Note: Descriptions are shown in the official language in which they were submitted.
3L13~3~;
The lnvention relates to therapeutic agents which are
novel derivatlves of 4-amino-2-plperldlnoqulnazoline, and 19
partlcularly concerned with d~rivatives having a substituted alkoxy
group in the 4- positlon o~ tha plperidino ring. Such compou~ds
S are useful a~ re~ulator~ of the cardiovascular syste~ and, in
partlcular, in the treabment of hypertensio~.
Th~ novel compounds o~ the invention are tho~e hav~ng
the general form ~a:-
,N3 0 X CX2
N~
. NE~2
10 wherein R i9 Cl-C4 alkyl, benzyl or(C3-C6 cycloalky~methyl; R is C~-C4
X i9 -C~2C~2- substituted by a phenyl group and optionally
by 1 or 2 methyl groups;
. , .
and- R Ls hydrogen, Cl-C4 alkyl, or phenyl
optionally su~stltuted by one or two substituents selected from
15 Cl-C4 alkyl, Cl-C4 alkoxy, halogen, CF3, -CONR R and -S02MR R
: 3 4
wherein R and R each represent hydrogen or Cl-C4 alkyl;
and the pharmaceutically accept~ble acid additlon salts thereo~.
~,
.
','
~ (RLC. 290)
,
..
~L3~3~
Pharmaceutically acceptable acid addition salts ~e those
formed from acids whi~h form non-toxic acid-addition salts contain~
ing pharmaceutlcally acceptable anions such a3 the hydrochloride
hydrobromide, sulphate or bisulphate, phosphate or acid phosphate,
ac~tate, maleats, fumarat~, lactate, tartrate, citrate, g~uconate,
s ccharatc or p-toluQ~esulphonate salts.
Th~ cDmpounds of the inventlon cont~ining one or more
a3ymmetric centre~ will exist as one or re palrs of enantiomer~,
and such pairs or individual enantiomer~ may be separabl~ by physical
method , e.g. by fractional crystRllisation of suitable q~lts.
The invention lncludes the separated pairs as well a~ mi~ture~
thereof, as rac~mic mi~tures or as separated d- and l- optloaIly active
isomeric forms.
"~alogen" means fluorine, chlorin~, bromine or lodine
C3 and C4 alkyl and alX~ ~ groups may be straight or
branched chain.
In one aspect o the invention R is Cl-C4 alkyl_
R is preferably C~3, C2~5, ben~yl or cyclopropylmet~yl.
R i~ preferably CH30
R is prefexably H, methyl, ethyl or phenyl.
~ i~ pref2rably -C~(phenyl)C~2-, -C~2C~(phenyl)- or
{:~2C(CE~3) (phenyl)--
-~ The preferred individual compound3 are those of Examples 1
and 3.
~; 25 The compounds o~ the in~ention can be prepared by the
following routes:
(PLC. 290
~31~36
~1) The compounds of the inv~ntion ln which R is Cl-C4 alkyl or
benzyl can be prepared by the following ~cheme:
~ ~ 3 x o~2 ~N~--X ~112
N N
R0 2 R0 2
~II) ~III) (I~
R, Rl, R and~X re as de~ined above and Q repre~ents a
facile leaving group such as chloro, bromol iodo, (Cl-C4 aLkyl)thio
or ~Cl-C4 alk~L) sulphDnyl.
Q ls preferably Cl or Br.
.
. ' ~ .
In a typical procedure the react~nts are heated t~gether,
e.g. at a temperature o~ from 70 to 130 C, preferably under refIux,
in an inert organic sol~ent, e.g. n butan~l, for periods of up to
about 48 houxs. The product can be lsolated and puxified by con-
ventional pr~cedur2~.
The intermedlate o~ the fo~m~la (II) and ~III) are ei~her
knwwn co~pounds or can be prepared by procedures a`nalogous to those
of the prior art. The preparation of many intermediates of the
fonmula ~III) is in fact illu~trated in the Preparatlons given
herein~after.
~LC. 290)
.~ .
36
,
- _ 5 _
(2) The CCmpOUndB in which R i8 Cl-C4 alXyl or(C3-C6 cyclo-
alky ~ ethyl can be prepared v~a the following reaction sche~e:
.
R;l ~ N ~ N ~ o - X - QR2
PhC~20 ~ N
(IA) 2
ydkogena ~ Pd/C 2
R O ~ N ~ N ~ O - X - OR
~O ~ N
V) ~.Q~Q i~ a fac~le leaving group, preferably.Cl,
se ~ B,r or I)
R10 ~ N ~ N ~ O - X - OR
RO
~; (I9~ 2
The hydrogenation may be ca~ried out by conventlonal
procedures, e.g. by hydrogenat~,ng th~ compound of the formula (Ia)
-` ~ in a suitable solvQnt, aOg. ethanol, over a Pd/C catalyst, typically
', at r~om t~perature and 15 p.s.i. for a few hourq.
'`~ 10 ~he hydroxy~comEound (IV) can then be react2d with ~he
,~ , compound o~ th~ formula RQ in a suitabLe solvent, e.g. dimethyl-
form1mide, in the pxesence of a base, e.g. sodium hydroxide,
~ , and under a nitrogen at~osphere. Generally long reaction times are,
'- nece6~ary, e.g. up to 24 hours. The product may be isolat~d and
",~ 15 purified by con~ent1onal procedure
.
.~ The starting matexials of the fonmula tIA~ may be
prepared vLa route (.) ~bove,
.
,
~ ~3~3~
,, - -
. .
. .
.
~ ( ~ The phanmaceutic~lly acceptable acid addition salts of
.~ . the c~mpounds of th~ formula (I) can be prepared by conventlonal
,
pro~edures, e.g. by:mixi~g ths free base witX the appropriate acid
in a suitable solvent, e.g~ iso-propanol, filterlng, and i~
nace3sary, recry3tallising the thu~-produced salt to purity. Often
of course the product of route (1) wlll.b~ in the fDrm o~ an acid
addition salt.
The antihyperte~sive acti~lty of the compounds of the
invention is shown by.thair abllity to lower the blood preqsure of
conscious ~pontaneously hypertensive rat3 and conscious renPlly
hypertensive dogs, when admini~tered orally a~ doses o~ up to 5 mg/kg.
The compounds of the in~ention can be administered alone,
but will generally be administered in adm~ture with a pharmaceutical
carrler ~elect~d with regard bo the intend2d route of adm~ni tratio~
and st~ndard pharmaceu~ical practice.
.
,:
::
(PLC. 290)
.
.
-- 7 --
For example, they can be administered orally in the form of tablets
containing such excipients as starch or lactose, or in capsules
either alone or in admixture with excipients, or in the form of
elixirs or suspensions containing flavouring or colouring agents.
S They can be in~ected parenterally, for example, intramuscularly,
lntravenously or subcutaneously. For parenteral administration,
they are best used in the fonm of a sterile aqueous solution which
may contain other solutes, for example, enough salLs or glucose to
make the solution isotonic.
Thus the invention also provides a pharmaceutical compo-
sition comprising a compound of the formula ~I) or a pharmaceutically
acceptable addition salt thereof together with a pharmaceutically
acceptable diluent or carrier.
The compounds of the invention can be administered to
humans for the treabment of hypertension by either the oral or
parenteral routes, and can be administered orally at dosage le~els
approximately within the range 1 to 50 mg/day for an average adult
patient (70 kg), given in a single dose or up to 3 divided doses.
Intravenous dosage levels would be expected to be ab~ut -5th to-lOth
~; 20 of the daily oral dose. Thus for an average adult patient,
individual oral doses in ta~let or capsule form will~enerally be
in the range from 1 to 50 mg of the active compound. Variations
; will necessarily occur depending on the weight and condition of the
sub~ect being treated and the particular route of administration
chosen as will be known to those skilled in the art.
(PLC. 290)
~.3 3~
~ he invention yet further provides a method of trea~ing
an animal, including a human being, having hypertension, which
comprises administering to the animal an antihypertensive amount
oE a compound of the formula (I) or pharmaceutically acceptable
acid addition salt thereof or pharmaceutlcal composition as defined
above.
The following Examples illustrate the invention:-
;~ .
:
(PLC. 290)
: -
-
3~L31~3~
E2~MPLE 1
Preparation of 4-Amino-6,7-dimethoxy-2-/4-(2-ethoxy-1-phenylethoxy)
. . , . _ . _ . , _ _
piperidino7quinazoline hydrochloride
3~Cl C ~N ~
C}13 N~2 _ ~ ~ ~ N 2 2 5
4-~mino-2-chloro-6,7-~methoxyquinazol~ne ~2.6 g) and
4-~2-eth~xy-1-phenyleth~xy)piperidine (3.0 g) in n-butanol (100 ml)
~; w~re heated undQr reflux for 22 hours. The ~olution wa9 then
cooled, f1.ltered and the filtrate evaporated in va~uo. The residue
was trituxated with diethylather and recrystallised twice from
iscpropanol to give ~
; ethoxy)piperidino7quinazoline hydrochloride (2~0 g), m.p. 229 -
230.
~: ~
~ound:C, 61.0; ~, 6~9; N, 11.5
C25~32N44O~C1: C, 61.4; ~, 6.8; N, 11~5.
(PLC..290)
.
~L~3~63~ .
-- 1o-- _,
EX~MPLE 2
PreE~ration of 4-Amlno-6,7-Dimethoxy-2-~4-~2-phenoxy-1-phenylethoxy2
~ , . .
piparldlno7quinazoiine hydrochloride hydrate
~33 ~ ~ 33O =
C~ ~ ~ ~ N ~ 2
2 3 N~2
\=/-
4-Am.~no-2-chloro-6,7-dlmethoxyqyinazoline (1.44 g) and
4-(2-phenoxy~ henylethoxy)piperidine (2.0 g2 in n-~utanol (100 ml)
were heat~d und~r reflux for 20 hours. The solvent was then
evaporated in ~acuo~ the re~idue triturated with ether and crystal-
lised ~rom ~ ropanol. The solid was partitioned between chlorofvrm
: 10 and aqueous sodium carbonate sDlution, the chlorofonm extract
dried (MgSO ~ and the ~olvent e~aporated ~n vacuo. Ihe residue wa3
4 ~ _
chromatographed on ~ilica (100 g2 eluti~g with chloroform ollowed
by chlorofo ~ metha 1 (20:1). Fractions containing the product
were oom~ined, the ~D}Vent ~vapora~ed in vacuo and the resldue
converted to the hydrochloride salt by treatment of a chloroform
solution wlth ethereal h~drogen chloride.
,
(PLC. 290)
3~
-- 11
The sol'~d hydrochloride salt was collected and recrystallised from
isopropanol to give 4-amino-6,7-dimethoxy-2-/4-~2-phenoxy-1-phenyl-
ethoxy)piperidino7quinazol~ne, hydrochloride hydrate, ~0.85~ -m.p. 202 -
204.
Analysis ~:-
Found: C, 62.8; H, 6.1; N, 10.0
alculated for C29H32N4O4.HCl.H2O: C, 62.8; H, 6.4; N, 10-1-
EXAMPLES 3 ~ro 6
The following compounds were prepared similarly to the
previous Examples, starting from 4-amino-2-chloro-6,7-dimethoxy-
quinazol~ne and the appropriate plperidine, viz., the product of
Example 3 was prepared similarly to Example 1, and the products of
Examples 4, 5 and 6 were prepared similarly to Example 2, but the
~ product of Example 5 was not converted to a hydrochloride salt.
:'
; '
:;:
,';
~ (PLC.,290)
` '
, .
.
~L~3~;3~i :
-- ~ 2 -- .
~- ' '.
~ ~ . ~ U ~ ,
:~ b~ ~ ~-
~ ~ 3~ 3~
~;~ . ' .
(RLC: 290
~L~3~;3~i
~ ~, ',
z ~o~ a) ~ ~
U ~
(PLC: 290)
- ~ '
~L~3~;3ti
- 14 -
EXAMPLE 7
Preparation of 4-Amino-6-cyclopropylmethoxy-2-/4-(2-ethoxy-1-
phenylethoxy)piperidino7~7-methoxy qulnazoline, D(+) tartrate
4-Amino 2-/4-(2-ethoxy-1-phenylethox~)piperidin~-6-
hydroxy-7-methoxyquinazoline hydrochloride (0.75 g) in dimethyl-
formamide (50 ml) and sodium hydroxide solution (1 ml, 5N) was
stirred at room temperature under an atmosphere of nitrogen for 40
minutes in the dark. Cyclopropylmethyl bromide (0.27 g) was then
added and the solution stirred under N2 fox 20 hours. Potassium
iodide (5 mgs) followed by further cyclopropylme~hyl bromide (0.27 g)
were added and stirring was continued for 2 hours at room temperature.
The solvent was evaporated in vacuo, and ~he ~esidue was ~aken up in
H2O (50 ml), kasified to p~ l2 with 2N sodium hydroxide, and extracted
-~ with ~hloroform ~3 x 100 ml). The combined chlorofonm la~ers were
dried (Na2SO4) and the solvent evaporated in vauco to give a semi-
solid. The product was chromatographed on silica (7 g) eluting
with chloroform. Fractions containing the product were combined and
the solvent evaporated in vacuo. The residùe was converted to the
tartrate salt by treatment of a chloroform solution with a solution
of D(~) tartaric acid in ether. The resulting solid was filtered
off, washed with ether and dried under reduced pressure to give
4-amino-6-cyclopropylmethoxy-2-/4-(2-ethoxy-1-phenylethoxy)piperidino7
(115 mg), m.p. 142 - 145.
Analysis %:-
25 Found: C, 59.8; ~, 6.5; N, 8.9.
Calaulated for C28336N44 C4d66
,~ .
~'
' '
~3~3~ ' -
. . .
- 15 -
ExAMæLE 8
Pr ~ o~ 4-Amino-6-ethoxy-2-/4-(2-ethoxy-1-pheny}ethoxy)
piperldi~o7-7-methoxyquinaæollne h~droiodide
~he tltle compound wa~ prepared similarly to E$ample 7 ¦ -
starting from 4-amino-2-/4-(2-eth~xy-1-phenylethoxy)piperidino7-6-
hydroxy-7 methoxy~inazoline and ethyl iodide in the presence of
sodium hydroxide,and had a m.p. of 227 - 228. t
Anal~sls
Found: C, 52.1, ~, 5.8, N, 9.
Calculated f~r C26~34N44 ~I - C, 52.5, ~, 5.9, ~, 904.
~j~
Preparation o~ 4-Amino-6-~enzyloxy-2-/4-(2-ethoxy-1-phenylethoxy) ~--
~ I
- piperidin~ th~ ~line, hydrochloride
4-Amlno-6-benzyloxy-2-chloro-7-methoxyquinazoline (0.72 g)
/J. Med. Chem. 1977, 20, 1467 and 4-(2-ethoxy-1-phenylethoxy) -
piperidine (0.57 g) i~ n-butanol (~0 ml) were heated undier re lux
for 30 hours. The solvent wac evapRrated in ~ -and the residue t~-
- turated wlth ether to give a solid whlch was recrystalllcied ~rom _ -
p~opa~ol/dilsopropylether to give 4
~ hydro~hloride (7~0
mg). A sample recry~itallised from ethanol had a m.p. of 238 -
240.
Anal ~ ~ :-
Found: C, 65.5; ~, 6.5; N, 10.0
Calculated or C31~36N44-aCl C, 65.9; ~, 6.6; N, 9.9.
~1.3~
-lG-
The following Preparations illustrate the preparatlon
of certain of the starting materials:- -
Preparation A
Preparation o~ 4-(2-hydro yphenethyloxy)piperidine
N-~cetyl-4-hydroxypiperidine (5.0 g) in tetrahydrofuran
(THF)(50 ml) was added to a stirred suspension of sodium hydride
(1.84 g, 50~ dispersion in mineral oil) in tetrahydrofuran (THF)
(25 ml) under an atmosphere of nitrogen. When effervescence had
ceased, styrene oxide (4.6 g) in THF (25 ml) was added, then the
reaction mixture was diluted with dimethylformamide (DMF)(25 ml)
and stirred at 60 C for 18 hours. After addition of isopropanol
to the cooled solution, the solvent was removed in vacuo, the
residue ~reated with water, ad~usted to pH 4 with 2N hydrochloric
~; ac~d, and extracted withcHoroform. The chloroorm extract was
dried (Na2SO4) and the solvent evaporated in vacuo to give N-acetyl-
4-(2-hydroxypheneth~loxy)piperidine. This product in ethanol (50 ml)
and 5N sodium hydroxide solution (100 ml) was heated under reflux
for 3 hours. The solvent was then removed in vacuo, the residue
taken up in water, extracted with chloroform, dried and the
solvent evaporated in vacuov The product in chloroform was con-
verted to the hydrochloride salt by treatment with ethereal hydrogen
chloride and evaporation of the solvent.
.,
''~
:
~ (PLC. 2~0)
.~.................................. .
, ,
'
,'~, ' .
.
~3~3t;
The residue wa~ taken up in me~hanol, ~reated with ether, the
precipitated solid separated and recrystallised from isopropanol
_ to give 4-(2-hydrox~phenethyloxy)~iperidine h~drochloride tO.6 g),
m.p. 174 - 175C.
Analysis ~:-
Found. C, 60.1~~, 7.8; N, 5.2
Calculated ~or C13~19N02.HCl: C, 60.6; ~, 708; N, 5.4.
. ~ .
Prepar~tion of 4-(2-othoxyphenethyloxy)piperidlne
10 N-Acetyl-4-(2-hydroxyphenethy.toxy)piperidine (8.0 g),
prepared as in Preparation A,and 1,2-dimethDxyethane (0.3 g) in dry
DMF (50 ml) were added dropwise to a stirred suspension of sodium
hydride (2.96 g, 50~ disper.~ion in minerat oil) in dry DMF (50 ml).
The suspension wa~ stirred at room temperature for 3.5 h~ur~,
cooled to 0-5 C then a solution of ethyl iodide (9.6 g) in D~F
~25 ml) added dropwise. The mixture was allowed to warm to room
temperatur~ ~20C.), then st~rred at room temperature for 2 hours.
Isopropanol ~75 ml) wa added, the solvent rqmoved in vacuo and
the residue partitioned between chloro~orm and water. The chloro-
form layer was dried and the solYent evaporated in vacuo to giveN-acetyl-4-(2-ethoxyphenethyloxy)piperldine ~5.2 g).
(PLC. 290)
. . .
~3~i3~
This product ln ethanol ~50 ml) and sodium hydroxide solution
(50 ml, 5N) was heated under reflux for 3.5 hours. The organic
solvent was removed in vacuo and the aqueous residue extracted
with chloroform. The organic extract was dried (Na2SO4),
evaporated in vacuo, then the residue partitioned between 2N
hydrochloric acid solution and ether. The aqueous phase was then
basified with sodium carbonate solution and extracted with chloro-
form. The chloroform extract was dried (Na2SO4), the solvent
evaporated in vacuo, then the residue was taken up in ether and
converted to the oxalate salt. Recrystallisation from isopropanol
gave 4-(2-ethoxyphene hyloxy)piperidine~oxalate salt (1.6 g),
m.p. 136 - 137C.
Analysis %:-
Found: C, 60.3; E, 7.4; N, 4.1
CalcUlated for C15E23NO2-C2 2 4 C, 60.2; H, 7.4; N, 4.1.
(PLC. 290)
:~3~
~ ~ Prep~ration C
-- Preparation of 4-(2-etho ~ h ny~ethoxy~piperidine
,
1. Na~ ~
~ ~ ~ f ~02C2~S
~ ~ J 3~ ~-b~ L~Lo ~~~ ~~ ~rJ
f o ~o
C~3 C~3
Li~El,g
OC2~5 ~ c~2
N 3~ NaO~/C~3o~ ~
~ ~ C~ O
... .. . .. .... .... .. . . -- , .. -- ..
(i) ~[y =~ , .
.~. - N-Acetyl-~-hYdro~ypiperidlne (27.5 g) in dry DMF (100 ml)
wa.~ added 510wly to a stirred suspension o~ sodium hydride ~25 g,
50~ di persion in mineral oil) in D~F (150 ml) and 1,2-dimethoxyethane
( 1 0 m~
"~
. (PLC. 290)
:
- . .
, ' ~ ' ' ~
:
~L3~
~he ~uspenslon was stirred at room temperature for 3 hours.
CC -BromophenyLacetic acid t45 g) in DMF ~250 mL) was then added
slowly with ice/water cooling. The miKture was stlrred at room
temperature for 20 hour~, then isopropanol added and the solvent
avaporated in vacuo. The rssidue wa~ taken up ln water, ~cldlfied
to pH 1 with 2N hydrochlorlc acid and e~tracted four times with
chloroform (300 mL). The combined chLoroform eKtracts wre washed
with watec and brine, dried (MgS04) and the solvent evaporatea
ln vacuo. The resldue in anhydrous etha~ol (450 ml) with concen-
trated sulphuric acid (9 ml) wa~ heated und ¢ reflux for B ~ours.
The cooled solution was cautiously neutralised with aqueou~ sDdium
carbonate solution and the organlc solvent evaporat~d in vacuo.
The aqueou~ residue wa~ ad~usted to pH 10 with sodium carbonate
solution and extracted twice with chlorofo D . The c~bined chlo m - -
5 form extr~cts were dried (MgSD ), and evaporated in vacuo.----
Distillation of the residue gave ~C-(N-acety~-4-piper~dinoxy)
_ _ _ . _
phenylacetlc acid, ethyl ester (3/.2 g), b.p. 190 - 194C/0.18 mm.
A~.y8i!3 %:--
Found: C, 66.4; H, 7.8; N, 4.5
Cal~ulated for C17H23N04: C, 66.9; ~, 7.6p N, 4.6.
.
(~LC. 290)
~3~
~.,
(ii) N-Acetyl-4-(2-hydroxy-1-phenylethoxy)piperidine
Llthium borohydride (3.24 g) was added portionwise to a
solution of ~C -~N-acetyl-4-piperidinoxy)~phenylacetic acid, ethyl
ester (11.2 g) in dry THF (200 ml). When the hydrogen evolution
had subslded the reaction mixture was heated under reflux for 4
hours. Water was added to the cooled solution, the solvent
evaporated _ vacuo, then the residue taken up in chloroform (200 ml)
and washed with dilute hydrochloric acid, water and brine. The
chloroform extract was dried (MgS04) and the solvent evaporated
in vacuo. Thin layer chromatographic analysis of the product
indicated that reduction was incomplete~ therefore the product in
THF (100 ml) was treated with a further quantity of lithium boro-
hydride (3.24 g) and heated under reflux for 4 hours. The reaction
mixture was treated as above to give N-acetyl-4-(2-hydroxy-1-phenyl-
ethoxy)piperidine (9.5 g) as an oil which solidified on standing.A sample crystallised from ether and had a m.p. of 92 - 94 C.
Analysis %:-
Found: C, 68.1; ~, 8.1; N, 5.7
Calculated ~or C15H21N03: C, 68.4; H, 8.1; N, 5.3.
' :
,~
:'
" .
(PLC. 290)
. ,
','
,,
,
'
` ~3~6
- 22-
(iii) 4-(2-Ethoxy-l-phenylethoxy)piperidine
This compound was prepared similarly to Preparation B,
starting from N-acetyl-4-(2-hydroxy-1-phenylethoxy)piperidine
(prepared as ln part (ii) above) and ethyl iodide, followed by
basic hydrolysis of the N-acetyl group. A sample was characterised
as the oxalate salt, m.p. 137 - 139C.
Analysis ~:-
Found: C, 59.9; H, 7.4; N, 4.0
Calculated for C15~23NO2-C2R2O4 C, 60.2; H, 7.4; N, 4.1.
Preparation D
4-(2-Phenoxy-l-phenyleth~xy)piperidine
.
N-.~cetyl-4-(2-hydroxy-1-phenylethoxy)piperidine (5.25 g)
(prepared as in Preparation C ~i~diethyl azodicarboxylate (4.2 g),
triphenylphosphine (6.3 g) and phenol (2.25 g) in dry tetrahydro-
furan (100 ml) were stirred at 0C for 2 hours then left at room
temperature for 48 hours. The solvent was evaporated in vacuo,
the residue taken up in refluxing diethyl ether (50 ml) and left
in a refrigerator overnight. The precipitated hiproducts were
removed by filtration and the filtrate evaporated to dryness. The
residue wasagain taken up in ether, set aside to cool and the
~ precipitated solid fil~ered off. The ether filtrate was evaporated
~~ to dryness and the residue in me~hanol (50 ml) and sodium hydroxide
solution (30 ml, 5N) was heated under reflux for 5 hours.
(PLC. ~90
.~
. :
. ~
~, ' .
,. . .
:;
3 ~ ~ 3
- Z3-
The organlc 301vsnt wa~ r~moved in vacu , the aqueous residue l -
acidified to p~ 3 with 2N hydrochloric acld and extracted.twice
with ether, the organic extract3 being di~carded. The aqueou~ pha3e wa~
ad~uqted to p~ 12 wlth sodlum hydroxlde solutlon, extracted with ether (3 x
S 100 ml), the ether extract~ comhined,drled ~MgS04),and the solvent evaporate:
in vacuo to give 4-t2-phen~xy-1-~heny.lethoxy)piperidinQ ~3.55 g) as ..
an oil. A sample wa-~ converted to the oxalate salt which was
recrystallised from isopropanol and had a m.p. of 170 - 172C.
Analysi3 ~:-
.10 Found: C, 64.9~ ~, 6.6; N, 3.8
CalcUlated for C19~23N~2-C2~2 4 C, 6501;. ~, 6.5; N, 3_6.
:
,
~PLC. 290)
:~
: .
36
- 2~r-
Preparation E
Preparation of 4-(2-hydroxy-2-phenyl-n-propoxy)piperidine
2 3rC32 ~ ~ 3g(0~) O N2C - 03
' ~ 3 N~ON/
`CH3OH N
= IC= o H
3 CH3
(i) N-Acetyl-4-(2-ahenylallv~oxy)piperidine
N-Acetyl-4-hydroxypiperidine (13.6 g) in DMF (50 ml) was
added dropwise to a stirred suspension of sodium hydride (10 g,
50~ dispersion in mineral oil) in DMF (50 ml) under nitrogen. The
- mixture was stirred at room temperat~re for 3 hours then ~-(bromo-
methyl)styrene (20 g) in DMF (50 ml) was added dropwise. The
- 10 mixture was stirred at room temperature for 4 hoarsj then diluted
with water and extracted with chloroform (3 x 200 ml). The
combined chloroform extracts were dried (Na2S04), evaporated in
vacuo, and distilled to give N-acety~-4-(2-phenylallyloxy)Iiperidine
(25 g), b.p. 170 - 180C/0.3 mm with an n.m.r. spectrum in accordance
with this structure.
,-`~
' ,
(PLC. 290)
,
.,
,......... - .
.:
.
,
3~
- 25-
(ii) 4-(2-~ydroxy-2-phenyl-n-propoxy)piperidine
N-Acetyl-4-~2-phenylallyloxy)piperidine (4.0 g) in dry
THF (60 ml) was added dropwise to a stirred solution of mercuric
acetate (6.35 g) in water (60 ml) and the solution stirred at
room temperature for 1 hour. Sodium hydroxide solution (40 ml,
; 3N) and sodi~ borohydride (0.75 g) in sodium hydroxide solution
(40 ml, 3N) were then added dropwise to the stirred solution at 0C.
The grey suspension was stirred at 0C for 1 hour, glacial acetic
acid was added to pH 6, then the suspension iltered and the
filtrate extracted with chloroform (3 x 150 ml). The combined
chloroform extracts were dried (Na2SO4) and evaporated in vacuo
to give N-acetyl-4-(2-hydroxy-2-phenyl-n-propo~y)piperidine (2.1 g).
This product in methanol (30 ml) and sodium hydroxide solution
(20 ml, 5N) uas heated under reflux for 4 hours. The organic
solvent was evaporated and the aqueous solution extracted with
chloroform (3 x 20 ml), dried (Na2SO4) and the solvent evaporated
in vacuo to give 4-(2-hydroxy-2-phenyl-n-propoxy)piperidine (1.8 g)
as an oil. A sample was characterised as the oxalate salt which
recrystallised from ethyl acetate and had a m.p. of 132 - 13~ C.
Analysis %:-
Found: C, 58.8; ~, 7.1; N, 4.8
Calculated for C14H21NO2-C2 2 4 C, 59.1; H, 7.1; N, 4.3.
~ .
(PLC. 293)
:
. ' :
- 26-
Preparation F
Preparation of 4-(2-ethoxy-2-phenyl-n-propoxy)piperidine
_~ .
N-Acetyl-4-(2-phenylallyloxy)piperidine (7.0 g)(prepared
as ln Preparation E) in ethanol (10 ml) was added to a stirred
suspension of mercuric acetate (9.2 g) in ethanol (50 ml) at
room temperature. The mixture was stirred at room temperature for
1 hour then cooled to 0C. Sodium hydroxide solution (20 ml, 5N)
followed by sodium borohydride (1.03 g) in sodium hydroxide solution
(20 ml, 5N) were added to the stirred suspension and after 10
minutes glacial acetic acid was added to p~ 6. The suspension was
filtered, the filtrate concentrated and the residue partitioned
between chlorofoxm and water. The organic layer was dried (Na2S04)
and the solvent evaporated in vacuo. Gas-liquid chromatographic
(GLC) analysis of the product indicated incomplete conversion to the
desired product therefore the oxymercura~ion process was repeated
as ahove to giYe N-acetyl-4-(2-ethoxy~2-phenyl-n-propoxy)piperidine
(7.4 g), 84% pure by GLC. The product in ethanol (100 ml) and
sodium hydroxide solution (30 ml) was heated under reflux for 11
hours. The organic solvent was evaporated and the aqueous solution
was extracted with chloroform (3 x 30 ml). The combined chloroform
extracts were dried (Na2SO4) and the solvent evaporated in vacuo to
give ~ as an oil (3.8 g).
A sample was converted to the oxalate salt which was recrystallised
twice ~rom ethyl acetate then acetone and had a m.p. of 126 - 127 C.
~PLC. 290)
36
Analysis ~:-
Found: C, 60.4; H, 7.6; N, 4.1
Calculated for C16H25N02-C2 2 4 4 2
Preparation G
Preparation of 4-Amino-2-/4-~2-ethoxy-1-phenylethoxy)piperidino7-6-
_
hydroxy-7-methoxyquinazoline, hydrochloride hydrate
4-Amino-6-benzyloxy-2-/4-(2-ethoxy-1-phsnylethoxy)piperidino7
-7-methoxy-quinazoline, hydrochloride (0.9 g) in dry ethanol (150 ml)
was hydrogenated over 5% Pd/~. at room temperature and 15 p.s.i. for 2
hours. The catalyst was removed by filtration and the filtrate
evaporated to dryness in vacuo. The residue was triturated with
ether to give a white solid (0.S5 g). A sample (200 mg) was recrystal-
lisad from isopropanol to give 4-ami -2-/4-(2-ethoxy~ henylethoxy)
piperidino7-6~hydroxy-7-methoxyquinazoline, hydrochloride hydrate
(71 mg). m.p. 141 - 144.
Analysis %:-
,
Found: C, 58.0; ~, 6.5; N, 11.5.
Calculated for C24H30N44 ~Cl ~2
(PLC. 290)
