Note: Descriptions are shown in the official language in which they were submitted.
1 - 20~6129
PROCESS FOR PREPARING 1,5-BENZOTHIAZEPIN_ DERIVATIVE
BACKGROUND OF THE INVENTION
The present invention relates to a process for
preparing hydrochloride of 3-acetoxy-2,3-dihydro-5-[2-
(dimethyl~mino)ethyl]-2-(p-methoxyphenyl)-1,5-
5 benzothiazepin-4(5H)-one which is useful as a medicinal
compound.
Hydrochloride of 3-acetoxy-2,3-dihydro-5-[2-
(dimethyl~mi no)ethyl]-2-(p-methoxyphenyl)- 1,5-
benzothiazepin-4(5H)-one (hereinafter referred to as
10 desired compound), particularly, d-cis form thereof is a
medicinal compound useful as a coronary vasodilator and an
anti-hypertensive agent. Hitherto, there have been known
some processes for preparing the desired compound.
Examples of these processes are, for instance, (1) a
15 process wherein 3-hydroxy-2,3-dihydlo 5-[2-(dimethyl-
amino)ethyl]-2-(p-methoxyphenyl)-1,5-~enzothiazepin-
4(5H)-one (hereinafter referred to as 3-hydroxy compound)
is reacted with an acetylating agent such as acetic
anhydride with heating to give 3-acetoxy-2,3-dihydro-
20 5-[2-(dimethyl~mino)ethyl]-2-(p-methoxyphenyl)-1,5-
benzothiazepin-4(5H)-one (hereinafter referred to
3-acetoxy compound) according to a conventional method and
then the resulting 3-acetoxy compound is treated with
ethanolic hydrogen chloride (or methanolic hydrogen
25 chloride) (see Japanese Fx~mined Patent Publication No.
813/1972 and No. 18038/1978), (2) a process wherein the
3-hydroxy compound is reacted with acetic anhydride in the
presence of hydrochloric acid in one step (see Japanese
Un~x~mine-l Patent Publication No. 132876/1987) and the
30 like.
However, in the process (1), two steps, namely,
a step for the acetylation and a step for the formation of
hydrochloride, are required to ~e carried out separately,
although the acetylation can be suitably carried out in
35 the absence of water. On the other hand, in the process
(2), hydrochloric acid must be at first added with cooling
'~
20~6129
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and then the acetylation is carried out with heating,
since heat is generated on the addition of hydrochloric
acid (aqueous solution of hydrogen chloride) used as a
supplier of hydrogen chloride. The operations in the
5 method (2) are, therefore, complicated. Further, it is
always required in the method (2) to use a large exess of
acetic anhydride for removing water existing in the
reaction system, which is introduced on the addition of
hydrochloric acid, since the acetylation cannot be
10 completed in the presence of water.
An object of the invention is to provide a
process for simply preparing the desired compound from the
3-hydroxy compound in one step without cooling the
reaction system or using a large excess of an acetylating
15 agent.
This and the other objects of the present
invention will become apparent from the description
hereinafter.
2 0 SUMMARY OF THE INVENTION
It has now been found that a process for
preparing hydrochloride of 3-acetoxy-2, 3-dihydro-5-[ 2-
(dimethyl~mino)ethyl]-2-(p-methoxyphenyl)-1, 5-
benzothiazepin-4(5H)-one which comprises reacting
3-hydroxy-2, 3-dihydro-5-[ 2-(dimethylamino)ethyl]-2-(p-
methoxyphenyl)-l, 5-benzothiazepin-4(5H)-one with acetyl
chloride in acetic acid or a mixed solvent of acetic acid
and acetic anhydride overcomes the defects of the above-
mentioned conventional processes.
DETAILED DESCRIPTION
The above-mentioned process of the present
invention is estaUished based upon a novel knowledge that
acetyl chloride acts as not only an acetylating agent for
35 the 3-hydroxy compound but also a supplier of hydrogen
chloride, resulting in giving the desired compound.
According to the process of the present invention,
therefore, the desired compound can be prepared
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quantitatively without supplying hydrogen chloride
separately, using a large excess of an acetylating agent
or cooling the reaction system which are needed in
conventional processes.
In the process of the present invention, acetic
acid or a mixed solvent of acetic acid and acetic
anhydride can be suitably used as a solvent. As to the
mi xi ng ratio of the mixed solvent, the amount of acetic
anhydride may be about one-tenth of the amount of acetic
10 acid or may be increased to several times of the amount of
acetic acid. The mixing ratio of the mixed solvent can
be appropriately selected according to the reaction
temperature or a desired reaction time. The amount of
the solvent to be used is not particularly limited and,
15 for example, the amount is sufficiently from about 1 to
about 5 parts by weight per part by weight of the
3-hydroxy compound. Suitable amount of acetyl chloride to
be used may vary according to the solvent, but are usually
within 1 to 20 moles per mole of the 3-hydroxy compound.
20 For example, when only acetic acid is used as the solvent,
it is preferred to use acetyl chloride in an amount of
more than 1 mole, preferably 1.01 to 10 moles, more
preferably 1.05 to 1.5 moles, per mole of the 3-hydroxy
compound. On the other hand, when a mixture of acetic
25 acid and acetic anhydride is used as the solvent, it is
preferred to use acetyl chloride in an amount of not less
than 1 mole, preferably 1 to 5 moles, more preferably 1 to
1.5 moles, per mole of the 3-hydroxy compound.
The process of the present invention can be
30 carried out at from a low temperature with cooling, for
instance 5C, to a high temperature with heating, for
instance 130C, preferaUy from the room temperature to a
refluxing temperature. Especially, when only acetic acid
is used as the solvent, it is preferred to carry out the
35 process at 10 to 110C, more preferably 40 to 80C. On
the other hand, when a mixture of acetic acid and acetic
anhydride is used as the solvent, it is preferred to carry
out the process at 5 to 130C, more preferably 10 to
2056129
-- 4
110C -
In case that a mixed solvent of acetic acid and
acetic anhydride is used in the present invention, the
reaction is accelarated and the solvent is prevented from
5 freezing when temperature lowering.
With respect to the 3-hydroxy compound which is
the starting material of the present invention, there are
four stereoisomers owing to asymmetric carbon atoms at the
2-position and the 3-position. Since the process of the
10 present invention can be carried out without racemization,
the desired compound having an optical activity can
be obtained from the 3-hydroxy compound having the
corresponding optical activity.
Isolation of the desired compound after the
15 completion of the reaction can be easily carried out
according to the conventional methods such as
recrystallization after distilling the reaction solvent
away.
As indicated in the following Examples,
20 according to the process of the present invention, the
desired compound can be obtained in a high yield in one
step without carrying out another step to obtain the
hydrochloride after the acetylation or ~ ling hydrochloric
acid to a reaction system, since acethyl chloride acts as
25 not only an acetylating agent but also a supplier of
hydrogen chloride.
The process of the present invention, therefore,
has an industrially excellent advantage that the desired
compound can be obtained by a simple operation in a high
30 yield, compared with other conventional methods. For
example, while two steps, namely a step for the
acetylation and a step for the formation of the
hydrochloride, are required to be carried out separetely
in the process ( 1) described in Japanese F.x~min~l Patent
35 Publication No. 813/1972 and No. 13038/1978, the desired
compound can be obtained in one step in the present
invention. Further, while a large excess of acetic
anhydride is required to be used in order to remove water
2056129
existing in the reaction system, which is intruduced on
the addition of hydrochloric acid (aqueous solution of
hydrogen chloride), from the reaction system in the
process (2) described in Japanese Unex~mine-l Patent
5 Publication No. 132876/1987, only 1 mole or a little more
than 1 mole of acetyl chloride per mole of the 3-hydroxy
compound may be sufficiently used in the present
invention, which does not require the addition of
hydrochloric acid with cooling, to obtain the desired
10 compound in a high yield.
The present invention is more specifically
described and explained by means of the following
Experimental ~mples and Examples. It is to be
understood that the present invention is not limited to
15 the Ex~mples, and various changes and modifications may be
made in the invention without departing from the sprit and
scope thereof.
Experimental Example 1
[ Effect of a solvent for the acetylation on conversion
20 rate]
In 200 ml of each solvent described in Table 1
were mixed 25 g of the d-cis-3-hyd~o~y compound and 5.8 g
of acetyl chloride ( 1.1 moles per mole of the d-cis-3-
hydroxy compound) and each mixture was stirred at 30C for
2 5 2 hours. Conversion rate to the desired compound was
determined by high performance liquid chromatography. The
results are shown in the following Table 1. When acetic
acid or a mixed solvent of acetic acid and acetic
anhydride was used, the desired compound was obtained in a
3 o significantly high conversion rate compared with those
in case of using other solvents.
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Table 1
Solvent Conversion rate to
the desired compound
Solvents used Acetic acid 95 %
in the present
invention Mixed solvent A 99.98 % ~2)
Mixed solvent B 100 % ~2)
Acetic anhydride 33 % ~2)
Other Chloroform 78 %
solvents
(Reference) Methylene chloride 70 %
Dichloroethane 77 %
Acetone 51 %
Trichloroethane 66 %
Toluene 78 %
Mixed solvent A: acetic acid: acetic anhydride = 1: 1
Mixed solvent B: acetic acid: acetic anhydride = 1: 3
~2) The used amount of acetyl chloride was 1.2 moles per
mole of the d-cis-3-hydroxy compound and the reaction
system was stirred at 60C for 3 hours.
Example 1
In 15 ml of acetic acid was dissolved 7.45 g
(0.02 mole) of d-cis-3-hydroxy-2,3-dihydro-5-[ 2-
35 (dimethyl~mino)ethyl]-2-(p-methoxyphenyl)-1, 5-benzo-
thiazepin-4(5H)-one with heating. Then thereto was added
1.71 g (0.022 mole) of acetyl chloride at 20C and the
mixture was stirred at room temperature for 72 hours.
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After the reaction, acetic acid was distilled away and the
residue was recrystallized from ethanol to give 7.53 g of
hydrochloride of d-cis-3-acetoxy-2, 3-dihydro-5-[ 2-
(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1, 5-benzo-
thiazepin-4(5H)-one.
yield: 83 %
m.p.: 213 - 214~C
Example 2
The procedure of Example 1 was repeated except
that the reaction was carried out at 70 - 80 C for 3
hours with stirring and 97 % ethanol was used for the
recrystallization to give 8. 4 5 g of hydrochloride of the
d-cis-3-acetoxy compound.
yield: 9 4 %
Physical properties of the obtained compound
coincided with those of the desired compound in Example 1.
F.Y~mrle 3
The procedure of Example 1 was repeated except
for the followings. As reactants, 50 g (0.13 mole) of
d-cis-3-hydroxy-2, 3-dih~ o 5~ 2-(dimethylamino)ethyl]-
2-(p-methoxyphenyl)-1, 5-benzothiazepin-4(5H)-one and 12. 7
25 g (0.16 mole) of acetyl chloride were used. The reaction
was carried out at 60~ for 3 hours with stirring in a
mixed solvent of 81 ml of acetic acid and 19 ml of
acetic anhydride and 97 % ethanol was used for the
recrystallization. Thus 55.9 g of the hydrochloride of
30 the d-cis-3-acetoxy compound was obt~ine i
yield: 92 %
Physical properties of the obtained compound
coincided with those of the desired compound in Example 1
Example 4
The procedure of FY~mple 1 was repeated except
for the followings. As reactants, 50 g (0.13 mole) of
20561~9
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d-cis-3-hydroxy-2, 3-dihydro-5-[ 2-(dimethylamino)ethyl]-2-
(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one and 10.8 g
(0.13 mole) of acetyl chloride were used. The reaction
was carried out at 100 - 110C for 6 hours with stirring
5 in a mixed solvent of 50 ml of acetic acid and 50 ml of
acetic anhydride and 9 7 % ethanol was used for the
recrystallization. Thus 53.7 g of the hydrochloride of
the d-cis-3-acetoxy compound was obtained.
yield: 89 %
Physical properties of the obtained compound
coincided with those of the desired compound in Example 1.
Example 5
The procedure of Example 1 was repeated except
for followings. As reactants, 50 g (0.13 mole) of d-cis-
3-hydroxy-2, 3-dihydro-5-[ 2-(dimethylamino)ethyl]-2-(p-
methoxyphenyl)-1,5-benzothiazepin-4(5H)-one and 12.7 g
(0.16 mole) of acethyl chloride were used. The reaction
20 was carried out at 60C for 3 hours with stirring in a
mixed solvent of 25 ml of acetic acid and 75 ml of
acetic anhydride and 9 7 % ethanol was used for the
recrystallization. Thus 54.7 g of the hydrochloride of
the d-cis-3-acetoxy compound was obtained.
yield: 90.4 %
Physical properties of the obtained compound
coincided with those of the desired compound in Example 1.
