boron trifluoride etherate are added sequentially to 5.00 g of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine.
ExAmple la, in 11.1 ml of glacial acetic acid. The reaction is stirred at 55-fi~C. for 48 hours. The e~ccess rea~,ents are remoYed at 80C. in vacuo and the residue is tal;en up with a 1:1 ether-21~ hydrochloride acid mixture. This biphasic mixture is stirred for 2.5 hours and then for an ~dditional ten minutes a~ter 50 ~1 of ice are added. The ether layer is decanted off. The aqueous layer is sequentially washed with ether and filtered to collect a crude product. The product is washed with a small portion of water and then a large portion of ether to give a white powder. The powder is recrystallized from acetone to give white crystals, mp 164-166C.
of 4-(4-chlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine ,9 hydrochloride.
Analysis:
Calculated for ClgH21NClFS HCl: 59~08%C; 5~74~H; 3~63~; 4~92%E
Found: 59~04ZC; 5~56%H; 3~68~o~; 4~78%E
b, A solution of sodium methylsulfinylmethide is produced from 0.7 g of (50%) sodium hydride and 15 ml of dimethylsulfoxide as in Example lc. A solution of 4.2 g of 4-(4-chlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine, free base of a, in 15 ml of dimethylsulfoxide is added to tiliS
solution over a three m,inute span. After total addition, the ~ixture is stirred at ambient temperature for one hour and thcn poured onto 70 ml of ice-water. The mixture is diluted with water to 1~0 ml total volume before being filtered to collect the crude product. The product is washed with water and then dissolved with ether. The ethereal solution is sequentially washed thrice with water and once Wit]l a saturated sodium chloride solution and dried to give yellow-white crystals. Tlle crystals are chromato~raphed with ether ~lrough an alumilla column to give white crystals, mp 121-123C of 3-(4-chlorophellyl~
1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine~.
Analysis:
Calculated for ClgH20Cl~S: 69.19,.C; 6.11%ll; 4.25Y.N; 10.75~Cl.
Found: 69.24%C; 6.21%~; 3.96~; 10.74~Cl Example 3 ~ A mi~ture of 2.3 g of 1,3-dihydro-1'-methyl-3-pilenyl-spirotbenzotc)thiophene-1,4'-piperidine], Example 1, 1.4 g of phenyl chloroformate and 0.5 g of sodium bicarbonate in 40 ml of methylene chloride is stirred at ambient temperature for 4 hours before being filtered. The filtrate is sequentially washed with a dilute sodium hydroxide solution and water a~ld 112'~5 dried. The solvent is removed in vacuo, leaving a solid residue which is recrystallized from a benzene-hexane mixture to give rosettes, mp 171-173C, of 1,3-dihydro-1'-phenoxycarbonyl-3-phenylspiro~ benzo(c)thiophene-1,4'-piperidine 7.
Analysis:
Caluclated for C25H23N02S: 74.78 % C; 5.77 % H; 3.49 % N.
Found: 75.04 % C; 5.84 % H; 3.43 % N.
a. A mixture of 3.0 g of 1,3-dihydro-1'-phenoxycar-bonyl-3-phenylspiro/ benzo(c)thiophene-1,4'-piperidine 7, Example 3, 8.0 g of potassium hydroxide pellets in 50 ml of ethylene glycol is stirred at 155C until a clear solu-tion results. The solution is permitted to cool, diluted with water and the biphasic mixture extracted thrice with chloroform. The combined chloroform extracts are washed carefully with water and dried and the chloroform removed leaving a solid residue. The residue is recryQtallized from an acetone-hexane to ~ive prisms, mp 142-144C of 1,3-dihydro-3-phenylspiro/ benzo(c)thiophene-1,4'-pipe-ridine 7.
Analysis:
Calculated for Cl8HlgNS:
76.83 % C; 6.80 % H; 4.98 % N; 11.39 g S.
Found: 77.05 ~ C; 6.84 % H; 4.68 % N; 11.26 % S.
1~2Z985 A mixture of 2.8 g of 1,3-dihydro-3-phenylspiro/ ben-zo(c)thiophene 7, Example 4a, 1.4 g of benzyl chloride and 3.5 g of sodiu~. bicarbonate in 50 ml of dimethylform-amide is stirred at 70C for two hours. Water is added to the cooled mixture and the biphasic mixture is extract-ed four times with methylene chloride. The methylene chlo ride extracts are dried and concentrated in vacuo leaving an oily residue which crystallizes in standing. The product is recrystallized from an ether-hexane mixture to give fine needles, mp 144-145C of 1'-benzyl-1,3-dihydro-3-phenyl-spiro/ benzo(c)thiophene-1,4'-piperidine 7.
Analysis:
Calculated for C25H25NS:
80.82 % C; 6.78 % H; 3.78 % N; 8.63 % S.
Found: 60.81 % C; 6.68 % H; 3.65 % N; 8.76 % S.
EXAMPL~ 6 A mixture of 3.9 g of 1,3-dihydro-3-phenylspiro~ benzo (c)thiophene-1,4'-piperidine 7, Example 4, 3.4 g of diben-zoyl peroxide, 4.0 g of potassium carbonate in 60 ml of benzene is stirred at a temperature of 65-70C for 16 hours before being filtered. The filtrate is washed and dried and the solvent removed in vacuo, leaving a crude oily product. The product is chromatographed through a silica gel column with a methylene chloride eluant to provide l'-benzoyloxy-1,3-dihydro-3-phenylspiro/~benzo(c)thiophene-1,4'-piperidine 7.
Analysis:
Calculated for C25H23N02S: 74.7& ~ C; 5-77 ~ ~; 3-48 g ~-29 Found: 74.67 ~ C; 5.82 % H; 3~33 ~ N.
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1~L2Z~85 a. A salllple of 2-brano-1 ,4-difluor~benzLne is tredted according to the multi-step procedure of Exdm~le 1~ to ultimdtely obtain 4-(2,5-difluorophenyl)-4-hydroxy-1-methylpiperidine, which is converted to its mdleic acid salt which is recryst211ized from an acetone-eth-er mixture to obtain the pure salt, m.p. 163-165~C.
b. A mixture of 4-(2,5-difluorophenyl)-4-hydroxy-l-methyl-piperidine, free base of a, 4 ml of boron trifluoride etherateJ 5 ml of benzyl mercaptan dnd 5 ml of glaci~l dcetic ~cid is stirred at 65C for 16 hours. Excess acid is removed under reduc~d pressure with the residue equilibrated with 0.5N hydrochloric dCid and ether and the resulting solution is stirred dt 10-20C tor four hours. The resulting crystalline precipitdte is sequentidlly collected by filtrdtion, bdsified and ~xtrdcted with ether l)rovidiny the desired product as an oil. The oil is converted to itS IlldleiC
acid sdlt which is recrystdllized from dn acetone-ether mixture tu provide prisms, m.p. 164-166C of 4-benzyl thio-4-(2 ,S-difluoro-phenyl)-l-methylpiperidine maledte.
c. A solution of sodiunl nle~hylsulfinylll~t;hidL which u,as prepared by hedting 250 mg of sodium hydride (50~ dis~ersion, wdshed with pentdne) in 10 ml of dimethylsulfoxide 3t ~0C fùr 30 minu~es is added o~er a five-minute spdn dt dmbient temperdture to d mixture of 4-benzylthio-4-(2,5-difluorophenyl)-1-methylpiperidine, fr~e bdse of b, in 5 ml of dilnethylsulfoxide. After totdl dddition, the mixture is stirred dt ambient temperdture for 30 minutes before being poured onto 50 g of ice water. The mixture is extracted thrice with methylene chloride and the combined extracts are washed with water and dried. The methylene chloride is re~oved under vacuum, leaving a solid residue. The residue is recrystallized fron an ether-pentane mixture to give granular crystals, m.p.
136-317C. of 6-fluoro-1,3-dihydro-1'-methyl-3-phenylspiro-~benzo~c)thiophene-1,4'-pi~eridine].
Analysis:
Calculated for C19H20FtlS: 72.81%C; 6.42~/~11; 4.47~ ; 6.06%F; 10.23C/~S
Found: 72.52%C; 6.46%H; 4.27V/~; 5.88%~; 10.49%S
, Example ~1 A mixture of 0.3 ~ of 6-fluoro-1,3-dihydro-1'-rnethyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidin~] and 0.3 g of phenyl chloroformate in 10 ml of meth~lene c~lloride which was ~reviously stirred at ambient temperature for 16 hours is sequentially ~uenclled ~ith ~tater, washed with 10% sodium hydroxide and dried. The reaction mixture is concentrated under vacuu~
leaving a viscous oii ~hich crvstallized wi~h standing. The solid product is recrystallized from an ether-pentane mixture to ~ive prisms, m.p. 156-15~C. of 6-~luoro-1,3-dihydro-3-phenyl-l'-phenoxycarbonyl~.piro[benzo(c)thiopllene-1,4'-piperidine].
Analysis:
Calculated for C25H22F~IO~S: 71.57%C; 5.?9~ ; 3.34~/~.
Found: ~ 71.65%C; 5.33~,'H; 3.15 ~xample 22 A solution of 2.5 ~, of 3-(3,4-dichlorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine], free base of Example 19, and 1.3 g of phenyl chloroformate in 30 ml of methylene chloride is stirred at ambient tem~erature for 16 hours. The wel stirred solution is washed successively ~ith dilute sodium hydroxide and water and then dried, effecting a crystallin~ product. The product is recrystallized from an acetone-pentane mixture to give fine needles, m.p. 200-202C.
of 3-(3,4-dichlorophenyl)-1,3-dihydro-1'-phenoxycarbonyls~iro-! [benzo(c)t~iophene-1,4'-piperidine].
Analysis:
Calculated for C2s~I21C12~02S
Found:63~ 71%C; 4.56,'I~; 2. 93%N~
Example 23 a. ~2 ml of boron trifluoride etherate are added to a mixture of 30~ 0 g of 4-(2-fluorophenyl)-4-hvdroxy-1-methvl-piperidine of ~xample la and ~2 ~1 of ~.-methylbenæyl mercaptan.
The resultin~, solution is stirred and heated at 75C. for six hours and then the excess reagents sre distilled at 80-100C.
The oil re~ainin~, in the flasl; is stirred with 250 ml of 2~1 HCl and 500 ml of ether for one hour after which 1500 ml of ice is added to form a slurry. The slurry is stirred an additional hour a~d filtered to yield a white solid which is washed with ether and air dried. The material is recrystallized fro~ methanol-acetone-ether to give the ~r,oduct, 4-( -fluorophenyl)-l-methvl-4-(2-methvlbenzylthio)piperidine 1 1 Z25~8S
hydrochloride. An elemental analysis sample was further recrystallized from acetone-ether to give a sample with constant melting point of 206 - 208C.
Analysis:
Calculated for C20H24FNS HCl: 65.64 % C; 6.89 % H; 3.83 % N
Found: 65.46 % C; 6.82 % H; 3.55 % N.
b. A 0.73 g sample of sodium hydride, 50 % in mine-ral oil, is cleaned by triturating with hexane. To the cleaned sodium hydride, is added 20 ml of dimethylsulfoxide and the solution heated in an oil bath at 80 - 90C for 30 minutes. The solution is cooled to room temperature and 4.05 g of 4-(2-fluorophenyl)-1-methyl-4-(2-methylbenzyl-thio)piperidine of Example 23a in 15 ml of dimethylsulf-oxide is added over a 5-minute period. The reaction is stirred for thirty minutes, poured into 100 ml of ice-wa-ter, and filtered. The resulting tan solid i9 dissolved in dichloromethane and chromatographed on an A12C3/ether column (eluting with ether) m.p. 132 - 143C. The sample is recrystallized from ether-hexane to obtain 1,3-dihydro-1'-methyl-3-(2-methylphenyl)spiro! benzo(c)thiophene-1,4'-piperidine 7, m.p. 132 - 134C.
Analys i9:
Calculated for C20H23NS: 77.62 % C; 7.49 Z H; 4.53 % N.
Found: 77.63 Z C; 7.67 % H; 4.35 % N.
A suspension of 3-(3,4-dichlorophenyl)-1,3-dihydro-~l'-phenoxycarbonylspiro/ benzo(c)thiophene-1,4'-piperidine 7 (2.35 g), 7.0 g of potassium hydroxide (85 %) in 30 ml of 29 ethylene glycol is stirred at 160C for 30 minutes. The 112~85 mixture is cooled, diluted with water and extracted with 3 portions (tO0 ml) of dichloromethane. Following drying (MgS04) and evaporation in vacuo, the crude amine is con-verted to a crystalline maleate in ether. Recrystalliza-5 tion from methanol-ether gives rhombic crystals of 3-(3,4-dichlorophenyl)-1,3-dihydrospiro/ benzo(c)thiophene-1,4'-piperidine 7maleate m.p. 192 - 193C.
Analysis:
d for C1gH~7Cl2NS C4H404 56.65 % C; 4.54 % H7 3.00 % N; 15.20 % Cl.
Found: 56.75 Z C; 4.51 % H; 2.88 % N; 14.91 % Cl.
A mixture of 1.5 g of the free base 3-(3,4-dichloro-phenyl)-1,3-dihydrospiro/ benzo(c)thiophene-1,4'-piperi-15 dine 7 of Example 24, 1.3 g of ~chlorobutyrophenone ethy-lene ketal, 0.9 g of potassium iodide, 0.9 g of sodium bi-carbonate in 15 ml of anhydrous dimethylformamide is stir-red at 80C for 16 hours. The mixture is diluted with ice-water and extracted three times with CH2Cl2. The CH2Cl2 20 solution is dried (K2C03) and concentrated in vacuo to an oily residue. Purification is carried out by column chro-matography (alumina-ether) and upon treatment with ethere-al-HBr, a crystalline hydrobromide is obtained with simul-taneous cleavage of the ketal ring. Recrystallization of 25 the granular hydrobromide from methanol ether gives color-less crystals of 3-(3,4-dichlorophenyl)-~'-/ 3-(4-fluoro-benzoyl)propyl 7-1,3-dihydrospiro/ benzo(c)thiophene-- 1,4'-piperidine 7hydrobromide.
:1~122~85 Analysis:
for C28H26cl2FNos HBr:
56.47 % C; 4.57 % H; 2.23 % N
Found:56.43 % C; 4.59 % H; 2.31 % N.
A mixture of the free base 3-(3,4-dichlorophenyl)-1,3-dihydrospiro/ benzo(c)thiophene-1,4'-piperidin~ 7 of Ex-ample 24 (2.0 g), of ~-chloro-4-fluorobutyrophenone ethy-lene ketal, 0.9 g of sodium bicarbonate, 0.9 g of potassium iodide in 15 ml of anhydrous DMF is stirred at 80C for 16 hours. The cooled mixture is diluted with water and ether and the layers are separated. The organic solution is washed with water, dried (MgS04) and concentrated to an oily residue in vacuo. Purification of the crude product is accompli~hed by passing through a short alumina-ether column. Elution with ether gives a pale yellowish oil which is converted to a crystalline maleate in ether. Re-crystallization from acetone-ether gives granulars, m.p.
116 - 119C of 3-(3,4-dichlorophenyl)-1'-! 3-(4-fluoroben-zoyl)propyl 7-1,3-dihydrospiro/ benzotc)thiophene-1,4'-piperidine 7 ethylene ketal maleate.
Analysis:
60.5~ % C; 5.08 % H; 2.08 % N.
Found:60.53 % C; 5.05 % H; 1.86 % N.
a. A mixture of 4-(-2-fluorophenyl)-4-hydroxy-1-me-thylpiperidine of Example la (10.5 g), 10 g of p-fluoroben-29 zyl mercaptan, 18 ml of boron trifluoride etherate and 10 llZZ~?85 ml of glacial acetic acid is stirred at 60 - 65C for 16 hours. The excess reagents are removed under reduced pressure at 100C and the oily residue is triturated with an exces, of 0.5 N hydrochloric acid and 200 ml of ether.
A white precipitate is filtered after 2 hours at 5 - 10C
and is basified to give the desired product. The oily amine is converted to a crystalline maleate in ether, re-crystallized from methanol-ether gives colorless prisms, m.p. 123 - 125C of 4-(4-fluorobenzylthio)-4-(2~fluorophe-nyl)-l-methylpiperidine maleate.
Analysis:
19 21 2NS 4H404:
61.45 % C; 5.61 % H; 3.12 % N.
Found: 61.71 % C; 5.75 % H; 3.15 % N.
b. A solution of sodium methylsulfinyl methide is prepared by heating 0.87 g of sodium hydride in 80 ml of dimethylsulfoxide at 80OC for 30 minutes. The solution is then treated with 8.9 g of the free base 4-(4-fluorobenzyl-thio)-4-(2-~luorophenyl)-1-methylpiperidine of Example 27a in 20 ml of DMS0 over 2 minutes and stirring continued for 15 minutes at 80C before quenching with ice-water. The mixture is extracted 3 times with CH2C12, the combined CH2C12 solution washed with water and dried, and concen-trated to an oily residue. Purification of the crude product is carried out by column chromatography (alumina-ether) and concentration of the combined effluent affords a heavy oil which crystallizes on cooling. Recrystalliza-tion from ether-pentane gives long needles, m.p. 109 -29 110C, of 3-(4-fluorophenyl)-1,3-dihydro~ methylspiro-112~9~3~
/ benzo(c)thiophene-1,4'-piperidine 7.
Analysis:
Calculated for ClgH20FNS
72.81 ~ C; 6.43 ~ H; 4.47 % N; 6.38 % F.
Found: 73.05 % C; 6.31 % H; 4.58 ~ N; 6.23 % F.
A mixture of 3-(4-fluorophenyl)-1,3-dihydro-1'-me-thylspiro/ benzo(c)thiophene-1,4'-piperidine 7 of Ex-ample 27 (3.6 g), 2.1 g of phenyl chloroformate in 100 ml of CH2C12 is stirred at room temperature for 64 hours.
The solution i9 washed with 10 % aqueous NaOH, water, and dried over MgSO4. Evaporation under reduced pressure affords a crystalline residue, m.p. 198 - 200C. Recry-stallization of the crude product from acetone-pentane gives granular crystals, m.p. 200 - 201C of 3-(4-fluoro-phenyl)-1,3-dihydro-1'-phenoxycarbonylspiro /benzo(c)thio-phene-1,4'-piperidine 7.
Analysis:
Calculated for C25H22FN~2S: 71.57 % C; 5.28 % H; 3.34 % N.
Found: 71.73 % C; 5.25 % H; 3.20 % N.
__ A mixture of 3-(4-fluorophenyl)-1,3-dihydro-1'-phen-oxycarbonylspiro/ benzo(c)thiophene-1,4'-piperidine 7 of Example 28 (4 3 g), 1.4 g of potassium hydroxide in 50 ml of ethylene glycol is stirred at 160C for 30 minutes.
The cooled mixture is diluted with water and extracted three - times with 150 ml portions of ether. The combined ether extract is washed with water (3 - 4 times), dried, and con-29 centrated to an oily residue of secondary amine. The se-1122~1~5 condary amine is converted to its hydrochloride in a con-ventional manner by stirring without heating with hydro-chloric acid for several hours. Recrystallization from methanol-acetone-ether gives crys~als, m.p. 259 - 260C of 3-(4-fluorophenyl)-1,3-dihydrosplro /benzo(c)thiophene-1,4'-piperidine 7 hydrochloride.
Analysis:
Calculated for C18H18FNS HCl:
64.36 % C; 5.70 % H; 4.17 % N; 5.65 % F.
Found: 64.09 % C; 5.55 % H; 4.28 % N; 5.78 % F.
EXA~PLE 30 A mixture of 3-(4-fluorophenyl)-1,3-dihydrospiro-/ benzo(c)thiophene-1,4'-piperidine 7 (2.2 g of the free base of Example 29) 2.2 g of 3~-chloro-4-fluorobutyro-phenone ethylene ketal, 1.5 g of sodium bicarbonate, 1.5 gof potassium iodide in 25 ml of DMF is stirred at 80C for 16 hours. The cooled mixture is quenched with water, ex-tracted 3 times with ether and dried. Removal of the sol-vent in vacuo at 80C leaves a reddish oil which is puri-fied by passing through a short column of alumina packed inether. Elution with ether gives a pure tertiary amine which is converted into a crystalline maleate. Recrystal-lization from acetone-ether affords colorless prisms, m.p.
175 - 177C of 1'-/ 3-(4-fluorobenzoyl)-propyl 7-3-(4-fluorophenyl)-1,3-dihydrospiro ~enzo(c)thiophene-1,4'-piperidine 7 ethylene ketal maleate.
Analysis:
ated for C30H31F2No2s C4H404:
65.46 % C; 5.64 % H; 2.24 ~ N.
Found: 65.28 % C; 5.71 ~ H; 2.21 % N.
~:lZZ~85 Example 31 A solution of 1'-[3-(p-fluorobenzoyl)l~ropyl]-3-(4-fluorophenyl)-1,3-dihydro-spiro[benzo(c~tlliophene-1,4'-piperidine] ethylene l;etal of Example 30 (2.3 g of the free 5 base) in 200 ml of ether and 10 ml of methanol is saturated with anhydrous hydro~,en bromide. After standing at room temperature for 2 hours, the mixture is carefully neutraliæed with 1~l ammonia and the ether solu~ion is washed 3 times with water, dried and concentrated to an oily residue. The free 10 base is con~Terted to a crystalline maleate in ether and recrystalli7.ation from acetone-ether gives off-white prisr.ls, m.p. 149-150C., of 1'-~3-(4-fluorobenæoyl)~ropyl]-3-(4-fluoroph~nyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4~-piperidine maleate.
15Analysis:
C28H27F2~0S.Cl~H4O4: ~;~.31r/~,; 5.40~/~; 2-42V~ 55~F
Found: ~)6~41%C; 5.22~H; 2.36~ .64 ~.xample 32 a. 59.7 g of 2-chlorobenzylmercaptan, followed by 55 ml of boron trifluoride etherate are added to ?.5 ~, of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine of ~ample la in 55 ml of acetic acid. The reaction is stirred at 55-fi5C. for 20 hours.
The excess acid is removed under reduced pressllre at 80-100C.
The oily residue is then equilibrated ~Jith 200 ml of 2I~
25 hydrochloric acid and 200 ml of ether. The etiler, and two more 125 ml portions of ether, is decanted off. The oil and water mixture i~
112Z~85 diluted to 650 ml volume with water and is stored at 0C
for about three days to produce crystals. The mixture is diluted and filtered. The precipitate is washed with water and ether, and dried. The solld is recrystallized (acetone:ether) to a broad melting (122 - 129C) solid.
A portion of the solid is placed in water, basified with 10 % aqueous NaOH, extracted into ether, washed,dried and treated with ethereal hydrogen chloride to give a white powder. The powder is recrystallized from acetone-ether to give a white crystalline solid, m.p. 173 - 175C of 4-(2-chlorobenzylthio)-4-(2-fluorophenyl)-t-methylpiperi-dine hydrochloride.
Analysis:
Calculated for C19H2lClFNS:
59.08 % C; 5.74 % H; 3.63 % N; 4.92 % F.
Found: 58.81 % C; 5.63 % H; 3.37 % N; 5.03 % F.
b. A 0.2 g sample of sodium hydride, (prepared by washing a 50 % oil dispersion) is heated at 80C with stir-ring in 15 ml of dimethylsulfoxide for 30 minutes. Then 2.1 g of the free base 4-(2-chlorobenzylthio)-4-(2-fluoro-phenyl)-l-methylpiperidine of Example 32a in 10 ml of dry DMS0 is added in one portion and the oil bath is removed.
The reaction is allowed to stir without heating for 40 mi-nutes, then is poured onto 250 cc of ice with 250 ml of ether. The layers are shaken and separated and the aque-ous portion extracted again with 150 ml of ether. The com-bined ether is washed with two 100 ml portions of water and one 10 ml portion of saturated sodium chloride solu-~ 29 tion, and is dried over magnesium sulfate to give an oil.
2~85 The oil is chromatographed on a column of alumina with ether to a material (free base) showing one spot (Rf û.54;
25 % MeOH: CH2Cl2, silica) by tlc. The product in ether is treated with excess e.hereal maleic acid, washed witn 5 ether, and dried to give a white powder, m.p. 173 - 176C, of 3-(2-chlorophenyl)-1,3-dihydro-1'-methylspiro/ benzo(c)-thiophene-1,4'-piperidine 7maleate.
A small portion of the salt is recrystallized twice from acetone to give crystals melting at 178 - 178.5C.
Analysis:
Calculated for C19H20ClNS-C4H4O4:
~1.95 % C; 5.43 % H; 3.14 % N; 7.95 % Cl.
Found: 62.03 % C; 5.46 % H; 3.10 % N; 7.94 % Cl.
a. A mixture of 4-(2-fluorophenyl)-4-hydroxy-1-me-thylpiperidine of Example la (15.8 g), 12 ml of 2-fluoro-benzyl mercaptan and 20 ml of boron trifluoride etherate in 15 ml of glacial acetic acid is stirred at 65 - 70C
for 16 hours. The excess reagents are removed under re-20 duced pressure, the residue is triturated with 300 ml of 0.5 N HCl and 100 ml of ether. After standing at 5 - 10C
for 30 minutes, a crystalline precipitate is filtered, air driea and made basic with lO % aqueous NH40H. The liberat-ed amine is taken up in ether, dried and concentrated to a 25 yellowish oil which is then converted to its maleate in ether, recrystallization of the crude salt from methanol-ether gives colorless prisms, m.p. 153 - 154C of 4-(2-fluorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine - 29 maleate.
112Z~85 Analysls:
Calculated for C~gH21F2NS-C4H404 61.45 % C; 5.61 % H; 3.12 % N.
Found: 61.28 % C; 5.57 % ~; 2.98 % N.
b. A solution of sodium methylsulfinyl methide is prepared by heating 1.2 g of sodium hydride in 100 ml of DMS0 at 80C for 30 minutes. The mixture is cooled to room temperature and to it is added 12 g of the free base 4-(2-fluorobenzylthio)-4-(2-f'uorophenyl)-1-methylpiperi-dine in 40 ml of DMS0 over a period of 5 minutes. Follow-ing the addition is stirred at 70 - 80C for an additional 30 minutes, The mixture is d~luted with ice-water, ex-tracted 3 times with ether. lhe combined ether solution is washed 4 times with water, dried and concentrated to a thick oil. Chromatography over Al203-ether removes a small amount of impurities and the purified amine is con-verted to a crystalline hydrobromide in ether. Recrystal-lization from methanol-ether gives colorless crystals, m.p. 263 - 265C (dec.) of 3-(2-fiuorophenyl)-1,3-dihydro-l'-methylspiro-/ benzo(c)thiophene-1,4'-piperidine 7 hydrobromide.
Analysis:
Calculated for ClgH20FNS'HBr:
57,86 % C; 5.37 % H; 3.55 % N; 4.82 % F.
Found: 57.67 ~ C; 5.47 % H; 3.58 % N; 4.80 % F.
A mixture of the free amine 3-(2-fluorophenyl)-1,3-dihydro-l'-methylspiro/ benzo(c)thiophene-1,4'-piperidine 7 ~ ~ ~ .
112~85 Example 33 (6.3 g), 3.9 g of phenyl chloroformate in 100 ml of anhydrous CH2C12 is stirred at room temperature for 4 hours. The reaction mixture is washed with 10 %
aqu*ous sodium hydride and dried over MgS04 for 2 hours.
Removal of solvent under reduced pressure leads to a thi~k oil which is purified through a short silica gel column packed in CH2C12. Elution with a large excess of CH2C12 gave, after concentration, a colorless oil which solidified on standing, to yield 3-(2-fluorophenyl)-1,3-di-hydro-l'-phenoxycarbonylspiro/ benzo(c)thiophene-1,4'-pi-peridine 7 m.p. 122 - 123C.
Analysis:
Calculated for C25H22FN02S:
71.57 % C; 5.28 % H; 3.34 % N.
Found: 71.49 % C; 5.23 % H; 3.27 % N.
A mixture of 3-(2-fluorphenyl)-1,3-dihydro-1'-phenoxy-carbonylspiro/ benzo(c)thiophene-1,4'-piperidine 7 of Example 34 (5.6 g), 18 g of potassium hydroxide in 100 ml of ethylene glycol is stirred at 170C for 30 minutes.
The mixture is poured into water and extracted 3 times with ether. The ether solution is washed with water, dried and concentrated in vacuo to give a viscous oil of free amine.
A crystalline maleate is prepared and recrystallized from methanol-acetone-ether to give a white powder of 3-(2-fluo-- rophenyl)-1,3-dihydrospiro/~benzo(c)thiophene-1,4'-piperi-dine 7 maleate.
Analysis:
29 Calculated for C1gH1gFNs;c4~4o4 ll~Z~85 - 44 _ 63.5~ % C; 5.34 % H; 3.37 % N; 4.57 % F.
Found:63.55 % C; 5.33 % H; 3.10 % N; 4.52 % F.
A mixture of 3-(2-fluorophenyl)-1,3-dihydrospiro/ ben-zo(c)thiophene-1,4'-piperidine 7 of Example 35 (2.2 g), 2.2 g of ~-chloro-4-fluorobutyrophenone ethylene ketal compound, 1.5 g of potassium iodide, 1.5 g of sodium bicarbonate in 25 ml of DMF is stirred at 70-75C for 16 hours. The cooled mixture is diluted with water and the mixture ex-tracted 3 times with ether. The ether solution, after washing with water and drying, is concentrated in vacuo to an oily residue which is purified through a short column of alumina, elution with ether gives a colorless oil which is converted to a crystalline maleate, m.p. 105-151C of 15 1'-/ 3-(4-fluorobenzoyl)propyl 7-3-(2-fluorophenyl)-1,3-di-hydrospiro/ benzo(c)thiophene-1,4'-piperidine 7 ethylene ketal maleate.
Analysis:
Calculated for C30H30F2N02S C4 4 4 65.46 % C; 5.64 % H; 2.24 % N.
Found: 65.46 % C; 5.37 % H; 2.12 % N.
A solution of 1'-/ 3-(4-fluorobenzoyl)propyl 7-3-(2-fluorophenyl~-1,3-dihydrospiro/ benzo(c)thiophene-1,4'-25 piperidine 7 ethylene ketal of Example 36 (2.0 g) in 20 ml - of ethanol and 20 ml of 3N hydrochloric acid is heated on a steam bath for 30 minutes. The cooled solution is basifi-ed with 40 % aqueous sodium hydroxide and extracted 3 : ~ 29 times with ether. The combined ether solution is washed 2~ ~ 5 thoroughly with water, dried and treated with an excess of ethereal maleic acid. A crystalline maleate is recrystal-lized from acetone-ether to give all-white prisms, m.p.
137-138.5C, of 1'-/ 3-(4-fluorobenzoyl)propyl 7-3-(2-fluorophenyl)-1,3-dihydrospiro/ benzo(c)thiophene-1,4'-piperidine 7 maleate.
Analysis:
Calculated for C2gH27F2N C4H404 66.31 % C; 5.40 ~ H; 2.42 % N; 6.55 % F.
Found: 66.18 % C; 5.34 % H; 2.42 % N; 6.49 % F.
A 4.5 g sample of phenyl chloroformate in 150 ml of dichloromethane is stirred at 25C while 7.5 g of 1.3-di-hydro-l'-methyl-3-(2-methylphenyl)spiro/ benzo(c)thiophene-1,4'-piperidine 7 of Example 23 in 75 ml of dichloromethane is rapidly added. The reaction is stirred a total of 24 hours at 25C and quenched with 225 ml of 10 % aqueous NaOH solution. The organic layer is separated, washed with water, dried over MgS04, filtered and evaporated to an oil. The oil is column chromatographed on a silica gel/
CH2C12 column with CH2C12 being used for elution.
The isolated product is a pale yellow oil of 1,3-dihydro-3-(2-methylphenyl)-1'phenoxycarbonylspiro/ benzo(c)thiophene-1,4'-piperidine 7.
25 Analysis:
26H25N02S: 75.15 % C; 6.06 % H.
Found:74.90 % C; 6.05 % H.
- ~12Z~85 Example 39 A solution of 16 g of potassiu~ hydro~ide dissolved in 100 ~1 of ethylene glycol is added tc 6.~ g of 1,3-dihydro-3-(2-methylphenyl)~ phenoxycarbonyls~iro[benzo(c)thiophene-1,4'-piperidine] of Exa~.ple 38. ~he re~ult ng solution is stirred and heated at 160C. for one hour. The solution is poured into 300 ml of ice water and extracted with ether. The ether fractions are combined, washed with water, dried over MgSO4, filtered, and evaporated to a residue which is converted to a white, granular, ~aleate salt, 1,3-dihvdro-3-(2-methylphenyl~s~iro[benzo(c)thiophene-1,4'-pi~eridine] maleate, which is recrvstallized from methanol-ether and has a ~.p.
178-179C.
Analysis:
ClgH21~S-C4H404: 67.13%C; 6.12%H; 3 40V~I
Found: 67.10%C; ~. 96~/oH; 3 ~14~/oN
~xample 40 A nixture of 6.0 g of 1,3-dihydro-3-(4-methylphenyl)-l'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-pi~eridine] of Exa~ple 13, 16.0 g of potassium hydroxide and 100 ml of ethylene glycol is stirred and heated at 160C. for one hour. The reaction mixture is quenched with ice water and e~tracted with ether. The ether extracts are combined, washed with water, dried over ~IgS04, and evaporated to an oil. The oil is converted to 1,3~dihydro-3-(4-methylphenyl)spiro[benzo(c)-thiophene-1,4'-piperidine] maleate. m.~. 214-215C.
.
Analysis:
Calculated for C19H21NS-C4H404~ 67.13 % C; 6.12 % H; 3.40 % N.
Found: 67.05 % C; 6.20 % H; 3.21 % N.
a. To 25 g of 4-(2-fluorophenyl)-4-hydroxyl-1-me-thylpiperidine of Example 1a is added 50 g of m-methylbenzyl mercaptan. To this mixture is added 68 ml of boron tri-fluoride etherate. The reaction is stirred at 65-70C
for about three days. Excess reagent is then removed under aspirator pressure at 60-100C. The mixture is poured into 360 ml of 0.5 N hydrochlorid acid with 300 ml of ether. An oil falls out, from which the water and ether are decanted. The oil is placed under 250 ml of 0.5 N
hydrochloric acid and 200 ml of ether. The oil is again separated from the solutions and is placed under 150 ml of water with 20 ml of lO % aqueous sodium hydroxide solution.
The suspension is diluted further with 200 ml of water and is extracted with two 200 ml portions and one 100 ml por-tion of ether. The combined amine ether extracts are added to a solution of l2.5 ml of 4O ~ aqueous hydrogen bromide in 300 ml of water to glve a white salt. The mixture is allowed to stand 16 hours, then the ether is decanted off. The aqueous mixture is washed again by adding and decanting 200 ml of ether. The salt is then filtered off, washed with water and ether, and dried to a white powder, m.p. 143-145C, of 4-(2-fluorophenyl)-4-(3-methylbenzylthio)-l-methylpiperidine hydrobromide. A
thrice recrystallized (acetone-ether) sample melts at 29- 145-146C.
112~985 Analysis:
Calculated for C20H24FNS HBr: 58.54 % C; 6.14 % H; 3.4 % N.
Found: 58.45 % C; 6.16 ~ H; 3.16 % N.
b. A 3.43 g portion o~ 50 % sodium hydride dispersion is washed with hexane under dry nitrogen and then heated with 100 ml of sieve dried dimethylsulfoxide at 80-85C
for 40 minutes. Then 18.48 g of the free base of 4-(2-fluorophenyl)-4-(3-methylbenzylthio)-1-methylpiperidine of Example 4la in 70 ml of dry DMS0 is added over 60 seconds.
The red mixture is stirred, cooled to room temperature over one hour, and poured into 500 cc of ice water. The aqueous mixture is extracted with three 200 ml portions of dichlo-romethane. Combined dichloromethane extracts are washed with four 200 ml portions of water and one 100 ml portion of saturated aqueous sodium chloride solution, and dried over magnesium sulfate to yield an oil. The oil is dissolv-ed in ether, filtered, evaporated, and chromatographed on 400 ml of alumina with ether to give an oil which is dis-solved in ether and treated with ethereal hydrogen bromide to give a salt. The salt is washed with ether and recry-stallized from methanol-acetone-ether to give a white, crystalline powder, m.p. 258-260C of 1,3-dihydro-1'-methyl-3-(3-methylphenyl)spiro/ benzo(c)thiophene-1,4'-piperidine 7 hydrobromide.
25 Analysis:
Calculated for C20H23NS-HBr 61.54 % C; 6.20 ~ H; 3.59 % N.
Found: 61.27 % C; 6.24 % H; 3.45 % N.
~ ~, .
_ 49 ~ Z985 ~xample 42 A solution of 0~70 g of the a~ine 1,3-dihydro-3-(2-nethylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine] of Examp~e 3~, 0.76 g of y-chloro-p-fluorobut~rophenone ethylene ketal, 0.3~ g of sodium bicarbonate, 0.3~ g of ~', and 10 ml of anhydrous DMF is stirred and heated at 70-80C for 24 hours.
The reaction is ~orked up by pouring it into water and extracting with ether. The ether fractions are combined, washed with water, and dried over ~qgS04~ The solution is iltered, evaporated and the resulting oil colu~n chromatographed on a A1203/ether colu~n (eluted with ether). The isolated product is converted to a maleate salt of 1'-[3-(4-fluorobenæoyl)propyl]-1,3-dihydro-3-(2-methylphenylspiro[benzo(c)thiophene-1,4'-piperidine] ethylene ketal maleate, m.p. 157-159C.
16 Anal~sis:
Calculated for C31H34~lO2S-C4H40~ 67.~3C,'C; 6-18%H; 2-26%N-Found: 67.7~C,'C; 6.02%H. 2.24%N.
Example ~3 To 3.33 ~ of phenyl chlorofo~ate in 850 ml of dichloromethane is added a solution of 6.73 ~, of the free base 3-(2-chlorophenyl)-1,3-dihydro-1'-methvlspiro[benzo(c)thiopllene-1,4'-piperidine] of Example 32 in 75 ml of dichloromethane over two minutes. The reaction is stirred at ambient temperature for 64 hours, then diluted with 200 ml of dichloronethane and washed~th t~ 3~0 ~a ~orti~ls of 57 a~ueous sodium hvdroxide solution, th~ 200 112~85 ml portions of water and one 75 ml portion of brine. The solution is dried over magnesium sulfate and evaporated to an oil. The oil is chromatographed on a silica gel with dichloromethane to give an oil of 3-(2-chlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro-/ benzo(c)thiophene-1,4'-piperidine 7.
Analysis:
Calculated for C25H22ClN02S: 68.88 % C; 5.09 % H; 3.21 % N.
Found: 69.36 % C; 4.94 % H; 3.33 % N.
To 1.81 g of phenyl chloroformate in 40 ml of dichlo-romethane is added a solution of 2.9~ g of the free base 1,3-dihydr-o-1'-methyl-3-(3-methylphenyl)spiro/ benzo(c) thiophene-1,4'-piperidine 7 of Example 41 in 35 ml of di-chloromethane over 5 minutes. The reaction is stirred at ambient temperature for 21 hours. The reaction is then diluted with 100 ml of dichloromethane; wahsed with two 150 ml portions of 5 % aqueous sodium hydroxide solution, two 100 ml portions of water and one 50 ml portion of brine;
and dried over magnesium sulfate to an oil. The oil is chromatographed on silica gel with dichloromethane to yield 1,3-dihydro-3-(3-methylphenyl)-1'-phenoxycarbonylspiro/ ben-zo(c)-thiophene-1,4'-piperidine 7, m.p. 154-157C. A por-tion is recrystallized from toluene-hexane, m.p. 157-160C.
Analysis:
Calculated for C26H25N02S: 75.16 % C; 6.07 ~ H; 3.37 % N.
29 Found: 75.28 % C; 6.12 % H; 3.17 % N.
llZZ~?8S
To 6.19 g of 3-(-2-chlorophenyl)-1,3-dihydro-1'-phen-oxycarbonylspiro/ benzo(c)thic,phene-1,4'-piperidine 7 of E~ample 43 in 95 ml of ethylene glycol at 150C is added 15.1 g of 85 % potassium hydroxide pellets. The reaction is stirred in a 160-165C bath for 40 minutes, then cooled to room temperature and poured into 250 ml of water.
The mixture is diluted to 500 ml with water and extracted with three 150 ml portions of water and one 40 ml portion of saturated sodium chloride ~solution and dried over magne-sium sulfate to an oil. The oil is dissolved in ether, filtered, and treated with etihereal maleic acid. The crude salt is washed with ether and recrystallized from methanol-acetone-ether to give a white salt of 3-(2-chlorophenyl)-1,3-dihydrospiro/ benzo(c)thiophene-1,4'-piperidine 7 maleate, 15 m.p. 172-173C.
Analysiq:
Calculated for C18Hl8ClNS:
61,18 % C; 5.14 % H; 3.24 % N; 8.21 % Cl.
Found: 61.47 % C; 5.22 % ~; 3.18 % N; 7.85 % Cl.
To 2.48 g of the free ba~e, 3-(2-chlorophenyl)-1,3-dihydro-spiro/ benzo(c)thiophene-1,4'-piperidine 7 of Example 45, in 28 ml of sieve-dried dimethylformamide with 2.78 g of ~ -chloro-p-fluorophenylbutyrophenone ethylene 25 ketal is added 2.02 g of sodium bicarbonate and 2.02 g of potassium iodide. The reaction is then heated in an 85-50 C bath for 17 hours. The mixture is diluted with 90 ml - of chloroform and fultered through paper. The solution is 29 evaporated and the oil partit~oned between 140 ml of di-.
chloromethane and 75 ml of water. The dichloromethane is washed with 75 ml of water and one 25 ml portion of saturat-ed sodium chloride solution and dried over magnesium sulfa-te. The oil is chro~latographed on alumina with ether and treated with ethereal oxalic acid to give a salt. The salt is washed with ether and recrystallized from methanol-acetone-ether (m.p. 200-201C) to give a white solid of 3-(2-chlorophenyl)-1'-/ 3-(4-fluorobenzoyl)propyl 7-1,3-di-hydrospiro/ benzo(c)thiophene-1,4'-piperidine 7ethylene ketal oxalate, m.p. 200-201C.
Analysis:
62.59 ~ C; 5.42 % H; 2.28 % N.
Found:62.53 % C; 5.44 % H; 2.26 % N.
a.To 14.45 g of 4-(2-fluorophenyl)-4-hydroxy-l-methylpiperidine of Example la is added 39.45 g of 2,4-di-chlorobenzyl mercaptan followed by 40 ml of boron trifluori-de etherate. The reaction is stirred at 80-85C for about 4 days. The excess reagent is removed under aspira-tor pressure to 110C and the residual oil poured into 200 ml of 0.5 N hydrochloric acid and 200 ml of ether. The mixture is allowed to stand 18 hours, the ether decanted off and two more 200 ml portions of ether are added and decanted. The crude precipitate is filtered, washed with 75 ml of water and three 125 ml portions of ether, and dried to an apparently mixed salt. A portion of the salt is basified in aqueous ammonium hydroxide, extracted with 29 ether, washed with water and brine, and dried over magne-~12'~85 sium sulfate. The ethereal solution is treated with ethe-real hydrogen bromide to give a salt. The salt is washed with ether and dried to give a white powder of 4-(2,4-dichlorobenzylthio)-4-(2-fluorophenyl)-l-methylpi-peridine hydrobromide, m.p. 208.5-210C.
Analysis:
Calculated for C19H20Cl2FNS HBr: 49.05 % C; 4.55 % H; 3.01 % N.
Found: 48.87 % C; 4.52 % H; 2.96 % N.
b. A 0,3 g of sodium hydride (50 %) is washed with hexane under nitrogen and heated at 80C with 11 ml of dry dimethylsulfoxide for 30 minutes. Then 1.6~ g of the free base, 4~(2,4-dichlorobenzylthio)-4-(2-fluorophenyl)-1-me-thylpiperidine of Example 47a in 7.3 ml of dry DMS0 is added at once and the heating removed. The reaction is stirred under nitrogen, while cooling to room temperature over 45 minutes, then poured onto ice and extracted with 50 ml of ether and 150 ml of dichloromethane. Co~.bined orga-nic phases are washed with two lO0 ml portions of water and one 25 ml portion of brine, and dried over magnesium sulfate to an oil. The oil is chromatographed on alumina with ether to give an oil. The oil, in ether, is treated with ethereal hydrogen bromide to form a salt. The salt is washed with ether and recrystallized from acetone-ether to give a yellowish-white salt of 3-~2,4-dichlorophenyl)-1,3-dihydro-l'-methyl-spiro(benzo(c)thiophene-1,4'-piperidine) hydrobromide, m.p. 259.5-261C. A portion of the crude salt is recrystallized thrice from methanol-acetone ether to give a m.p. 260-261C.
- 29 Analysis:
Calculated for C19H19Cl2NS HBr:
51.26 % C; 4.53 % H; 3.15 % N; 15.93 % Cl.
Found: 51.43 % C; '~.56 % H; 3.15 % N; 15.65 % Cl.
To 1.34 g of 1,3-dihydro-3-(3-methylphenyl)-1'-phen-oxycarbonylspiro/ benzo(c)thiophene-1,4'-piperidine 7 of Example 44 in 22 ml of ethylene glycol, under nitrogen, at 150C is added 3,44 g of 85 % aqueous potassium hydroxide.
The rection is stirred at 160C for 40 minutes, then is poured into 50 ml of ice water, diluted to 120 ml and extracted with two 50 ml portions of dichloromethane. The combined dichloromethane extract is washed with two 50 ml portions of water and one 20 ml portion of saturated sodium chloride solution, and dried over magnesium sulfate to an oil. The oil is purified by swirling and decanting one 50 ml portion and two 25 ml portions of boiling hexane. The evaporated hexane gives an oil (free base) which is dissolv-ed in ether, treated with ethereal maleic acid, and recry-stallized from acetone to a white powder of l,3-dihydro-3-(3-methylphenyl)spiro! benzo(c)thiophene-1,4'-piperidine 7 maleate, m.p. 175-176C.
Analys i9:
Calculated for ClgH21SN~C4H404 67.14 % C; 6.12 % H; 3.41 % N.
25 Found: 67.29 % C; 6.13 % H; 3.30 % N.
To 4.02 g of the free base 3-(2-chlorophenyl)-l'-/ 3-I4-fluorobenzoyl)propyl 7-1,3-dihydrospiro/ benzo(c) : ~- 29 thiophene-1,4-piperidine 7 ethylene ketal of Example 46 in liZ;~3S
250 ml of ether with 15 ml of methanol is added 120 ml of an ethereal hydrogen bromide solution. The reaction is allowed to stir for two hours, then 120 ml of 1:4, 58 %
ammonium hydroxide: water is added with stirring to dissolve all material. The layers are separated and the ether washed with three 100 ml portions of water and one 25 ml portion of saturated aqueous sodium chloride solution and dried over magnesium sulfate to yield a solid. The solid is stirred in a mixture of 125 ml of ether and 64 ml of 15:1, water: 58 % ammonium hydroxide for one hour. The layers are separated and the aqueous layer washed with two 50 ml por-tions of ether, and then filtered and dried to a solid. The combined ether solutions are washed with water and brine, dried, evaporated, and the solids recrystallized from ethyl acetate and combined to give a solid of 3-(2-chlorophenyl)-1'-/ 3-(4-fluorobenzoylpropyl 7dihydrospiro / benzo(c)thiophene-1,4'-piperidine 7, melting at 144-148C.
Analysis:
Calculated for C28H27ClFNOS:
70.07 % C; 5.67 % H; 2.92 % N; 7.39 % Cl.
Found: 69,81 % C; 5.54 % H; 2.79 % N; 7.29 % Cl.
To 5.25 g of the free base, 1.3-dihydro-3-(3-methyl-phenyl)spiro! benzo(c)thlophene-1,4'-piperidine 7 of Example 48 in 65 ml of sieve-dried dimethylformamide is added 5.43 g of ~-chloro-p-fluorobutyrophenone ethylene ketal, followed by 3.6 g of sodium bicarbonate and 3.6 g of potassium iodide. The reaction is stirred in an 85C
29 bath for 24 hours, then diluted with 130 ml of chloroform and filtered. The solvent is removed and the residual oil is partitioned between 250 ml of dichloromethane and 150 ml portion of water and one 35 ml portion of saturated sodium chloride solution and dried over magnesium sulfate to an oil. The oil is chromatographed on alumina with ether and is converted to the maleate salt by treatment with ethereal maleic acid. Recrystallization from acetone-ether yield l'-/ 3-(4-fluorobenzoyl)propyl 7-1,3-dihydro-3-(3-methyl-phenyl)spir~/ benæo(c)thiophene-1,4'-piperidine 7ethylene ketal maleate, m.p. 155-157C.
Analysis:
Calculated for C31H34FN02S C4H404:
67.84 % C; 6.18 g H; 2.26 % N.
Found: 67.76 % C; 6.19 % H; 2.15 % N.
To 8.5 g of phenyl chloroformate in 130 ml of dry dichloromethane under nitrogen is added a solution of 15.56 g of the fr~e base of 3-(2,4-dichlorobenzylthio)-1,3-dihy-dro-l'-methylspiro~ benzo(c)thiophene-1,4'-piperidine 7 of Example 47 in lO0 ml of dry dichloromethane over 15 minutes.
The reaction is stirred at ambient temperature for 21 hours, then diluted with 450 ml of dichloromethane, washed with two 300 ml portions of 10 % aqueous sodium hydroxide solu-tion, two 300 ml portions of water and one 100 ml portion of brine and dried over magnesium sulfate to an oil. The oil is chromatographed on silica gel with dichloromethane to give a clear oil of 3-(2,4-dichlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro/ benzo(c)thiophene-1,4'-piperidine 7 29 A:nalysis:
Calculated for C25H21C12N2S 63-84 % C; 4-50 % H; 2-98 % N-Found: 63.71 % C; 4.52 % H; 2.79 % N.
A solution of 2.85 g of the free base 1'-/ 3-(4-fluoro-benzoyl)propyl 7-1,3-dihydro-3-(2-methylphenyl)spiro/ benzo (c)thiophene-1,4'-piperidine 7 ethylene ketal of Example 42, 30 ml of absolute ethanol, and 30 ml of 3N HCl solution is refluxed for 45 minutes. The reaction is cooled, made basic with 40 % aqueous NaOH solution, and extracted with CH2C12. The CH2C12 fractions are combined, washed with water, and dried over MgS04. The solution is filter-ed and evaporated to a solid which is recrystallized from ethyl acetate to give a pure product of 1'-/ 3-(4-fluoro-benzoyl)propyl 7-1,3-dihydro-3-(2-methylphenyl)spiro/ benzo (c)thiophene-1,4'-piperidine 7, m.p. 143-145C.
Analysis:
Calculated for C29H30FNOS: 75.78 % C; 6.58 % H; 3.05 % N.
Found: 75.51 % C; 6.70 % H; 2.85 % N.
To 15.12 g of 3-(2,4-dichlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro! benzo(c)thiophene-1,4'-piperidine 7 of Example 51 in 216 ml of ethylene glycol at 150C, un-der nitrogen, is added 34,2 g of 85 % potassium hydroxide pellets. The reaction is stirred at 160C for 45 minutes, then poured into 1.4 1 of water and extracted with three 350 ml portions of dichloromethane. The combined dichloro-methane extract is washed with two 400 ml portions of water and one 100 ml portion of saturated aqueous sodium chloride 29 solution and dried over magnesium sulfate to an oil. The `
.
1~2~985 oil is purified by decanting with three 225 ml portions of boiling hexane to yield a solid. A portion of the solid is dissolved in ether and treated with ethereal maleic ac~d to give a salt. The salt is washed with ether and recrystallized from methanol-acetone-ether to a white powder of 3-(2,4-dichlorophenyl)-1,3-dihydrospiro / benzo (c)thiophene-1,4'-piperidine 7 maleate, m.p. 171-172.5C.
Analysis:
Calculated for C18Hl7C12NS C4H404:
56.66 % C; 4.54 % H; 3.00 % N; 15.20 % Cl.
Found: 56.49 % C; 4.54 % H; 2.81 % N; 14.99 % Cl.
To 3.0 g of the free base 3-(2,4-dichlorophenyl)-1,3-dihydrospiro/ benzo(c)thiophene-1,4'-piperidine 7 of Example 53 in 35 ml of sieve-dried dimethylformamide is added 2.62 g of ~-chloro-p-fluorobutyrophenone ethylene ketal, followed by 1.7 g of sodium bicarbonate and 1.7 g of potassium iodide. The reaction is stirred at 80-90C for 20 hours.
The mixture is diluted with 75 ml of chloroform, filtered, and rotary evaporated at 75C to an oil. The oil is partitioned between 125 ml of dichloromethane and 85 ml of water. The mixture is diluted with 10 ml of saturated aqueous sodium bicarbonate solution, and the organic layer separated and washed with one 80 ml portion of water and one 30 ml portion of saturated sodium chloride solution.
The dichlorornethane solution is dried and evaporated to an oil~ The oil is chromatographed on alumina with ether and a portion of the resultant oil is placed in ether and 29 treated with ethereal oxalic acid to give a salt.
The salt is washed with ether and recrystallized from methanol-acetone-ether to yield a white powder of 3-(2,4-dichlorophenyl)-1'-/ 3-(4-fluorobenzoyl)-propyl 7-1,3-dihydrospiro/ benzo~c)thiophene-1,4'-piperidine 7 5 ethylene ketal oxalate, m.p. 164-165C.
Analysis:
59.26 % C; 4.97 % H; 2.16 % N.
Found:59.15 % C; 4.81 % H; 2.11 % N.
a.To 26.33 g of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine of Example 1a with 20 ml (approximately 23.3 g) of m-fluorobenzylmercaptan in 25 ml of glacial acetic acid is added 33 ml of boron trifluoride ethane.
The reaction is stirred at 65-68C for 44 hours, then an additional 17 ml of boron trifluoride etherate is added and stirring at 65-68C is resumed for about three more days.
Excess solvent is removed under reduced pressure to 110C.
The residue is mixed with 450 ml of 0.5 N HCl and 175 ml of ether to form an oil. The oil and water layer is washed by decanting with ether, then the aqueous acid is carefully decanted from the oil. The oil is placed under water, treated to pH=9-lO with ammonium hydroxide and extracted with ether. The ethereal solution is washed with water until neutral, then is poured into a solution of 30 ml of 48 % hydrogen bromide diluted to 350 ml to form a salt.
The salt is filtered off, washed with a small amount of water and a generous amount of ether to give a white salt 29 of 4-(3-fluorobenzylthio-)-4-(2-fluorophenyl)-1-methylpipe-liZZ~85 ridine hydrobromide, m.p. 176-178.5C. A thrice recrystal-lized (methanol-acetone-ether) sample melts at 178-179C.
Analysis:
Calculated for C19H21F2NS HBr:
55.08 % C; 5.35 % H; 3.38 % N.
Found: 55.05 % C; 5.38 % H; 3.38 % N.
b. To 1.404 g of sodium hydride (from 2.87 g of a 50 % dispersion), under nitrogen, is added 120 ml of sieve-dried dimethylsulfoxid. The mixture is stirred in an 80 -85C bath for 35 minutes, then cooled to room ~empera-ture. A solution of 14.0 g of the free base 4-(3-fluoro-benzylthio)-4-(2-fluorophenyl)-1-methylpiperidine of Ex-ample 55a in 47 ml of DMS0 is added over 60 seconds and the solution stirred for one hour. The reacti~n is then poured into 700 ml of ice water and extracted with three 200 ml portions of dichloromethane. The combined dichloro-methane extracts are washed with three 300 ml ~ortions of water and one 75 ml portion of saturated sodium chlo-ride solution, and dried over magnesium - 61 - l i 2~'~85 sulfate to an oil. The oil is chromatogr2phed on alumina with ether to give crystals. A portion of ~his, in ether is treated with ethereal maleic acid. The resulting salt is washed with ether and dried to give a powder of 3-(3-fluorophenyl)-1,3-S dihydro-l'-methylspiro[benzo(c)thiophene-1,4'-piperidine~ maleate, m.p. 137-140C. A twice recrystallized portion melts at 138.5-140.5~C. Upon continued heating, a new crvstalline form develops which collapses in the 175-180C. rang~.
Analysis:
Calculated for ClgH2~JS-C4H4O4: 64.32%C; 5.637~; 3.26~/~J; 4.42%F.
Found:64.26%C; 5.5~,'DH; 2.95V/oIl; 4.58%F.
~xample 56 To 3.26 ~, of the free base 3-(2,4-dichlorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine] ethylene ketal of Example 54 in 30 rnl of warm ethanol is slo~ly added 30 ml of 3N hydrochloric acid. The mixture is heated over a steam bath for 45 minutes. 10 ml of additional ethanol is added and heatin~ is resu~ed for 45 minutes.
The reaction is then cooled to room temperature and basified with 40% aqueous sodium hydroxide solu~ion. The mixuture is diluted with 200 ml of water and extracted with three ~0 r.ll portions of dichlorothane, The combined dichlorometh~ne extracts are washed with two lOOr~
portions of water, one 50 ml portion of saturated aqueous sodiu~
chloride solution and dried over magnesium sulfate to an oil. The oil is 11~298S
dissolved in ether, filtered through celite, and treated with ethereal maleic acid to form a salt. The salt is washed well with ether and recrystallized from acetone-ether to give a white powder of 3-(2,4-dichlorophenyl)~
/ 3-(4-fluorobenzoyl)propyl 7-1,3-dihydrospiro/ benzo(c) thiophene-1,4'-piperidine 7 maleate, m.p. 124-127C.
A thrice recrystallized sample melts at 127-129C.
Analysis:
Calculated for C28H26Cl2FN~S C4H404:
60.96 % C; 4.80 % H; 2.22 % N; 11.25 % C1.
Found: 61.13 % C; 4.78 % H; 2.06 ~ N; 11.02 % Cl~
To 5.0 g of phenyl chloroformate in 80 ml of dichlo-romethane added 7.89 g of the free base, 3-(3-fluorophe-nyl)-1,3-dihydro-l'-methylspiro/ benzo(c)thiophene-1,4'-piperidine 7 of Example 55, in lO ml of dichloromethane over 20 minutes. The reaction mixture is stirred at room temperature for 21 hours, then diluted with 200 ml of dichloromethane. The resultant mixture is washed with two 175 ml portions of lO % aqueous sodium hydroxide solution, two 150 ml portions of water and one 70 ml portion of saturated aqueous sodium chloride solution, and dried over magnesium sulfate to give an oil. The oil is chromatograph ed on silica gel with dichloromethane to give an oil, which crystallizes to yield 3-(3-fluorophenyl)-1,3-dihydro-l'-phenoxycarbonylspiro/ benzo(c)thiophene-1,4'-piperidine 7, m.p. 134-142C. A portion is recrystallized twice from toluene: hexane, m.p. 144-146C.
29 -Analysis:
~12Z~85 Calculated for C2~H22FN02S: 71.58 % C; 5.29 % H; 3.34 % N.
Found: 71.60 % C, 5.33 % H, 3.22 % N.
To 6.97 g of 3-(3-fluorophenyl)-1,3-dihydro-1'-phen-oxycarbonylspiro/ benzo(c)thiophene-1,4'-piperidine 7 of Example 57 in 100 ml of ethylene glycol, under nitrogen, at 150C is added 16 g of 85 % potassium hydroxide pellets.
The reaction is stirred in a 160C bath for 45 minutes.
The solution is then poured into 225 ml of ice-water, diluted to 500 ml and extracted with three 175 ml portions of dichloromethane. The combined dichloromethane extracts are washed with ~00 ml portions of water and one 50 ml portion of saturated aqueous sodium chloride solution, and dried over magnesium sulfate to give a solid free base.
The free base in ether is treated with ethereal maleic acid to give a salt. The salt is washed with ether and recry-stallized from methanol-acetone-ether to give a white powder of 3-(3-fluorophenyl)-1,3-dihydrospiro/ ~enzo(c) thiophene-1,4'-piperidine 7 maleate, m.p. 188-188.5C.
Analysis:
Calculated for C18Hl8FNS:
63.61 % C, 5.34 ~ H; 3.37 % N; 4.57 % F.
Found: 63.53 % C; 5.37 % H; 3.31 % N; 4.45 % F.
To 2.75 g (9.19 mmols) of free base 3-(3-fluorophenyl)-1,3-dihydrospiro/~benzo(c)thiophene-1,4'-piperidine 7 of Example 58 in 47 ml of sieve-dried dimethylformamide is added 2.81 g of ~-chloro-p-fluorobutyrophenone ethylene ke-29 tal with 1.~2 g of potassium iodide and 1.82 g of sodium 11225~85 bicarbonate. The reaction is stirred at 65-90C for 20 hours; then diluted with 75 ml of chloroform, filtered and rotary evaporated at 75C to an oil. The oil is parti-tioned between 125 ml of dichloromethane and 85 ml of water. A lO ml portion of saturated aqueous sodium bicar-bonate is added and the solutions separated. The organic layer is washed with one 80 ml portion of water and one 30 ml portion of saturated aqueous sodium chloride solution and dried over magnesium sulfate to an oil. The oil is chromato~raphed on alumina with ether to give 3-(3-fluoro-phenyl)-1l~/ 3-(4-fluorobenzoyl)propyl 7-1,3-dihydro-spiro/ benzo(c)thiophene-1,4'-piperidine 7 ehtylene ketal.
Recrystallization from cyclohexane-pentane yields a sample which melts at 121.5-123C.
15 Analysis:
or C30H31F2N02S: 70.98 % C; 6.17 % H; 2-76 % N-Found:70.97 % C; 6.20 % H; 2.43 % N.
To 3.75 6 Of 3-(3-fluorophenyl)-l'-/ 3-(4-fluoroben-zoyl)propyl 7-1,3-dihydrospiro~ benzo(c)thiophene-1,4'-pi-peridine 7 ethylene ketal of Exampie 59 in 38 ml of ethanol is added 38 ml of 3N hydrochlorid acid. The reaction is refluxed for two hours and allowed to stand at room tempe-rature for 16 hours. The solution is diluted with lO0 ml of water and a few ml of 40 % aqueous sodium hydroxide solution are added to achieve a pH of ll. The mixture is then diluted with 175 ml of water and extracted with three 175 ml portions Qf dichloromethane solution. The combined 29 dichloromethane extract is washed with two 125 ml portions l~.Z~85 of water and one 60 ml portion of saturated aqueous sodium chloride solution and dried over magnesium sulfate to an oil. The oil, in ether, is treated with ethereal maleic acid, and the resulting salt washed with ether and recry-stallized from acetone ether to a white, crystalline powderof 1'-/ 3-(4-fluorobenzoyl)propyl 7-3-(3-fluorophenyl)-1,3-dihydrospiro-! benzo(c)thiophene-1,4'piperidine 7 maleate, m.p. 149-150.5C.
Analysis:
Calculated for C28H27F2NOS C4H404 66.31 % C; 5.39 % H; 2.42 % N; 6.56 % Fo Four.d: 66.35 % C; 5.54 ~ H; 2.14 % N; 6.61 ~ F.
To a solution of 3.10 g of the free base 1,3-dihydro-3-(4-methylphenyl)spiro/ benzo(c)thiophene-1,4'-piperidine 7 of Example 40 in 54 ml of dimethylformamide is added 3.21 g of the ~-chloro-p-fluorobutyrophenone ethylene ketal, 2.07 g of potassium iodide and 2.07 g of sodium bicarbonate.
The reaction mixture is stirred and heated at 65-90C 18 hours. The reaction mixture is diluted with 75 ml of chlo-roform, filtered, and evaporated to an oil. The oil is par-titioned between 150 ml of dichloromethane and 125 ml of water. The organic layer is washed with water and an aque-OU9 sodium chloride solution and then dried over MgS04:
The solution is filtered and evaporated to an oil which is column chromatographed on an Al203/Et2O. A sample of the resultant free base is converted to the oxalate salt of 1'-/ 3-(4-fluorobenzoyl)propyl 7-3-(4-methyl-phenyl)-1,3-29 dihydrospiro/ benzo(c)thiophene-1,4'-piperidine ~ eth l ~i2~85 ketal oxalate.
Analysis:
Calculated for C31H34FNO2S C2H24 66.76 % C; 6.11 % H; 2.36 % N.
Found: 66.85 % C; 6.12 % H; 2.32 % N.
A solution of 2.57 g of 1'-/ 3-(4-fluorobenzoyl)pro-pyl 7-1,3-dihydro-3-(4-methylphenyl)spiro/ benzo(c)thio-phene-1,4'-piperidine 7 ethylene ketal of Example 61, 27 ml 'O of absolute ethanol, and 27 ml of 3N HCl is heated on a steam bath for 45 minutes. The reaction is cooled, diluted with 75 ml of water, and taken to pH 11 using a 40 % aque-ous NaOH solution. The solution is diluted with 150 ml of water and extracted with dichloromethane. The CH2C12 fractions are combined, washed with water and brine, and dried over MgSO4. The dried CH2C12 solution is fi'ltered and evaporated to an oil which solidifies under pentane. The filtered product is recrystallized from ethyl acetate to give l '-! 3-(4-fluorobenzoyl)propyl 7-1,3-dihy-dro-3-(4-methylphenyl)spiro/ benzo(c)thiophene-1,4'-piperi-dine 7, m.p. 134-135C.
Ana lys is:
Calculated for C29H30FNOS: 75.78 % C; 6.58 % H; 3.05 % N.
Found: 75.61 % C; 6.67 % H; 3.07 % N.
To 6.87 g of 3~(4-chlorophenyl)-1)3-dihydrospiro/ ben-zo(c)thiophene-1,4'-piperidine 7 of Example 15 in a solu-tion of 33 ml of 2-butanone with 33 ml of dimethylformamide 29 is added 6.04 g of ~ -chloro-2,4-difluorobutyrophenone ethylene ketal followed by 6.5 g of sodium bicarbonate and 4.08 g of potassium iodide. The reaction is stirred at 75-80C for 18 hours, then 400 ml of ice-water is added and the mixture extracted with three 125 ml portions of ether. The combined ether extracts are washed with two 150 ml portions of water and one 30 ml portion of brine and dried over magnesium sulfate to yield an oil. The oil is chromatographed on 300 ml of alumina with ether to give an oil which eventually crystallizes to a product. A portion of the product is diluted with ether, treated with ethereal maleic acid to form the salt. The salt is recrystallized once from methanol-ether and once from acetone-ethyl aceta-te pentane to give 3-(4-chlorophenyl)-l'-/ 3-(2,4-difluoro-benzoyl)propyl 7-1 ,3-dihydrospiro! benzo(c)thiophene-1,4'-15 piperidine 7 ethylene ketal maleate, melting at 148-149C.
Analysis:
62.05 % C; 5.21 % H; 2.13 % N.
Found:61.94 % C; 5.01 % H; 2.16 % N.
To 8.21 g (15.15 mmols) of free base 3-(4-chlorophe-nyl)-l-! 3-(2,4-difluorobenzoyl)propyl 7-1 ,3-dihydrospiro ~ benzo(c)thiophene-1,4'-piperidine 7 ethylene ketal of Example 63 in 62 ml of warm 95 % ethanol is added 31 ml of 3N hydrochloric acid, slowly, to give a SUQpenSiOn. The reaction is stirred at room temperature for 3 hours and on a steam bath for 45 minutes. The reaction is then diluted with 400 ml of water and basified with ammonium hydroxide.
. 29 The aqueous mixture is extracted with two 150 ml portions 9~3S
of ether and two 250 ml portions of 1:1, ether: toluene.
Combined organic layers are washed with water and saturated aqueous sodium chloride solution and dried over magneQiUm sulfate to a brown oil. The oil is chro~tographed on silica gel with ether to give a solid. A portion of the product is recrystallized thrice from ether-pentane to give 3-(4-chlorophenyl)-1'-/ 3-(2,4-difluorobenzoyl)propyl 7-1,3-dihydrospiro/ benzo(c)thiophene-1,'~'-piperidine 7, melting at 98-100C.
Analysis:
Calculated for C28H26ClF2NOS: 67.52 % C; 5.26 % H; 2.81 % N.
Found: 67.25 g C; 5.4~ % H; 2.69 % N.
A mixture of l,3-dihydro-3-phenylspiro/ benzo(c)thio-phene-1,4'-piperidine 7 of Example 4 (3.75 g), 3.7 g of ~ -chloro-2,4-difluorobutyrophenone ethylene ketal, 2.5 g of Kl, 4.0 ~ of sodium bicarbonate in a mixture of 20 ml DMF
and 20 ml of 2-butanone is refluxed for 3 hours. The cooled mixture i9 diluted with water, extracted three times with ether and the washed, dried ether solution concentrat-ed to an oily residue. The residual is purified by passing through an alumina column. Elution with ether affords the tertiary amine which is converted to a crystalline maleate of l'-/ 3-(2,4-difluorobenzoyl)propyl 7-1,3-dihydro-3~phe-nylspiro/ benzo(c)thiophene-1,4'-piperidine 7 ethylene ketal maleate, m.p. 171-172.5C.
Analysis:
- 30H31F2N02S 4H404:
29 65.47 % C; 5.66 % H; 5.14 % S.
112~g85 Found: 65.21 % C; 5.68 % H; 5.36 % S.
A solution of 5.0 g of the free base 1'-/ 3-(2,4-di-~luorobenzoyl)propyl 7-1,3-dihydro-3-phenylspiro/ benzo(c) thiophene-1,4'-piperidine 7 ethylene ketal of Example 65 in 20 ml of 3N HCl and 20 ml of water is allowed to stand at room temperature for 3 hours. The excess acid and solvents are removed under pressure at 60C, the residue is basifi-ed with concentrated NH40H. The liberated oil is taken up in ether, washed and dried. Removal of solvents yields a clear oil which is converted to a crystalline maleate in ether of l'-/ 3-(2,4-difluorobenzoyl)propyl 7-1,3-dihydro-3-phenylspiro/ benzo(c)thiophene-1,4'-piperidine 7 maleate, m.p. 134-135C.
15 Analysis:
or C2gH27F2N0s C4H404 66.67 % C; 5.39 % H; 5.53 % S.
Found: 66.21 % C; 5.36 % H; 5.79 % S.
EX~MPLE 67 To 5.60 ~ of the free base 1'-/ 3-(4-fluorobenzoyl)-propyl 7-3-t3-methylphenyl)-1,3-dihydrospiro/ benzo(c)thio-phene-1,4'-piperidine 7 ethylene ketal of Example 50 in 56 ml of warm ethanol is slowly added 56 ml of 3N hydro-chloric acid. The reaction is refluxed for 45 minutes, then cooled to room temperature, basified with a small amount of 40 % aqueous sodium hydroxide, and diluted with 350 ml of water. The solution is extracted with three 15Q ml portions of dichloromethane. The combined dichloro-- 29 methane extract is washed with two 2ao ml portions of w~ter, -- 7~ --one 75 ml portion of brine and dried over magnesium sulfate to give an oil. The oil is dissolved in ether, filtered, and treated with ethereal hydrogen bromide to form a salt.
The salt is washed with ether and recrysta'lized from me-thanol-acetone-ether to give a powder o. 1'-/' 3-(4-fluoro-benzoyl)propyl-1,3-dihydro-3-(3-methylphenyl)spiro/ benzo (c)thiophene-1,4'-piperidine 7 hydrobromide which shrinks to a gel at 190-195C and melts to a dark fluid at 217-218C.
Analysis:
Calculated for C29H30FNOS HBr 64.44 % C; 5.78 % H; 2.59 % N; 3.52 % F.
Found: 64.30 % C; 5.79 % H; 2.48 % N; 3.56 % F.
.
Claims (4)
OR PRIVILEGE IS CIAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula I
I
or an optical antipode or a pharmaceutically acceptable salt thereof wherein R is hydrogen, benzoyloxy, loweralkyl, cyclo-alkylloweralkyl wherein the cycloalkyl portion contains from 3 to 6 carbon atoms, phenylloweralkyl, loweralkanoyl, benzoyllower-alkyl wherein the benzoyl may be substituted with halogen, phenyl-oxycarbonyl, cycloalkylcarbonyl of 4 to 8 carbon atoms or wherein Ph is phenyl which may be substituted with halogen; R1 and R2 are the same or different and R1 is hydrogen or halogen and R2 is hydrogen, halogen or loweralkyl, m, n and n' are integers from 1 to 3; and the sum of n and n' is 3 or 4, in which a) a 2-bromo-fluorobenzene of the formula II
II
is converted to its 2-lithio derivative with a lower alkyllithium at a temperature ranging from -80 to -20°C, in a suitable solvent, b) the 2-lithio derivative is reacted with a cycloazalkanone of the formula wherein R is loweralkyl or phenylloweralkyl to provide a phenyl-cycloazalkanol of the formula c) the phenylcycloazalkanol is reacted with a benzylmercaptan of the formula in the presence of a Lewis Acid at a temperature of from ambient to 100°C to provide a 4-benzylthio-4-phenylcycloazalkane of the formula d) the 4-bexzylthio-4-phenylcycloazalkane is cyclized, e) a compound of the formula I in which R is loweralkyl or phenylloweralkyl may be treated with phenyl chloroformate at a temperature of from 15 to 125°C with a suitable solvent to provide a compound of the formula Ia wherein R3 is and R1, R2, m, n, and n' are as defined above, f) a compound of the formula Ia in which R is or lower alkyl and R1 is as defined above may be treated with a basic medium at a temperature of from 15°C to reflux of the reaction mixture or with an acid medium at a temperature of from 15 to 125°C to provide a compound of the formula I in which R is hydrogen, g) a compound of the formula I in which R is hydrogen may be treated with a compound of the formula wherein R1, R2 and m are as defined above, to provide a compound of the formula wherein R1, R , m, n, n' and the sum of n and n' are as defined above, h) the compound obtained in step g) may be subjected to hydroly-sis to provide a compound of the formula wherein R1, R2, m, n, n' and the sum of n and n' are as defined above, or i) a compound of the formula I in which R is hydrogen may be reacted with lower alkanoyl chloride or anhydride, loweralkyl halide, cycloloweralkanoyl halide or phenylloweralkyl halide, to provide a compound of the formula I in which R1, R2, m, n, n' and the sum of n and n' are as defined above and R is loweralka-noyl, loweralkyl, cycloalkylalkanoyl and phenylloweralkyl, and k) a compound of the formula I in which R is hydrogen is reacted with a peroxide of the formula wherein R1 is as defined above under normal reaction conditions to provide the corresponding compound of the formula I wherein R is the group .
I
or an optical antipode or a pharmaceutically acceptable salt thereof wherein R is hydrogen, benzoyloxy, loweralkyl, cyclo-alkylloweralkyl wherein the cycloalkyl portion contains from 3 to 6 carbon atoms, phenylloweralkyl, loweralkanoyl, benzoyllower-alkyl wherein the benzoyl may be substituted with halogen, phenyl-oxycarbonyl, cycloalkylcarbonyl of 4 to 8 carbon atoms or wherein Ph is phenyl which may be substituted with halogen; R1 and R2 are the same or different and R1 is hydrogen or halogen and R2 is hydrogen, halogen or loweralkyl, m, n and n' are integers from 1 to 3; and the sum of n and n' is 3 or 4, in which a) a 2-bromo-fluorobenzene of the formula II
II
is converted to its 2-lithio derivative with a lower alkyllithium at a temperature ranging from -80 to -20°C, in a suitable solvent, b) the 2-lithio derivative is reacted with a cycloazalkanone of the formula wherein R is loweralkyl or phenylloweralkyl to provide a phenyl-cycloazalkanol of the formula c) the phenylcycloazalkanol is reacted with a benzylmercaptan of the formula in the presence of a Lewis Acid at a temperature of from ambient to 100°C to provide a 4-benzylthio-4-phenylcycloazalkane of the formula d) the 4-bexzylthio-4-phenylcycloazalkane is cyclized, e) a compound of the formula I in which R is loweralkyl or phenylloweralkyl may be treated with phenyl chloroformate at a temperature of from 15 to 125°C with a suitable solvent to provide a compound of the formula Ia wherein R3 is and R1, R2, m, n, and n' are as defined above, f) a compound of the formula Ia in which R is or lower alkyl and R1 is as defined above may be treated with a basic medium at a temperature of from 15°C to reflux of the reaction mixture or with an acid medium at a temperature of from 15 to 125°C to provide a compound of the formula I in which R is hydrogen, g) a compound of the formula I in which R is hydrogen may be treated with a compound of the formula wherein R1, R2 and m are as defined above, to provide a compound of the formula wherein R1, R , m, n, n' and the sum of n and n' are as defined above, h) the compound obtained in step g) may be subjected to hydroly-sis to provide a compound of the formula wherein R1, R2, m, n, n' and the sum of n and n' are as defined above, or i) a compound of the formula I in which R is hydrogen may be reacted with lower alkanoyl chloride or anhydride, loweralkyl halide, cycloloweralkanoyl halide or phenylloweralkyl halide, to provide a compound of the formula I in which R1, R2, m, n, n' and the sum of n and n' are as defined above and R is loweralka-noyl, loweralkyl, cycloalkylalkanoyl and phenylloweralkyl, and k) a compound of the formula I in which R is hydrogen is reacted with a peroxide of the formula wherein R1 is as defined above under normal reaction conditions to provide the corresponding compound of the formula I wherein R is the group .
2. A compound of the formula I whenever obtained according to a process as claimed in claim 1 or by an obvious chemical equivalent thereof.
3. A pxocess for the preparation of a compound of the formula I
I
or an optical antipode or a pharmaceutically acceptable salt thereof wherein R is hydrogen, benzoyloxy, loweralkyl, cycloal-kylloweralkyl wherein the cycloalkyl portion contains from 3 to 6 carbon atoms, phenylloweralkyl, loweralkanoyl, benzoyllower-alkyl wherein the benzoyl may be substituted with halogen, phen-yloxycarbonyl, cycloalkylcarbonyl of 4 to 8 carbon atoms or wherein Ph is phenyl which may be substituted with halogen; R1 and R2 are the same or different and R1 is hy-drogen or halogen and R2 is hydrogen, halogen or loweralkyl, m, n and n' are intege.rs from 1 to 3; and the sum of n and n' is 3 or 4, in which a) a 4-benzylthio-4-phenylcycloazalkane of the formula is cyclized to produce a compound of formula I, b) a compound of the formula I in which R is loweralkyl or phenylloweralkyl may be treated with phenyl chloroformate at a temperature of from 15 to 125°C with a suitable solvent to provide a compound of the formula (Ia) wherein R is and R1, R2, m, n, and n' are as defined above, c) a compound of the formula Ia in which R3 is or lower alkyl and R1 is as defined above may be treated with a basic medium at a temperature of from 15°C to reflux of the reaction mixture of with an acid medium at a temperature of from 15 to 125°C to provide a compound of the formula I in which R is hydrogen, d) a compound of the formula I in which R is hydrogen may be treated with a compound of the formula wherein R1, R2 and m are as defined above, to provide a compound of the formula wherein R1, R2, m, n, n' and the sum of n and n' are as defined above, e) the compound obtained in step d) may be subjected to hydrolysis to provide a compound of the formula wherein R1, R2, m, n, n' and the sum of n and n' are as defined above, or f) a compound of the formual I in which R is hydrogen may be reacted with lower alkanoyl chloride or anhydride, loweralkyl halide, cycloloweralkanoyl halide or phenylloweralkyl halide to provide a compound of the formula I in which Rl, R2, m, n, n' and the sum of n and n' are as defined above and R is loweralka-noyl, loweralkyl, cycloalkylalkanoyl and phenylloweralkyl, and g) a compound of the formula I in which R is hydrogen is reacted with a peroxide of the formula wherein R1 is as defined above under normal reaction conditions to provide the corresponding compound of the formual I wherein R is the group
I
or an optical antipode or a pharmaceutically acceptable salt thereof wherein R is hydrogen, benzoyloxy, loweralkyl, cycloal-kylloweralkyl wherein the cycloalkyl portion contains from 3 to 6 carbon atoms, phenylloweralkyl, loweralkanoyl, benzoyllower-alkyl wherein the benzoyl may be substituted with halogen, phen-yloxycarbonyl, cycloalkylcarbonyl of 4 to 8 carbon atoms or wherein Ph is phenyl which may be substituted with halogen; R1 and R2 are the same or different and R1 is hy-drogen or halogen and R2 is hydrogen, halogen or loweralkyl, m, n and n' are intege.rs from 1 to 3; and the sum of n and n' is 3 or 4, in which a) a 4-benzylthio-4-phenylcycloazalkane of the formula is cyclized to produce a compound of formula I, b) a compound of the formula I in which R is loweralkyl or phenylloweralkyl may be treated with phenyl chloroformate at a temperature of from 15 to 125°C with a suitable solvent to provide a compound of the formula (Ia) wherein R is and R1, R2, m, n, and n' are as defined above, c) a compound of the formula Ia in which R3 is or lower alkyl and R1 is as defined above may be treated with a basic medium at a temperature of from 15°C to reflux of the reaction mixture of with an acid medium at a temperature of from 15 to 125°C to provide a compound of the formula I in which R is hydrogen, d) a compound of the formula I in which R is hydrogen may be treated with a compound of the formula wherein R1, R2 and m are as defined above, to provide a compound of the formula wherein R1, R2, m, n, n' and the sum of n and n' are as defined above, e) the compound obtained in step d) may be subjected to hydrolysis to provide a compound of the formula wherein R1, R2, m, n, n' and the sum of n and n' are as defined above, or f) a compound of the formual I in which R is hydrogen may be reacted with lower alkanoyl chloride or anhydride, loweralkyl halide, cycloloweralkanoyl halide or phenylloweralkyl halide to provide a compound of the formula I in which Rl, R2, m, n, n' and the sum of n and n' are as defined above and R is loweralka-noyl, loweralkyl, cycloalkylalkanoyl and phenylloweralkyl, and g) a compound of the formula I in which R is hydrogen is reacted with a peroxide of the formula wherein R1 is as defined above under normal reaction conditions to provide the corresponding compound of the formual I wherein R is the group
4. A compound of the formula I as defined in claim 3 whenever obtained according to a process claimed in claim 3 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US85717777A | 1977-12-02 | 1977-12-02 | |
| US857,177 | 1977-12-02 | ||
| US94890878A | 1978-10-05 | 1978-10-05 | |
| US948,908 | 1978-10-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1122985A true CA1122985A (en) | 1982-05-04 |
Family
ID=27127396
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA317,255A Expired CA1122985A (en) | 1977-12-02 | 1978-12-01 | Substituted 1,3-dihydrospiro(benzo(c)thiophene)s |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0002283B1 (en) |
| JP (1) | JPS5498775A (en) |
| AT (1) | AT371468B (en) |
| AU (1) | AU522997B2 (en) |
| CA (1) | CA1122985A (en) |
| DE (1) | DE2862307D1 (en) |
| DK (1) | DK547278A (en) |
| EG (1) | EG13536A (en) |
| FI (1) | FI783664A (en) |
| GR (1) | GR74052B (en) |
| HU (1) | HU179984B (en) |
| IL (1) | IL56094A0 (en) |
| NO (1) | NO784039L (en) |
| NZ (1) | NZ189057A (en) |
| PT (1) | PT68855A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2519636A2 (en) * | 1982-01-14 | 1983-07-18 | Delalande Sa | Spiro iso:benzofuran and iso:benzothiophene derivs. - with anticonvulsant and analgesic activities |
| FR2498603A1 (en) * | 1981-01-29 | 1982-07-30 | Delalande Sa | Spiro iso:benzofuran and iso:benzothiophene derivs. - with anticonvulsant and analgesic activities |
| NZ243065A (en) * | 1991-06-13 | 1995-07-26 | Lundbeck & Co As H | Piperidine derivatives and pharmaceutical compositions |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3959475A (en) * | 1973-12-12 | 1976-05-25 | American Hoechst Corporation | Substituted 1,3-dihydrospiro(isobenzofuran)s |
-
1978
- 1978-11-29 EG EG677/78A patent/EG13536A/en active
- 1978-11-30 NZ NZ189057A patent/NZ189057A/en unknown
- 1978-11-30 IL IL56094A patent/IL56094A0/en unknown
- 1978-11-30 AU AU42073/78A patent/AU522997B2/en not_active Expired
- 1978-11-30 PT PT68855A patent/PT68855A/en unknown
- 1978-11-30 FI FI783664A patent/FI783664A/en unknown
- 1978-12-01 CA CA317,255A patent/CA1122985A/en not_active Expired
- 1978-12-01 DK DK547278A patent/DK547278A/en not_active Application Discontinuation
- 1978-12-01 AT AT0860978A patent/AT371468B/en not_active IP Right Cessation
- 1978-12-01 NO NO784039A patent/NO784039L/en unknown
- 1978-12-01 GR GR57790A patent/GR74052B/el unknown
- 1978-12-01 HU HU78HO2118A patent/HU179984B/en unknown
- 1978-12-02 JP JP14865078A patent/JPS5498775A/en active Pending
- 1978-12-04 DE DE7878101554T patent/DE2862307D1/en not_active Expired
- 1978-12-04 EP EP78101554A patent/EP0002283B1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| PT68855A (en) | 1978-12-01 |
| DK547278A (en) | 1978-12-01 |
| JPS5498775A (en) | 1979-08-03 |
| EP0002283B1 (en) | 1983-08-24 |
| NO784039L (en) | 1979-06-06 |
| GR74052B (en) | 1984-06-06 |
| EG13536A (en) | 1981-12-31 |
| AU4207378A (en) | 1979-06-07 |
| NZ189057A (en) | 1982-03-23 |
| EP0002283A1 (en) | 1979-06-13 |
| AT371468B (en) | 1983-06-27 |
| DE2862307D1 (en) | 1983-09-29 |
| FI783664A (en) | 1979-06-03 |
| IL56094A0 (en) | 1979-01-31 |
| HU179984B (en) | 1983-01-28 |
| AU522997B2 (en) | 1982-07-08 |
| ATA860978A (en) | 1982-11-15 |
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