Note: Descriptions are shown in the official language in which they were submitted.
~2;~ 35
Novel 1,5-benzothiazepine derivatives and processes for
preparinq the same
This invention relates to novel 1,5-benzothiazepine
derivatives and processes for preparing the same.
U.S. Patent 3,562,257 discloses various benzothiazepine
derivatives such as 2-(4-methoxyphenyl)-3-hydroxy (or
S acetoxy)-5-[2-dimethylamino)ethyll-7-chloro-2,3-dihydro-1,5-
benzothiazepine-4(5H)-one. The U.S. Patent also dlscloses
that these benzothiazepine derivatives show an antidepressive
activity, tranquilizer activity and/or coronary vasodilating
activity.
As a result of various investiqations, the inventors have
no~ found that the novel compounds of the present invention
or the salts thereof are useful as an intermediate in the
synthesis of novel 5-alkyl-1,5-benzothiazepine derivatives
which show potent hypotensive activity and potent cerebral
or coronary vasodilating activity, and which are claimed
in our related patent application serial no. 474,421, of
which the present application is a division.
The present invention provides a compound of the
formula:
:
~:
,.,
-
- ~
s
-- 2
~Rl
~ N = ~ OR (I)
wherein Rl is lower alkyl or lower alkoxy, R2 is
hydrogen atom or lower alkanoyl, Ring A is a sub-
stituted benzene ring of the formula:
S ~a ~ R ~ ~e ~
Ra is lower alkyl, lower alkoxy, lower alkylthio or benzyloxy,
each one o~ Rb and Rc is lower alkyl, lower alkoxy or halogen
atom, and either one o~ Rd and R is fluorine atom and the
other one is hydrogen atom, or a salt thereof.
Representative examples of the compounds of the present
invention include those of the formula (I) in which R1 is
: lower alkyl of one to 4 carbon atoms such as methyl, ethyl,
propyl or butyl, or lower alkoxy of one to 4 carbon atoms
such as:methoxy, ethoxy, propoxy or butoxy; R2 is hydrogen
atom or lower alkanoyl of 2 to 4 carbon atoms such as acetyl,
propionyl or butyryl; Ring A is a substituted benzene ring
: of the formula:
: ~ :
:
:
~" : :: `
,
~231~3S
-- 3 --
R ~ R ~ Re ~
Ra is lower alkyl of one to 4 carbon atoms such as methyl,
ethyl, propyl or butyl, lower alkoxy of one to 4 carbon
atoms such methoxy, ethoxy, propoxy or butoxy, lower alkyl-
S thio of one to 4 carbon atoms such as methylthio, ethylthio,propylthio or butylthio, or benzyloxy; each one of Rb and Rc
is lower alkyl of one to 4 carbon atoms such as methyl,
ethyl, propyl or butyl, lower alkoxy of one to 4 carbon
atoms such as methoxy, ethoxy, propoxy or butoxy, or halogen
atom such as chlorine atom, bromine atom or fluorine atom;
and either one of Rd and Re is fluorine atom and the other
one is hydrogen atom.
A preferred subgenus consists of those compounds o~ the
formula (I) in which Rl is methyl or methoxy. Another
preferred subgenus consists of those compounds of formula
(I) in which R is methyl or methoxy, Ring A is a substituted
ben~ene ring of formula:
~ ,
.,
~,~. .
:
.
:~ . :
.. : . : :
lZ;~1!3S3S
~a ~ R ~
R is methyl or methoxy, and Rb and Rc are methyl, methoxy
or a chlorine atom. A further preferred subgenus consists
of those compounds of formul~ (I) in which Rl is methyl or
methoxy, R is hydrogen or lower alkanoyl, Ring A is a
substituted benzene ring of the formula:
Ra~ RC)~
R is methyl or methoxy, and Rb and R are methyl. Still
further preferred subgenus consists of those compounds of
formula (I) in which Rl is methyl or methoxy~ R2 is
hydrogen or acetyl, Ring A is a substituted benzene ring
of the Eormula:
R ,~
Ra is methyl or methoxy, and Rb and Rc are methyl.
On the other ~hand, suitable examples of the salt of
the compound (Ij include, for example, alkali metal salts
(e.g., sodium salt or potassium~salt~and~alkaline~earth
~, ~
.
' ~
~2:~363S
-- 5
metal salts (e.g., calcium salt or barium salt). Such
salts are readily obtained by treating the compound (I)
with, for example, alkali metal hydroxide or alkaline
earth metal hydroxide in a solvent.
While the compound (I) of the present invention can
exist in the form of two stereoisomers (i.e., cis and trans
isomers) or four optical isomers (i.e., (+)-cis, (-)-cis,
(+)-trans and (-)-trans isomers) due to the two asymmetric
carbon atoms involved therein, all of these isomers or
mixtures thereof are included within the scope of the
invention.
According to the present invention, the compound (I)
of the invention is a novel compound and may be prepared,
for example, according to the method shown by the follow-
ing reaction schem~:
:
:~ : : :
~, : '
,
, ~ ,
123~63S
-- 6
Step (II) ~ R
+ R -~-CH -CH-COOR ~ ~ COOR 4
(II) (III) / (IV)
Step ~I) Step (III ~Step (IV) ~
\ ~ R ~ ~ R
N ~ OH , Step (V) ~ S ~
H COOH
(I-a) (V)
Step (VI)
R
~ ~R
: : H
~::
(I-b)
wherein R1 and Ring A are the same as defined above, R3 is
; lower alkanoyl and R4 is lower alkyl.
Step (I) in the above-mentioned reaction scheme can be
accomplished by heating a~mixture of the compound (II) and
III) at 150 to 165C either in a solvent (e.g., xylene, di~
phenyl ether, p-cymene)~ or without solvent. It is preferred
: . ~ ^~, :
, .~ ,
~Z3~3S
to carry it out in an inert gas (e.g., argon). When the
compound (I-a) is obtained as a rnixture of two stereoisomers
(i.e., cis and trans isomers), they may be separated from
each other by their difference in solubility in a solvent
~ such as lower alkanol (e.g., ethanol) or by column chromato-
graphy.
The reaction of the compound (II) with the compound
(III), i.e., Step (II), can be accomplished by heating a
mixture of the compounds (II) and ~III) in a solvent (e.g.
toluene, acetonitrile, ben~ene, dioxane) or without solvent.
It is preferred to carry out the reaction at 25 to 110C.
When the trans isomer of the compound (III~ is used as the
starting compound, the threo lsomer of the compound(IV) is
obtained.
The subsequent optional hydrolysls of the compound
(IV), i.e., Step (IV), can be conducted by treating it with
an alkali metal hydroxide ~e.g., potassium hydroxide, sodium
hydroxide) or an alkali metal carbonate ~e.g., potassium
~ carbonate, sodium carbonate~) at O to 100C in a solvent (e.g.,
`~ ~ 20 aqueous methanol, aqueous~ ethanol).
If required, the compound ~V) thus-obtained may be
resolved into each optical isomers~ by using a resolving
agent such as p-hydroxyphenylglycine esters. For~example,
the optical resolution of;(+)-threo-2-hydroxy-3-(2-amin
methylphenylthio)-3-(4-methoxyp~enyl)~propionic acid or
,
(+)-threo-2-hydroxy-3-~(2-amino-4,5-dimethylphenylthio)-3-
:~ :
~: :
:
:. , : :
~.
: : .,. . : ,: ,. ..
3l~231~;3S
-- 8
(4-methoxyphenyl)propionic acid can be accomplished by the
steps of reacting said compound with an optically active
p-hydroxyphenylglycine methyl ester to form the diastereo-
isomeric salts thereof, and separating the diastereoisomeric
salts from each other by selective crystallization. Selective
crystallization is carried out by recrystallizing the diastereo-
isomeric salts from a solvent (e.g., methanol, ethanol).
After the optical resolution, the optically active compound
(VJ in free form can be recovered by treating the thus-
1~ obtained diastereoisomeric salt with an acid (e.g., hydro-
chloric acidJ or an ion-exchange resin.
The intramolecular cyclization of the thus-obtained
racemic or optically active compound (IV~ or (V), i.e.,
Step (III) or (V), can be carried out by heating at 110 to
l_ 160C either in a solvent (e.g., xylene) or wlthout solvent.
The intramolecular cyclization of the compound (IV) may
also be carried out at 0 to 50C in the presence of ~ethyl-
sulfinylcarbanion (CH3SOCH2~) (prepared from dimethylsulfoxide
and sodium hydride) in dimethylsulfoxide. Alternatively,
the intramolecular cyclization of the compound (V) may be
carried out at -10 to 70C in a solvent (e.g., dimethyl-
formamide, dichloromethane, tetrahydrofuran or a mixture
thereof) in the presence of a condensing agent such as
dicyclohexylcarbodiimide or a mixture of dicyclohexylcarbo- !
I
diimide and N-hydroxybenzotriazole.
~ ~ ''''
: , :
;
:'
~ `
':
1~3~;35
If required, the racemic modification of the compound
(I-a) thus-obtained may be resolved into each optical
enantiomers thereof by using (S)-1-(2-naphthylsulfonyl)-
pyrrolidine-2-carbonyl chloride as a resolving agent,
i.e., by the steps of reacting the compound (I-a) with
said pyrrolidinecarbonyl chloride to give a pair of dia-
stereoisomers, and then separating said diastereoisomers
Erom each other by selective crystallizatin or by column
chromatography. Hydrolysis of each diastereoisomers gives
the optically active compound (I-a).
The subsequent optional acylation of the compound
(I-a), i.e. Step (VI~, can be accomplished by reacting
said compound with a compound of the formula: R3-oH
(R3 is the same as defined above) (VI) or a reactive
derivative thereof.
The condensation of the compound (I-a) or a salt
thereof with a reactive derivative of the compound (VI)
can be conducted in a solvent in the presence or absence
of an acid acceptor. The reactive derivative of the
compound (VI) include, for example, lower alkanoic acid
anhydride (e.g., acetic anhydride, propionic anhydride)
and lower alkanoyl halide (e.g., acetyl chloride, pro-
pionyl chloride, butyryl chloride). The acid acceptor
includes, for example, pyridine, triethylamine, N-methyl-
piperidine, N-methylmorpholine, N-methylpyrrolidine and
N-ethyl-N,N-diisopropylamine. Acetic acid, chloroform,
:
.
~. ' ' ,
~3~$~3S
-- 10 --
dichloromethane, dimethylformamide and tetrahydrofuran are
suitable as the solvent. When an excess amount of acetic
anhydride is used as the reactive derivative of the com-
pound (VI), it is not always necessary to use the solvent
because said acetic anhydride serves as the solvent. It
is preferred to carry out the reaction at a temperature of
-10 to 140C, especially at a temperature of 20 to 140C
if the lower alkanoic acid anhydride is used as the reac-
tive derivative of the compound (VI); or at a temperature
of -10 to 100C if the lower alkanoyl halide is used as
the reactive derivative of the compound (VI).
On the other hand, when the compound (VI) is used in
the form of free acid, the condensation thereof with the
compound (I-a) or a salt thereof may be carried out in a
solvent in the presence of a condensing agent. The con-
densing agent includes, for example, dicyclohexylcarbodi-
imide, N,W'-carbonyldiimidazole, l-methyl-2-halopyridinium
iodide (e.g., l-methyl-2-bromopyridinium iodide), methoxy-
acetylene and (C6H5)3P-CC14. Methylene chloride,
1,2-dichloroethane, chloroform, benzene, toluene, tetra-
~; hydrofuran and dioxane are suitable as the solvent. It is
preferred to carry out the reaction at a temperature of 0
to 50C, especially at 0 to 25C.~
Alternatively, the compound (I) may be prepared by
reacting a compound of the ~ormula:
~: : :
- : ':
- ,. ,
~2;38~;35
-- 11 --
SH
2 (VII)
wherein Ring A is the same as def:ined above, with the
compound (III), reducing the resu:Ltant compound of the
formula:
~ ~ OH (VIII)
c ooR4
wherein Rl, R4 and Ring A are the same as defined above, to
give the compound (rv3~ and th~n treating said compound in
the same manner as described in Step (III) to (VI) of the
above-mentioned reaction scheme.
The reaction of the compound~(VII) with the compound
(III) can be accompllshed by heating a mixture of said
~: compounds at 20 to 80C in a solvent (eOg., acetonitrile,
toluene, benzene).; The reduction of the compound (VIII)
can be accomplished~by reacting:it with a~reducing agent
(e.g., stannous chloride ln hydrochlorio~acid) at 0 to
50C in a solvent (e.g. aoetic acid).~ The reduction of
the compound tVI:II) may be~also accomplished by catalyt;ic
hydrogenation.
The compound (IV), (V) or (VIII) of the presen~t ~ :
invention:involves four optical isomers due to the two : ::
:: : : : ~ :: : :
.
,. ;-, : ::
~ : : `.: ., ,
~L23863S
- 12 -
asymmetric carbon atoms at 2- and 3-positions o the
propionic acid compound (IV), (V) or (VIII). However,
since the above-mentioned reactions according to the
invention can be carried out without racemization, the
compound (I) of the present invention in an opticall~
active form can be readily obtained from the corres-
ponding optically active isomer of the compound (IV),
(V) or (VIII).
The compound (I) of the present invention is useful
as an inter~ediate in the synthesis of novel 5-alkyl-
1,5-benzothiazepine derivative of the following for~ula:
/~Rl
i ~ RS (IX)
2 2 ~ R6
wherein each one of R and~R is lower alkyl and R1, R2
and Ring A are the sa~e as defined above.
The compound (IX) may be prepared from the compound
(I) of the present invention, for example, by condensing
the compound (I) or a salt thereof with amino alkyl compound
of the for~ula: :
:
: j R 5
X-CH2C-'12N ~ (X~
.
:, ~, .
; .
38~i35
- 13 -
~herein X is halogen atom, and R and R are the same as
defined a~ove, or a salt thereof (e.g., hydrochloride or
hydrobro~ide)in the presence or absence of an alkali agent
such as alkali metal hydroxide (e.g., potassium hydroxide or
sodium hydroxide), alkali metal carbonate (e.g., potassium
carbonate or sodium carbonate) and alkali metal hydride
(e.g., sodium hydride) in a solvent (e.g., acetone, ethyl
acetate, dimethylsulfoxide, dimethylformamide, acetonitrile,
tetrahydrofuran and dioxane) and, ~rhen R2 is hydrogen, if
lo required, condensing the resulting product with the
compound (VI) or a reactive derivative thereof in the same
manner as the condensation of the compound (I-a) with the
compound (VI) or a reactive derivati~e thereof.
As mentioned hereinbefore, the thus-obtained compound
(IX) has a potent hypotensive activity, a potent cerebral
or coronary vasodilating activity and a potent platelet
aggregation-inhibiting activity. Therefore, the compoun~
(IX) is useful for the treatment, amelioration or prophy-
laxis of hypertension; cerebral diseases such as cerebral
vasospasm or cerebral infarction; and heart diseases such
as angina pectoris, arrhythmias or coronary or cardiac
infarction.
Practical and presently preferred embodiments of the
present invention are lllustratively shown in the following
lines. Throughout the specification and claims, the term
: :: : : : :
~: '
~LZ3~i3S
- 14 -
"lower alkyl n~ 1l lower alkoxy", "lower alkanoyl", "lower
alkanoic acid anhydride" and "lower alkylthio" should be
interpreted as referring to alkyl of one to 4 carbon atoms,
alkoxy of one to 4 carbon atoms, alkanoyl of 2 to 4 carbon
atoms, alkanoic acid anhydride of 4 to 8 carbon atoms and
alkylthio of one to 4 carbon atoms, respectively.
Concomitantly, throughout t:he specification and claims,
the term "threo" means that the hydroxy and substituted-
phenylthio groups substituted at the 2- and 3-positions of
propionic acid have threo-type configuration (i.e., said two
groups are placed on opposite side of the central bond in
the Fisher's projection formula).
Example l
A mixture of 13 g of 2-amino-4-methoxy-thiophenol and
17.6 g of methyl (+)-trans-3-(4-methoxyphenyl)glycidate is
heated at 160C for 16 hours under argon atmosphere. After
cooling, ethanol is added to the mixture. The precipitated
crystals are collected by filtration and recrystallized from
chloroform. 4.52 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-
2~ 7-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are
obtained.
M.p. 220 - 222C
The mother liquors (The ethanol and chloroform solutions)
are comblned and evaporated to remove solvent. The residue
is purified by silica gel chromatography (Solvent: chloroform).
:
` : . , i
.' ; ~ ~ :
123!3i3S
- 15 -
2.9 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-7-methoxy-2,3-
dihydro-1,5-benzothiazepin-4(5~)-one and 1.1 g of (+)-trans-2-
(4-methoxyphenyl)-3-hydroxy-7-methoxy-2,3-dihydro-1,5-benzo-
thiazepin-4(5H)-one are further obtained from the eluates.
(+)-Trans-isomer:
M.p. 189 190C (recrysta:Llized from a mixture of
ethyl acetate and n-hexane~
Examples 2 to 10
The following compounds are obtained from the corres-
ponding starting materials in the same manner as descxibedin Ex,,ample l.
a ~ SH Rl ~ CH-CH-COOCH3 S ~ R
R ~ ~ R ~ ~ OH
NH2 H O
(II) (I-a)
~ ~ 1
:
;:: ~ : :
:: :
: ~
:
,
`
:
1;~ ;3S
- 16 -
_ _ . .. .
Compound (I-a)
Example ~- a
Nos. ~ R M.p., etc.
_ . . ~ _ _ . . . _ . _ _ . . _ . . _
Cis-isomer: 204 - 206C
2 OC~3 8-OCH3 (recrystallized from ethyl acetate)
Trans-isomer: 150 - 152C
(recrystallized from a mixture of
ethyl acetate and n-hexane~
. ~
Cis-isomer: 225 - 227 5C
3* OCH3 6 CH3 trecrystallized from a mixture
of dimethylformamide and ethanol)
Trans-isomer: 231 - 233C
(recrystallized from a mixture of
dimethylformamide and ethanol)
__ I
Cis-isomer: 182. 5 - 184. 5C
4 CH3 8-CH3 (recrystallized from a mixture of
dimethylformamide and ethanol)
. . _ _ . _ _ _ . _ _ . _ .
Cis-isomer-hemi hydrate: 208 - 210C
5 OCH3 6-OCH (recrystallized from a mixture of
3 chloroform and n-hexane)
~Cis-isomer: 202 - 206C
6 CH3 8-OCH3 (recrystallized from ethanol)
Trans-isomer: 185 - 188C
(recrystallized from ethanol)
_ , .,
Cis-isomer: 172 - 174C
7 OCH3 8- Irecrystallized from a mixture of
OCH C H~ dimethylformamide and ethanol)
-- -- ------ -- -- -- -- . -- -- ~ _ . _ . _ _ _ _ _
: : Cis-isomer: 219 - 221C
8 OCH3 8-CH3 (recrystallized from dimethyl-
formamide)
Cis-isomer: 218 - 22IC
: 9 OCH3 7-CH3 (recrystallized from dimethyl-
: formamide)
10 CH3 ~- Cis-isomer: 164 - 165C
OCH C H (recrystallized from ethanol)
_ _ ?~6 5 ~ _ _ _
:
::
'` ' ~ ' ~ ~';' ' ;
:.
:
;
;
:
~23~;35
- 17 -
Note: The compounds listed in the Table are all racemic
compounds.
* : Methyl (+)-threo-2-hydroxy-3-(4-methoxyphenyl)-3-
(2-amino-3-methylphenylthio)propionate is obtained
in addition to the compounds listed above.
M.p. 98 - 110C kecrystallized from ethanol)
Example 11
(a) A mixture of 29.1 g of 2-amino-5-methyl-thiophenol,
47.8 g of methyl (+)-trans-3-(4-methoxyphenyl)glycidate and
lO300 ml of toluene is heated at 60 - 65C for 3 days and
then at 70 - 80C for 2 days. The mixture is evaporated
under reduced pressure to remove solvent. Benzene is added
to the residue and the mixture is extracted with conc.
hydrochloric acid-water (1:1). The extract is neutralized
with potassium carbonate, and the aqueous solution is extracted
with benzene. The extract is washed with water, dried and then
evaporated to remove benzene. The residue is chromatographed
on silica gel (Solvent: benzene-ethyl acetate = 10:1). The
crude product thus obtained is recrystallized from a mixture
of ethanol and isopropyl ether. 15.8 g of methyl (~) threo-2-
.
~; ~hydroxy-3-(2-amino-5-methylphenylthio)-3-(4-methoxypnenyl)-
propionate are obtained~
M.p. 110 - 112~C
~;The following compounds are obtained from the
~ 25 corresponding startlng materials in the same manner as~
above.
, ~
~,_
,
- : :
: ` ` :
.
: :
.
~Z~3S
- 18 -
SH Rl ~ CH-CH-COOCH3 ~ R
Ra ~ (III) __~ ~a ~ ~ OH
NH2 H2 COOCH3
(II) (IV)
Compound (IV)
Nos.
R1Ra Reaction M.p., etc.
conditions
-
107 - 108C
i OCH34-CH3 60 - 70C, (recrystallized from
4 days ethanol-isopropyl ehter)
60C, 4 days 114 - 114.5C
ii CH35-CH3 + (recrystallized from
100C, 8 days isopropyl ether)
90C, 114 - 116C
iii* OCH5-SCH 20 hours (recrystallized from
3 3 ethanol)
: 90C, 130 132C
iv OCH4-SCH 20 hours lrecrystallized ~rom
3 3 ethanol)
70 - 75C, 99.5 - 102.5C:~
V OCH 5-OCH3 5 days ~ (recrystallized from
3 isopropanol)
Note: The compounds listed in the Table are all
(+)-threo isomers.~
* : (+)-Cis-2-( 4-methoxyphenyl)-3-hydroxy-8-methyl-thio-
2;3-dihydro-lt5-benzothiazepin-4(5H)~one is obtained ,
in addition to the compound Iisted above.
M.p. 183 - 184C (recrystallized from a mixture
of dlmethylformamlde and ethano1~ ~
:
: : ,
:
: ~ ~ .: . '
~;2313~35
-- 19 -
(b) A mixture of S g of methyl (~)-threo-2-hydroxy-
3-(2-amino-5-methylphenylthio)-3-(4-methoxyphenyl)propionate,
50 ml of an aqueous 5 ~ sodium hyclroxide solution and 50 ml
of methanol is stirred at room temperature for 2 hours.
After the reaction is completed, the mixture is adjusted to
pH 3 to 5 with 10 % hydrochloric acid under ice-cooling. The
precipitated crystals are collected by filtration, washed
with water, dried and then recrystallized from methanol.
4.3 g of (+)-threo-2-hydroxy-3-~2-amino-5-methylphenylthio)-3-
(4-methoxyphenyl)propionic acid are obtained.
M.p. 190 - 193C
The following compounds are obtained from the
corresponding starting materials in the same manner as
above.
~Rl > ~Rl
~NH2 ~ ~ NH2 ~ OH
COOCH3 COOH
(IV) (V)
. ..
., ~.
:: .~.
~23~3~
- 20 -
Compound (V~
No - 1 ~~~---~- --------- __
R R Solvent M.p., etc.
.. . . . ~
168 - 170C
i OCH3 4-CH3 Methanol (recrystallized from
methanol)
ii CH 5-CH Ethanol 168 - 172C
~ 3
S iii OCH 5-oCH Ethanol 210 - 212C (decomp.)
3 3
Note`: The compounds listed in the Table are all
(+)-threo isomers.
(c) 45.3 g L-lp-hydroxyphenyl)glyclne methyl ester
hydrochloride are dissolved in 1000 ml of methanol. A
solution of 11.7 g of potassium hydroxide in 100 ml of
methanol is added to the solution under ice-cooling, and the
precipitates (potassium chloride) are removed by filtration.
37.8 g of (+~-threo-2-hydroxy-3-(2-amino-5-methylphenyl-
thio)-3-(4-methoxyphenyl)propionic acid are added to the
filtrate. The mixture~ ~s warmed to about 50~C, and then 900
ml of methanol are added thereto to make a clear solution
: I
The clear solution is evaporated under reduced pressure at a
temperature of below 50C. 200 ml of ethanol are added to
the resldue, and the mixture is allowed to stand ln a
refrigerator overnight. ~The precipitated crystals are
colleated by filtration~(The mothe~r liquor lS referred as
"Mother liquor I".), and then recrystallized from ethanol
~ : !
~: , . . . ,~
,
. .
- ` : ` .
3S
- 21 -
(The mother liquor is referred as "Mother liquor II".).
The crude products thus obtained is further recrystallized
from ethanol. 20.7 g of (+)-threo-2-hydroxy-3-(2-amino-5-
methylphenylthio)-3-(4-methoxyphenyl)propionic acid~L-(p-
hydroxyphenyl)glycine methyl este-, salt (M.p. 164 - 167C, ~ 20
+255.8(c=0.655, methanol)) are obtained.
15.3 g of the product thus obtained are suspended in
a mixture of 240 ml of methanol and 200 ml of water, and 27
ml of cation exchange resins are added thereto. The mixture
is stirred at room temperature overnight. The resins are
removed by filtration and washed with methanol. The filtrate
and the washing are combined and evaporated under reduced
pressure to remove solvent. Water is added to the residue.
The precipitated crystals are collected by filtration and
then recrystallized from ethanol. 7 g of (~)-threo-2-
hydroxy-3-(2-amino-5-methylphenylthio)-3-(4-methoxyphenyl)-
propionic acid are obtained.
M.p. 158 - 160C
~D +296.0(c=0.290, methanol)
Mother liquors I and II are combined, and 13 ml of
conc. hydrochloric acid are added thereto. The mixture is
evaporated under reduced pressure to remove solvent. Water
is added to the residue, and the precipitated crystals are
collected by iltratin. Then, the crystals (lS.5 g) thus
obtained, 20.3 g of D-(p-hydroxyphenyl)glycine methyl ester
hydrochloride and 5.2 g o potassium hydroxide are treated
'
' .
~ . . .
:
,. .
~3~ S
-- 22 --
in the same manner as above. 12.9 g of (-)-threo-2-hydroxy-3-
(2-amino-5-methylphenylthio~-3-(4-methoxyphenyl)propionic
acid.D-(p-hydroxyphenyl)glycine methyl ester salt (M.p. 164 -
167C (recrystallized from ethanol, (lX)20 -254.8 (c=0.949,
methanol)) are obtained.
The product (15.3 g) thus obtained are then converted
into its free acid in the same manner as above. 6.5 g of
(-)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio)-3-(4-
methoxyphenyl)propionic acid are obtained.
~o M.p. 158 - 160C (recrystallized from ethanol)
~t)~)D -265.3 (c=0.331, methanol)
The following compounds are obtained from (+)-threo-
2-hydroxy-3-(2-amino-4-methylphenylthio)-3-(4-methoxyphenyl)-
propionic acid in the same manner as above.
lS (+)-Threo-2-hydroxy-3-(2-amino-4-methylphenylthio)-3-
(4-methoxyphenyl)propionic acid:
M.p. 168 - 170C trecrystallized from ethanol)
D +360.3 (c=0.342, methanol)
(-)-Threo-2-hydroxy-3-12-amino-4-methylphenylthio)-3-(4-
methoxyphenyl)propionic acid:
M.p. 173 - 176C (recrystallized from ethanol)
~D -360.5 lc~0.352, methanol)
(d) A mixture of 9 g of (+)-threo-2-hydroxy-3-(2-
amino-S-methylphenylthio)-3-(4-methoxyphenyl)propionic acid
Zs and 350 ml of xylene is refluxed for 24 hours. The resulting
water i~ removed during the reaction. After the reaction,
'
- ~23~`~35
- 23 _
(
the mixture is evaporated to remove xylene, and the residue
is recrystallized from ethyl acetate. 7.8 g of (~)-cis-2-
(4-methoxyphenyl)-3-nydroxy-8-methyl-2,3-dihydro-1,5-
benzothiazepin-~(5H)-one are obtained.
M~p. 223 - 226C (decomp.)
~CX~0 +123.8 (c=0.707, dimethylformamide)
The following compounds are obtained from the
corresponding starting materials in the same manner as
above.
R ~5 ~ ~ R
COOH H O
(V) (I-a)
:
:
: :
:; ~ : : :
. .
: ~ : -, ~ - ~ .-, ;
.'' ' ' '' ~
., : .
;3S
- 24 -
_
Compound tI-a
Nos.
Rl Ra optical M.p., etc.
isomer
224 - 226C ~decomp.,
i OCH8-CH3 - recrystallized from ethyl
3 ace~ate)
~ a3~u _ 123.7 (c=0.414,
clim8thylformamide)
-
213 - 216C (decomp.,
ii OCH7-CH3 + recrystallized from ethyl
3 ace~te)
L~u + 123.0 (c=û,246,
dim~thylformamide)
212 - 215C (decomp.,
iii OCH 7-CH - recrystallized from ethyl
3 3 ace~te)
t~l U -123.7 (c=û.358,
dim~thylformamide)
182 - 184C (recrystallized
iv CH 8-CH + from dimethylformamide-
3 3 ~ ethanol)
Note: The compounds listed in the Table are all
cis isomers.
Example 12
A mixture of l.S g of sodium hydride (63 ~ oil disper-
sion) and 25 ml of~dimethylsulfoxide is heated at 7ûC for 50
minutes in argon atmosphere. A solution of-7 g o~ methyl
(+)-threo-2-hydroxy-3-~2 amino-5-methylthiophenylthlo)-3-(4-
methoxyphenyl)propionate in 12 ml of dimethylsulfoxide is
added dropwise to the mixture under cooling. The mlxture ~
is stirred at room temperature for 2û minutes. After the ~ -
~: : :
-
-
., . . ~ ,
: ,,
. - ;
.
-` . .. ., ~ .
- .
.. : : .,
.. . .
~;23&~63~
- 25 -
!
reaction is completed, the mixture is poured into ice-water.
The precipitated crystals are collected by filtration,
washed with water, dried and then recrystallized from a
mixture of dimethylformamide and ethanol. 6.7 g of (~)-cis-
2-(4-methoxyphenyl)-3 hydroxy-8-methylthio-2,3-dihydro-1,5-
benzothiazepin-4(5H) one are obta:ined.
M.p. 183 - 184C
The following compound is obtained from the corres-
ponding starting material in the same manner as above.
~N~l~Rl ~N~Rl
~COOCH3 H O
(IV) (I-a)
:
Compound (I-a)
Nos.
R Ra optical M.p., etc.
isomer
211 - 214C (recrystallized
i OCH 7-SCH3 + from dimethylformamide-
3 ethanol)
Note: The compound listed in the Table is cis isomer.
:
:
- :
,,, ,., ., .
,~
:.
~31~;3S
- 26 -
!
Example 13
A mixture of 0.54 g of (+)-threo-2-hydroxy-3-(2-amino-
S-methoxyphenylthio)-3-(4-methoxyphenyl)propionic aid, 0.048
g of N-hydroxybenzotriazole monohydrate and 10 ml of dimethyl-
S formamide is cooled to 0 to 3C, and 0.442 g of N,N'-dicyclo-
hyxylcarbodiimide is added thereto. The mixture is stirred
at the same temperature for 8 hours, and then further stirred
at room temperature for 24 hours. After the reaction is
completed, the precipitated crystals are collected by filtra-
tion and washed with ethyl acetate. The filtrate and the
washing are combined and washed with an aqueous S ~ sodium
bicarbonate solution and water, successively. The solution
is dried and then evaporated to remo~e solvent. The crystals
and residue obtained above are combined and recrystallized
from acetone. 0.382 g of (+)-cis-2-(4-methoxyphenyl)-3-
hydroxy~8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one
is obtained.
M.p. 204 - 206
Example 14
~20 (a) A mixture of 4 g of (+)-cis-2-(4-methoxyphenyl)-
3-hydroxy-8-methoxy-2,3-dlhydro-1,5-benzothiazepin-4(SH)-one,
13 ml of pyridine and 5 ml of methylene chloride is cooled
with ice-water, and 4 g o~ (S)-1-(2-naphthylsulfonyl)pyrrolldine-
~; 2-carbonyl chloride (prepared from (S)-1-(2-naphthylsulfonyl)-
pyrrolidine-2-carboxylic acid and oxalyl chloride in anhydrous
benzene) are added therF~o. The mixture is stirred at room
~,
,
~123~3~35
_ 27 -
(
temperature for 3 hours. After the reaction is completed,
water and a mixture of ethyl acetate and chloroform (1:1)
are added to the mixture. The organic layer is collected
therefrom and washed with 10 ~ hydrochloric acid, water, an
aqueous 5 % sodium bicarbonate so:Lution and water, successively.
The solution is dried and then evaporated. The residue is
dissolved in benzene, and the precipitated crystals (3.7 g,
M.p. 148 - 150C (recrystallized from ethyl acetate), ~]D
-28.5 (c=0.75S,chloroform)) are collected by filtration
(The mother liquor is referred as "Mother liquor I".).
A mixture of 3.6 g of the crystals obtained above, 5
ml of chloroform, 50 ml of ethanol and 50 ml of an aqueous 5
~ sodium hydroxide is stirred at room temperature for 1
hour. After the reaction is completed, the mixture is
washed with water, dried and then evaporated. The residue
is recrystallized from ethyl acetate. 1.46 g of ~ cis-
2-(4-methoxyphenyl)-3-hydroxy-8-methoxy-2,3-dihydro-1,5-benzo-
thiazepin-4(5H)-one are obtained.
M.p. 187 - 189C
~D0 -98.7 (c=0~.290, dimethylformamide)
(b) Mother liquor I (benzene solution) is evaporated
and the residue is chromatographed on silica gel, whereby
3.4 g of the product (oil,~CX~20 -68.5 (c=0.539, chloroform))
are obtained.
; 25 3.3 g of the product obtained above, 5 ml of chloroform,
~ ~ 50 ml of ethanol and 50 ml of an aqueous 5 % sodium hydroxide
.
- :
. ~ . .
-: ' " . :
.. ~ :' ;
' ~ '' , '
~23~i35
- 28
(
are treated in the same manner as described in Paragraph
(a). 1.3 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-
methoxy-2,3-dihydro-i,5-benzothiazepin-4(5H)-one are obtained.
M.p. 187 - 190C (recrystallized from ethyl acetate)
~D +99~0 (c=0.257, dimethylformamide)
Examples 15 to-21
The following compounds are obtained from the corresponding
starting materials in the same manner as described in Example
1. ,
Rb SH 3 ~ Cd-Cd-COOCH3 ,S- ~ ~ OCH3
R Nd2 R ~ N
(II) (I-a)
-
Compound ~I a)
Example Nos. Rb, R M.p., etc.
Cis-isomer: 221 - 224C (decomp.,
7,8-(CH ) (recrystallized from a mlxture of
3 2 chloroform and dimethylformamide)
Trans-isomer: 235 - 237C (decomp,
recrystallized from a mixture of
ethyl acetate and n-hexane~
Cis-isomer: 240 - 241.5C (decomp.,
16 7,8-(CH 0) recrystallized from a mixture of
3 2 dimethylformamide and ethanol)
:
'
:: :
:
-:
::
~23~;3S
_ 29 -
(
-
Compound (I-a)
-
Example Nos. Rb, R M.p., etc.
_
Cis-isomer: 235 - 238C trecrysta-
17* 6,7-(CH )2 llized from ethyl acetate~
3 Trans-isomer: 270 - 271C
-
Cis-iso~ler: 208 - 210C (recrys-
18** 6,8-~CH3)2 tallized from ethyl acetate)
Trans-isomer: 161 - 163C
*** Cis-isomer: 246 - 249C
19 7,9-~CH3)2 Trans-isomer: 227 - 230C
Cis-isomer: 239 - 243C Idecomp.,
7,8-Cl recrystallized from a mixture o~
2 chloroform and ethanol) (turbid
melt at 210C)
Cis-isomer: 207 - 20gC (recrysta-
21 8,9-Cl2 llied from a mixture of chloroform
and ethanol)
Trans-isomer: 244 - 249C
Note: The compounds listed in the Table are all racemic
compounds.
* : Methyl (+)-threo-2-hydroxy-3-(2-amino-3,4-dimethyl-
phenylthio)-3-(4-methoxyphenyl~propionate is obtained
in addition to the compounds listed abve.
M.p. 109 - 111.5C (recrystallized from
isopropanol)
** : Methyl (+)-threo-2-hydroxy-3-(2-amino-3,5-dimethyl-
phenylthio)-3-(4-methoxyphenyl)propionate is obained
in addition to the cmpounds listed above.
M.p. 109 - 113C (recrystallized from
isopropyl ether)
*** : Methyl (+)-threo-2-hydroxy-3-(2-amino-4,6-dimethyl-
phenylthio)-3-t4~methoxyphenyl)propionate i5 obtained
in addition to the compound listed above.
M.p.~130 - 133C
:
:: :
:
31 ;~3863S
- 30 -
(
Example 22
(a) A mixture of 49.52 g of 2-amino-4,5-dimethyl-
thiophenol, 47.49 g of methyl t+)-trans-3 (4-methoxyphenyl)-
glycidate and S00 ml of toluene is heated at 95 - 100C for
23 hours. After cooling, the precipitated crystals (Cyrstals
I) are collected by filtration, and the filtrate is evaporated
to remove solvent. The residue is digested with diisopropyl
ether, and the crystals thus obtained (Crystals II) are
collected by filtration. Crystals I and Crystals II are
combined and then recrystallized from a mixture of ethyl
acetate and n-hexane. 58.95 g of methyl (+)-threo-2-hydroxy-
3-(2-amino-4,5-dimethylphenylthio)-3-(4-methoxyphenyllpropionate
are obtained.
M.p. 111 - 114C
(b) A mixture of 58.9 g of methyl ~+)-threo-2-hydroxy-
3-(2-amino-4,5-dimethylphenylthio)-3-~4-methoxyphenyl)propionate,
S90 ml of an aqueous 5 ~ sodium hydroxide solution and 590
ml of ethanol is stirred at room temperature for 2 hours.
After the reaction is completed, the mixture is adjusted to
; 20 pH 3 with 10 % hydrochloric acid. The precipitated crystals
are collected by filtration, washed with water and then
dried. 54.2 g of (+)-threo-2-hydroxy-3-(2-amino-4,5-dimethyl-
phenylthio)-3-(4-methoxyphenyl)propionic acid are obtained.
~ M.p. L63 - 168C
2~5 (c) 31.3 g of L- (p-hydro~yphenyl)glycine methyl
ester hydrochloride are dissolved in 750 ml of methanol. A
:: ::
.
:~ : :
~, ~ . .
lZ3B~;35
- 31 -
(
solution of 8.08 g of potassium hydroxide in 375 ml of
methanol is added to the solution, and the precipitates
(inorganic materials) are removed by filtration. 25 g of
(+)-threo-2-hydroxy-3-~2-amino-4,5-dimethylphenylthio)-3-
(4-methoxyphenyl)propionic acid are added to the filtrate,
and 375 ml of methanol are added thereto to make a clear
solution. The clear solution is evaporated under reduced
pressure to remove solvent. The residue is recrystallized
three times from ethanol (the mother liquor is referred to
as "Mother liquor I"), whereby 10.2 g of (~)-threo-2-hydroxy-
3-(2-amino-4,5-dimethylphenylthio)-3-(4-methoxyphenyl)propionic
acid-L-~p-hydroxyphenyl)glycine methyl ester salt are obtained.
M.p. 173 - 175C (decomp.)
~)20 + 290.8 (C= 0.410, dimethylformamide)
lS The product obtained above is dissolved in 10 %
hydrochloric acid, and the solution is adjusted to pH 4 with
potassium carbonate. The precipitated crystals are collected
by filtration, washed with water and then dried. 4.7 g of
(+)-threo-2-hydroxy-3-(2-amino-4,5-dimethylphenylthio)-3-(4-
methoxyphenyl)propionic~acid are obtained.
M.p. 167 - 169C (decomp.)
2 ~ 361.2 (C=0.556, N-NaOH)
Mother liquor I (ethanol solution) is evaporated
under reduced pressure to remove solvent. The residue is
dissolved in 10 ~ hydrochloric acld, and the solution lS
adjusted to pH 4 with potassium carbonate. The precipltated
:;
3L;~3~3~;35
- 32 -
(
crystals are collected by filtration. Then, a mixture of
the crystals tl3.3 g) thus obtained, 16.7 g of D-(p-hydroxy-
phenyl)glycine methyl ester hydrochloride and 4.3 g of
potassium hydroxide is treated in the same manner as above.
The crude product thus obtained is recrystallized from
ethanol, whereby 8.97 g of (-~-threo-2-hydroxy-3-(2-amino-
4,5-dimethylphenylthio)-3-(4-methoxyphenyl)propionic acid-
D-(p-hydroxyphenyl)glycine methyl ester salt are obtained.
M.p. 170 - 174C (decomp.)
~20 - 222.1 (C=0.664, dimethylformamide)
The product obtained above are converted to its free
acid in the same manner as above, whereby 2.66 g of (-)-threo-
2-hydroxy-3-(2-amino-4,5-dimethylphenylthio)-3-(4-methoxy-
phenyl)propionic acid are obtained.
M.p. 154 - 157C (decomp.)
~20 -316.8 (C=0.512, N-NaO~1
(d-1) A mixture of 4.7 g of (+)-threo-2-hydroxy-3-(2-
amino-4,5-dimethylphenylthio)-3-(4-methoxyphenyl)propionic
acid and 80 ml of xylene is refluxed for 24 hours. The
resulting water is removed during the reactlon. After the
reaction is completed,~ the mixture is evaporated to remove
solvent. 3.95 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-
7,3-dimethyl-2,3-~ihydro-1,5-benzothiazepin-4(5H)-one are
obtained.
`~ 25 M.p. 232 - 234C (decomp.)
2 + 131 4 (C=0.778, dimethylformamide)
:
: ~:
: : :
:: ; :
:, -, , -:. ~
` . : .
':
~;2 3~3~3S
- 33-
(
(d-2) A mixture of 2.6 g of (-)-threo-2-hydroxy-3-
12-amino-4,5-dimethylphenylthio)-3-(4-methoxvphenyl)propionic
acid and 45 ml of xylenen is treated in the same manner as
described in paragraph (d-1~. 1.98 g of l-)-cis-2-(4-methoxy-
phenyl)-3-hydroxy-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-
4(5H)~one are obtained.
M.p. 225 - 227C (decomp.)
~D -127.2 (C=0.66, dimethylformamide)
Examples 23 ~o 24
The following compounds are obtained from the corres-
ponding starting materials in the same manner as described
in Example 1.
R j~ S H C H 3 0~C~-C H-COOc H3 R ~ ~OC H 3
NH2 H 0
(II) (I-a)
:
:
,.
~ ~ .
lZ3863S
_ 34 _
Compound (I-a)
Example Nos. R Re M.p., etc.
Cis-isomer: 215 - 218C (recrysta-
23 H F llized from a mixture of dimethyl-
formamide and ethanol3
Cis-isomer: 218 - 222C (recrysta-
24* F H llized from a mixture of dimethyl-
formamide and ethanol1 (turbid melt
at 208C)
Trans-isomer: 231 - 235C (recrysta-
llized from a mixture of dimethyl-
formamide and ethanol) (turbid melt
at 215C)
Note: The compounds listed in the Table are all racemic
compounds.
* : Methyl (+)-threo-2-hydroxy-3-(2-amino-6-fluorophenyl-
thio)-3-~4-methoxyphenyl)propionate is obtained in
addition to the compounds listed above.
M.p.~110 - 112C (recrystallized from ethanol)
Example 25
A mixture of 0.683 g of sodium hydride (63 ~ oil
dispersion) and 12 ml of dimethylsulfoxide is stirred at
70C for 45 minutes~. After cooling, a solution of 3 g of
methyl (~)-threo-2-hydroxy-3-(2-amino-6-fluorophenylthio)-
3-(4-methoxyphenyl)propionate in 7 ml of dlmethylsulfoxide
is added dropwise to the mixture, and said mixture is stirred
at room temperature for 5 minutes. After the reaction is ~
completed, the mixture is poured into ice-water. The aqueous
mixture is adjusted to a pH of about 7 with acetic acid, and
the precipitated crystals are collected by filtration. Said
~ :
:' . ~ ''~ .,, . , : '
:: : : .: '; ' ~ -
. .
:
~3~35
- 35 -
(
crystals are washed with water and n-hexane and then dried.
2.39 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-9-fluoro-2,3-
dihydro-1,5-benzothiazepin-4(5~)-one are obtained.
The physico-chemical properties of this product are
identical with those of the product obtained in Example 24.
Example 26
A solution of 500 mg of (+)-cis-2-(4-methoxyphenyl)-
3-hydroxy-8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one
and 358 mg of pyridine in 8 ml of dimethylformamide is ice-
cooled, and a solution of 130 mg of acetyl chloride in 2 ml
of dimethylformamide is dropwise added thereto. The mixture
is stirred at room temperature for one hour. After the
reaction is completed, the mixture is poured into ice-water.
The aqueous mixture is extracted with chloroform, and the
lS extract is washed with 10 % hydrochloric acid and water,
successively. Then, the extract is dried and evaporated
under reduced pressure to remove solvent. The residue is
recrystallized from a mixture of dimethylformamide and
ethanol. 465 mg of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-
8-methoxy-2,3-dihydro-1,5-benzothiazepin-4t5H)-one 1/3 hydrate
are obtained.
; M.p. 21B -219C
Example 27
226 mg of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-1,8-
dimethyl-2,3-dihydro-1,5-benzothiazepin-4(s~)-one are suspended
:: ::
~ . :
`~
1;~3~3~;35
- 36 -
(
in 2 ml of pyridine, and 59 mg of acetyl chloride are added
thereto under ice-cooling. The mi~ture is stirred at room
temperature for 2 hours. After the reaction is completed,
ethyl acetate-chloroform (1 : 1) is added to the reaction
mixture. The mixture is washed with 10 ~ hydrochlric acid
and water, successively. Then, the mixture is dried and
evaporated under reduced pressure to remove solvent. 219 mg
of (+)-cis-2-(4-methoxyphenyl~-3-acetoxy-7,8-dimethyl-2,3-
dihydro-1,5-benzothiazepin-4(SH)-one are obtained.
Mop~ 227 - 229C
' :
~' :
::
.~ .
'`' '
''''- '~
s
- 37 -
Reference example 1
tl) A mixture of O.R28 g of (+)-cis-2-(4-methoxyphenyl)-3-
hydroxy-7-methoxy-2,3-dihydro-l,S-benzothiazepin-4(5H)-one,
0.307 g of potassium hydroxide and 15 ml of dimethylsulfoxide
S is stirred at room temperature for 2 hours, and then 0.396 g of
2-(dimethylamino)ethyl chloride hydrochloride is added thereto.
The mixture is stirred at room temperature for 16 hours.
After the reaction is completed, the mixture is poured into
ice-water, and the aqueous solution is extracted with ethyl
acetate. The ethyl acetate solution is extracted with a 10
~ hydrochloric acid solutiGn. The extract is adjusted to
about pH 10 with potassium c~rbonate. The alkaline solution
is extracted witn ethyl acetate, and the extract is washed
with water, dried and then evaporated to remove solvent.
The residue is recrystallized from a mixture of ethyl acetate
and n-hexane. 0.82 g of (-,)-cis-2-(4-methoxyphenyl)-3-
hydroxy-5-~2-(dimethylamino)ethyl)-7-methoxy-2,3-dihydro-1,5-
benzothiazepin-4(SH)-one is obtained.
M.p. 127 - 129C
Hydrochloride:
M.p. 212 - 214C (recrystallized from a mixture of
chloroform, ethanol and ether)
:
:: :: :
,
:; , ,
,,: ~ '
. , -
. .
,
363S
- 38 -
~ 2) A mixture of 1 g of (+)-cis-2-(4-methoxyphenyl)-3-
hydroxy-5-~2-tdimethylamino)ethyl)-7-methoxy-2,3-dihydro-1,5-
benzothiazepin-4(5H)-one hydrochloride, 1.5 ml of acetic
anhydride and 1.5 ml of acetic acid is stirred at 110C for
4 hours. After the reaction is completed, the mixture is
evaporated under reduced pressure to remove aeetie anhydride
and aeetie aeid. Benzeneis added to the residue, and the
mixture is evaporated under redueed ~ressure to remove aeetie
anhydride and aeetie aeid. The residue thus obtained is
recrystallized from a mixture of ethanol and ether. 0.87 g
of (+~-eis-2-(4-~ethoxyphenyl)-3-ae2toxy-5-~2-~dimethylamino)-
ethyl)-7-methoxy-2,3-dihydro-l,S-benzothiazepin-4(5H)-one
hydrochloride 1/2 hydrate is obtained.
M.p. 216 - 218C
Reference examDles 2 - 56
The following compounds are obtained from the
corresponding starting compounds in the same manner as
described ln Refe~ence exelDple 1-(1) or 1-(2~.
- ~, .: ;: :- :
~, :,~': '
, .
-` ~IL23~3~;3S
-- 39 --
R
N ~ ~ OH ~ R ~ ~ OH
H I O
(CH2)2N(C 3t2
(I ) (IX)
Reference Compound (IX)
Nos. 1 a Optical
R R isomer M.p., etc.
2 CH 8-CH + Free base: 142 - 143C
3 3 (recrystallized from ethyl
acetate)
Hydrochloride: 168 - 169C
(decomp., recrystallized
from a mixtuxe of ethanol
and ether)
: ~ :
3 OCH3 6-OCH3 + Hydrochloride: 199 - 202C
: ~ (decomp. recrystallized
~: : from a mixture of ethanol
and ether).
4 CH3 8-OCH3 : - Free base: 127 - 130C,
: Hydrochloride-hemi hydrate:
153 - 155C (recrystallized
from a mixture of ethanol
and ether) ~
-
: S OCH 8~ Hydrochloride-mono hydrate:~ :
3 OCH C H : 138 - 140C (recrystallized
2 6 5 from a mixture of ethanol and
ether)
~: :
::
,. :
: : :: : :: :
, .. :
. .
~38~3S
- 40 -
-
R + Compound (IX)
p e
Nos. 1 a Optical
R R isomer M.p., etc.
6 OCH3 8-CH3 + Free base : 157 - 158C
(recrystallized from ethyl
acetate)
Hydrochloride: 232 - 234C
(recrystallized from a mixture
of ethanol and ether)
7 OCH 7-CH + Free base: 125 - 129C
3 3 ~ (recrystallized from ethyl
acetate)
Hydrochloride: 235.5 - 236C
~decomp., recrystallized from
ethanol~
8 OCH3 8-CH3 + Free base: 120 - 122C
(recrystallized from ethyl
ace~te).
~)n fl55-0 (c=0.465,
metnanol)
'~
-9 OCH3 8-CH3 - Free base: 121 - 123C
recrystallized from ethyl
ace2.~te )
~D -153.1(c=0.40, methanol)
..... _ _ .
10 OCH 7-CH + Free base: 94 - 95C
3 3 (recrystallized from ethyl
ace~te)
D +159.8(c=0.43, methanol)
ll OCH3 7-CH3 - Free base: 94 - 95C
: (recrystallized from ethyl
ace~te)
D -160.8(c=0.325, methanol)
12 CH3 8- + Free base-hemi hydrate: 118 -
2 6 5 120C (recrystallized from a
: mi.~ture of ethyl acetate:and
isopropyl ether)
: ~ :
:: :
. ~:
-- ~.23~363S
- 41 -
.
Reference Compound (IX)
Nos. Optical
Rl Ra isomer M.p., etc.
.. . _ . . . . .
13 OCH3 8-OCH + Free base: 139 - 141C
- 3 (recrystallized from ethyl
ace~te), Yield: 96 %
~D +129.9(c=0.465, methanol)
l-~ OCH 8-OCH - Free base: 139 - 141C
3 3 (recrystallized from ethyl
ace~te), Yield: 93 %
~D -127.8¦c=0.385, methanol)
.
OCH3 8-SCH + Free base: 153 - 154C,
3 Yield: 86 %
Hydrochloride: 247 - 251C
(decomp., recrystallized from
ethanol)
16 OCH 7-SC~ , Free base:~167 - 168C,
3 3 ~ Yield: 70 %
Hydrochloride: 239 - 240C
(decomp., recrystallized from
ethanol3
___~
Hydrochloride 3/4 hydrate:
17 OCH3 6-CH + 112 - 115~C (recrystal-
3 lized from ethanol and
ether)
Hydrochloride-mono ethanol:
18 OCH 8-OCH + 130 - 132C (recrystallized from
3 3 ~ a mixture of chloroform, ethanol
and ether), Yield: 77 ~ ~
, .. -- : ~ -- -- --- :
Note: The compounds listed in the Table are all CiS--isQmers.
: ~
: : :
~-
: ~ :
:
3S
_ ~2 -
-R ~ Rl
'S ~ OH , R ~ l O
(C~2)2N(C~3)2 (CH2)2N(CH3)2
(IX-b) (IX-a)
Reference Compound (IX-a~
Example 1 a
Nos. R R M.p., etc.
l9 OCH 8-OCH Hydrochloride-mono ethanol:
3 3 192 - 194C (recrystallized
from a mixture of chloroform,
ethanol and etherl
_ . ~
OCH 6-OCH Oxalate-hemi hydrate: 212 -
-20-- 3 3 213C (decomp., recrystallized
from a mixture of ethanol,
chloroform and ether)
Ox21ate:
21 CH3 8-OCH3 209 - 211 C (decomp., rec.ystal-
lized ~rom chloroform, eth~nol
and ether)
. _ _ . , . __
22 OCH 6-CH Hydrochloride: 208 - 210C
3 3 (recrystallized from ethanol)
23 CH 8-CH Hydrochloride: L84 - }86C
3 3 (recrys~allized from a mi~ture
of isopropanol and ether)
_
OCH 8-CH Hydrochloride-mono ethanol-
24 3 ~ 3 183.5 - 185~5C (recrystaliized
from ethanoll
25- OCH 7-CH Hydrochloride: 157.5 - 159.5C
~ 3 3 (recrystallized from ethanol)
;~ Note: The comcounds listed in the Table are all (~)-cis
isomers.
.:,,: :: : :
:
'
.
.- . :
:
~Z3863S
43
~ OCH3 ~ OCH3
a ~ ~S ~ OH_ ~ R ~ ~ OCOC~3
CH2CH2N(CH3)2 CH2CH2N(CH3)2
(IX-b) (IX-a)
-
ReferenceCompound (IX-a)
Example a
Nos. R Optical M.p., etc.
isomer
2 6 5 Hydrochloride-mono isopropanol:
26 171 - 174C (recrystallized from
isopropanol) ~ -
27 8-CH3 - Hydrobromide: 151 - 154C (decomp.,
recrystallized from a mixture of
eth~ol and ether)
t~l D -82.1 (c=0.42, methanol)
:
28 7-CH 1 Hydrobromide-1/4 hydrate:
3 157 - 160C (recrystallized
from a mixture of ethanol
and2~ther)
t~] ~87.8 (c=0.303,
metRanol)
29 7-CH} - Hydrobromide-lt4 hydrate:
157 - 160C (recrystallized
from a mixture of ethanol
and2~ther)
[~3 -88.7 (c=0.549,
metRanol)
8-OCH - Hydrochloride: 164 - 166C
3 (recrystallized from a mixture
of ethanol and e~er),~
~ -79.9
(c=0.344, methanB1)
:
,-. :
.
:
,
.
-` ~IL23~63S
- 4~ -
Reference Com~ound (IX-a)
Example a
Nos. R Optical M.p., etc.
31 8-OCH3 + Hydrochloride: 164 - 166C
(recrystallized from a mixture
of ethanol and e~er)~
L~ ~ 79.4
(c=0.389, methan~l)
32 8-SCH ~ Hydrochloride-mono ethanol:
3 179 - 182C (recrystallized
from ethanol),
Hydrobromide: 151 - 152C
(decomp., recrystallized from
33 3-CH + ethanol and ether)
[~j20 + 82.5 (c=0.308, methanol)
_ .
34 7-SCH3 ~ Hydrochloride-mono isopropanol:
198 - 200~C (recr~stallized
from isopropanol)
.. . . _ . . _
Note: The compounds llsted in the Table are all cis isomers.
:~ :
~:
::
~:
:
.
:., :
3~35
_ 45 _
-o b / ~ ~ 3
(CH2)2N(CH3)2
(I) (IX)
Reference Compound (IX)
Example
Nos. Optical
R , R isomer M.p., etc.
_ . _ _ . . _ . . . . _
Free ~as~: 117 - 119C (recrys-
7,8-(CH3)2 - tallized from a mixture of
eth~ acetate and n-he~ane)
~ -lal.1 (c=0.792, methanol)
Free basa: 154.5 ~ 156C
36 7,8-(OCH3)2 , (recrystallized from methanol)
O~alate monohydrate: 192 -
194C (decomp., recrystallized
from methanol)
.. _ _ _ . . , .. _ , _ . . _ _ _ _ ... . _ . . _
Hydrochloride monoAydrate:
37 6,7-(C'~3)2 + 1}7 - 119C (decomp., recrys-
tallized from a mixture of
ethanol and ether~
Hydrochloride monohydrate:
38 6,8-(CH )2 + 124 - 148C (decomp., rec~s-
3 - tallized from ethanoL) (turbid
melt at ll9~C)
. _ _ . . . . .
Hydrochloride: 224 - 225C
39 7~9-(C~3)2 ~ tdecomp., recrystallized from
a mixture of ethanol and
ether) (turbid melt at 145~C)
;
- ::
:
:
: ...
~':
'~
.
;3S
- ~6 -
Reference Compound (IX)
Examp1e
Nos. Optic~1
R , R isomer ,~.p., etc.
Free base: 179 - 181C
Hydrochloride: 248 - 250 C
407,8-(CH3)2 -+ (decomp., recrystallized from
ch]oro~orm, ethanol and ether)
. . . _ . . _
Free base: 117 - 118C
(recrystallized from ethyl acetate
417,8-(CH3)2 ~ and n-hexane)
[~]D + 149.7 (c= 0.6B, methanol)
_ .
42 Free base: 178 - 179.5 C (recrystl-
7,8-Cl2 ~ liæed from ethyl acetate)
Hydrochloride: 232.5 - 234 C
(decomp., recrystallized from
methanol)
. ... . _ _
Free base: 175.5 - 176.5 C
43 8,9-Cl + (recrystallized from ethyl acetate)
2 - Hydrochloride 3/2 hydrate: 172 -
175 C (recrystallized from methanol
and ether) [230 - 233 C (decomp.)
(turbid melt at 156 C)]
Note: The compoundslisted in the Table are all cis-isomers.
`:
.~ :
,
. ~ ''
: : .
..
--` lZ3~3635
- 47 -
Rb /~;~OCH3 Rb ~-OCH3
~5 ~OH ~ ~3~ ~OCOCH3
(CH2)2N(CH3)2 (CH2)2N~CH~)2
(IX-b) (IX-a)
Reference Compound (IX-a)
Example
Nos. Optical
R, R isomer M.p., etc.
. . ~
4ds Oxalate hemihydxate;
7,8-(CH3)2 - 189 - 191C (decomp.,recrys-
tallized from a mixture of
chl~!6ofonn and ethanol)
~0~)D ~99-5 (c=0.79, dimethyl-
formamide)
Hydrochloride: 241.5 - 243C
7,8-(OCH )2 + (decomp., recrystallized from
3 ethanol)
.
Hydrochloride: 189 - 192C
46 7,8-Cl2 + (recrystallized from methanol)
; (turbid melt at 182C)
~ '
Hydrochloride hemihydrate:
47 8,9~Cl + 233 - 235C (decomp., re-
2 crystallized from a mixture
of methanol and ether),
Hydrochloide mono-ethanoI-
48 6,8~(CH3)2 + 218 - 221C ~recrystallized
- t from a mixture of ethanol and
ether)
Hydrochloride: 240 - 242C
49 7,9-(CH3)2 (decomp., recrystalli~ed from
+ a mixture of ethanol and ether),
`
:
. , :
: `~``' ~ ~ :
:
,', :.
`-`` l.Z3~3~3S
_ 48 -
Reference
ExamDle Compound (IX-a)
Nos Optical
R , R isomer M p., etc.
~ .
Hydrochloride: 209 - 211C(decomp.)
(recrystallized from ether,
7,8-(CH3)2 + chloroform and ethanol)
Oxalate 1/2 hydrate: 191 192 C
(decomp., recrystallized from
51 7,8-(CH3)2 + chloroform and ethanol)
~d]D + 101.9 (c= 0.736,
dimethylformamide)
52 ~,7-(CH ) ~ Hydrochloride 3/2 hydrate: 245C
3 2 - (decomp., turbid melt at 150 -
152 C) (recrystallized from
ethanol and ether)
Note: The compounds listed in the Table are all cis-isomers.
.
: :,
~: :
: ~ ,
:
: ~ : :
. ~ ., ~ : . ,: .
3~t;35
- 49 -
-- 01 ~ ~ N~`b
(I-) (cH2)2N(cH3)2
(IX)
. ~
Reference
Example Compound (IX)
Nos.
d e
R , R M.p., etc.
Hydrochloride: 197 - 198C
53 8-F (recrystallized from ether,
isopropanol and ethanol)
. . _ _ . . . _ _ .
54 9-F Hydrochloride: 202 - 205 C tturbid
melt at 198 C., recrystallized from
isopropanol )
_ _ _ . . . _ .
Note: The compounds listed in the Table are all (~)-cis isomers.
:::
::
,
, ,
~, ,, : :
.: ~ . , :
:
: :; .
'
. ~23~363S
so
' e R ~OC~3 e 2d /~OCH3
R ~ 5 ~ R ~[ 5 $
(CH2 ) 2N ( CH3 ) 2 (CH2 ) 2N (CH3 ) 2
(IX-b ) ( IX-â )
.
~eference ~ompound ~(IX-a)
Nos.
R, Re M . p ., e tc .
Hydrochloride 1/3 hydrate: 137 - 141C
~55 8-F (recrystallized from ethanol and
ether)
: Hydrochloride: 200 - 204 C (turbid
56 9-F melt at 194 C., recrystallized from
isopropanol and ether)
Note: The compounds listed in the Table are all (+)-cis isomers.
:: :
,
~:` :
:
:
:
.,,
~:
:~ ~ ~ : .
~3863S
_ 5l
Reference Example 57
A mixture of 406 mg of (+)-cis-2-(4-methoxyphenyl)-
3-acetoxy-8-methoxy-1,5-benzothiazepin-4(5H)-one, 170 mg of
2-(dimethylamino)ethyl chloride hyclrochloride, 370 mg of
potassium carbonate and 30 ml of acetone is refluxed for 20
hours. After the reaction is completed, insoluble materials
are removed by filtration and washed with hot acetone. The
filtrate and the washings are combined and then evaporated
under reduced pressure to remove solvent. The residue is
converted to its hydrochloride and recrystallized from a
mixture of chloroform, ethanol and ether. 440 mg of (+)-
cis-2-(4-methoxyphenyl)-3-acetoxy-5-~2-(dimethylamino)ethyl)-
8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride
ethanol are obtained.
M.p. 192 - 194C
Reference Example 58
A mixture of 190 mg of (+)-cis-2-(4-methoxyphenyl)-3-
acetoxy-7,8-dimethyl-2,3~dihydro-1,5-benzothiazepin-4(5H)-one,
81 mg of 2-(dimethylamino)ethyl chloride hydrochloride, 180 mg
20 of potassium carbonate and 15 ml of acetone is treated in the
same manner as described in Example 57. The crude product is
converted to its hydrochloride and recrystallized from a mixture
of chloroform, ethanol and ether. 177 mg of (+)-cis-2-(4-
methoxyphenyl)-3~acetoxy~5-[2-(dimethylamino3ethyl)-7,8-dimethyl-
25 2,3~dihydro-1,5-benothiazepin-4(5H)-one hydrochloride are obtained.
M.p. 209 - 211C (decomp.3
.. ~
'
