Note: Descriptions are shown in the official language in which they were submitted.
SPECIFICATION
Title of the Invention
A NOVEL PROCESS FOR PRODUCTION OF THE DEXTROROTATORY
OPTICAL ISOMER OF DIASTEREOMER A OF YM-09730
Detailed Explanation of the Invention:
The present invention relates to a novel process for
production of the dextrorotatory, optical isomer of diaste-
reomer A of YM-09730 useful as a blood vessel dilator and
its pharmaceutically acceptable acid addition sslt.
YM-09730 is given a chemical name of 2,6-dimethyl-4-
(m-nitrophenyl)-1,4,-dihydropyridine-3,5-dicarboxylic acid
3-(1-benzylpyrrolidin-3-yl) ester 5-methyl ester which is a
dihydropyridine-3,5-dicarboxylic acid ester derivative
represented by the following chemical structure:
G~NC)2
3 ~ COO
H CH2 ~9
It is reported that YM-09730 possesses a blood vessel
dilating activity and blood pressure reducing activity with
long durability (United States Patent No. 4,220,649).
YM 09730 possesses two asymmetric carbon atoms and it
is assumed that isomers would be present based on these
asymmetric carbon atoms from a viewpoint of stereochemistry.
~.
HoweveT7 the presence Or isome-s is unver~ie~ foT lac~
of the desc~ip~ion about isome~s in ~he above publica;ion.
Previously, some of ~he p~esent invento.s separated
diastereomer A of YM-09730 from diastereomeT B thereof
foT the fi~st time and found out that isome~ A exhibits
much mo~e excellent peculiar pharmacological effects
as compared to isome~ B o~ a mixture of both isomers
Ca~adia~ Patent Application No. 479,294
They have fur~he~ found that the dextrorotatory,
op~ical isome~,-the meltin-g-point of the hydrochlori~e
-thereof being 223 to 230~C (decomp.), of diasteTeomer A
can be produced by a method which comprises reac~in~ m-
nitroben-aldehyde, l-benzyl~3--acetoacetoxypyrTolidine
and methyl 3-aminoclotonate, subjecting the thus
obtained ~1-09730 to cloumn chToma~ography using
silica gel ~s a carrier znd ethyl acetate-acetic acid
as an eluent to separate dizsLeTomeT A and, then effecting
op,ical resol~.ion of dizs~ereomer A using L-(-~-malic acid,
and that the thus obtained isomer possesses much more
excellent peculiar phaTmacologiczl effe'cts zs compared to
the levorotatoTy, optical isomer OT a mixture of these
both ~somers Car adian Patent Application No. ~79,294
-As i result'of';nvestïgations on a process foT
production of this novel and useful dext~oTotatory,
-~ ~ -optical-isomeT of diaste~eomeT-A-of YM-09730, a process
for imp~oving the yield of the desired isomer has been
found and, the pTesent invention has been accomplished.
~?
~.~i '
41_",
g3~L
Here, diastereomer A ~dl-mixture) the hydro-
chloride of which shows the melting point of 200 to
206C (decomp.) is clearly distinguishabie from diaste-
reomer B the hydrochloride of which shows the melting
point of 180 to 185C ~decomp.).
Also, the hydrochloride of the dextrorotatory,
optical isomer of diastereomer A shows the melitng
point of 223 to 230C (decomp.) as indicated above.
The present invention provides the new process for
production of-the dextrorotatory, optical isomer of
diastereomer A of YM-09730 defined by sald melting
point of its hydrochloride, or a pharmaceutically
acceptab'le-acld,ad'dit.i'on sa,lt-...thereof. The pharmaceuti-.
cally acceptable acid addition salt referred to herein
includes an organic acid salt such as an L-(-)-malate~
etc. and a mineral acid salt such as hydrochloride~ etcO
---The dextrorotatory optica-l isomer (I) of diastereo-
mer A of the present invention can be produced by
reacting a levorotatory, optical isomer or a racemate
of 5-methoxycarbonyl-2,6-dimethyl-~-(m-nitrophenyl)-194-
dihydropyridine-3-carboxylic acid shown by formula ( f I) o
f~a2
~ (~)
----- - ,, ' .::'~~' ~;c~a ~ C~a~
E~C E ^ C--3
~`3~
or a reactive derivative thereof with a levorotatory,
optical isomer or a racemate of 1-ben~yl-3-hydroxy-
pyrrolidine shown by the formula (III):
Ho ~
NJ (III)
CH ~
This reaction involves the formation of a carboxylic
acid ester and generally applicable methods can appropria-
tely be used. No stereochemical inversion occurs in this
reaction. Examples of the reactive derivative of compound
(II) include an acid halide such as an acid chloride, an
acid bromide, etc.; an acid anhydride, a mixed acid
anhydride, an active ester and the like. In case that
compound ~II) is employed in the form of a free carboxylic
acid, the reaction is carried out in the presence of a
con~ensing agent such as dicyclohexyl-carbodiimide, etc.
The reaction is advantageously carried out in an
organic solvent such as methylene chloride, dimethylform-
amide, etc. under cooling or at room temperature.
When both the starting materials, compounds (II) and
(III), are levorotatory, optical isomers, the reaction
product comprises essentially only the dextrorotatory,
optical isomer of diastereomer A and the isomer can be
isolated from the reaction mixture in a conventional manner
~33~3~
J~ ,
such as extraction, concentration, etc., or by column
chromatography, if necessary. When at least one of
compounds (II) and (~II) is a racemate, the resultant
reaction mixture includes the desired dextrorotatory optical
isomer of diastereomer A as well as the levorotatory optical
isomer thereof, the levo- or dextrorotatory isomers of
diastereomer B, etc. and the desired isomer can be isolated
from the reaction mixture by column chromatography or
fractional crystallization.
For example, the obtained mixture of the
dextrorotatory, optical isomer of diastereomer A and the
levorotatory, optical isomer B of YM-09730 is subjected to
column chromatography using silica gel as a carrier and
ethyl acetate-acetic acid as an eluent, whereby the
dextrorotatory, optical isomer of diastereomer A of YM-09730
is separated from the mixture. Alternatively, the mixture
is reacted with L-(-)-malic acid and, the thus obtained
L-(-)-malates of the dextrorotatory, optical isomer of
diastereomer A and the levorotatory, optical isomer of
diastereomer B are fractionally recrystallized to obtain
L-(-)-malate of the dextrorotatory, optical isomer of
diastereomer A.
In the separation by means of column chromatography,
the dextrorotatory, optical isomer of diastereomer A can be
obtained from the first eluate and from the later eluate,
the levorotatory, optical isomer of diastereomer B can be
obtained. There is no particular limitation to silica gel
used as a carrier as long as it is generally employed in
; !
column chromatography. A mixing ratio of ethyl acetate and
acetic acid which is an eluent is not particularly limited
but, it is generally preferred that ethyl acetate can be
used as a major component and a small quantity of acetic
acid can be mixed therewith. It is advantageous that the
mixing ratio is approximately 1 to 10 v/v of acetic acid to
30 to 50 v/v of ethyl acetate. When the ratio of acetic
acid to be mixed decreases, a time period of eluting the
desired compound out is prolonged.
A rate of elution and temperature for treatment may be
appropriately adopted.
On the other hand, the method using L-(-)-malic acid is
also applicable to separation of the dextrorotatory, optical
isomer of diastereomer A through fractional recrystalli-
zation since L-(-~-malate of the dextrorotatory optical
isomer of diastereomer A is crystalline. As the solvents
which can be employed for the fractional recrystallization,
methanol, ethanol, ace-tone, aceonitrile, etc. may be
mentioned.
The thus obtained L-(-)-malate of the dextrorotatory,
optical isomer of diastereomer A can be provided as drugs as
they are, but acetate of this isomer and the like may
optionally be treated with a base to form a free form, which
is then treated with an appropriate acid to lead to suitable
other salts.
~3~
The dextrorotatory, optical isomer of diastereomer A of
YM-09730 and pharmaceutically acceptable acid addition salts
thereof which are the aimed compounds of the present
invention are novel compounds that have not been described
in any publication and, show an area ratio increased by
approximately 40 times over that of the levorotatory,
optical isomer (l-form) and an area ratio increased by 2.5
times over that of an equivalent mixture of both isomers
(dl-form), in a ra-te of increasing coronary blood flow
through direct administration to the coronary arteries and,
in addition, have high affinity to the coronary artery.
Accordlng to the process of the present invention, the
dextrorotatory, op-tical isomer of diastereomer A of YM-09730
which is novel and useful can be selectively produced in a
good yield and, is of extremely high utility value from an
industrial viewpoint.
Hereafter, the present invention will be described in
more detail with reference to the Examples. The raw
compounds (II) and (III) used in the present invention are
recognized to be known compounds; however, in application to
the present invention, the raw compounds could be produced
by novel, useful processes, which are shown as Reference
Examples.
Reference Example 1
(1) A solution of 6.04 g of m-nitrobenzaldehyde, 6.32 g
of tert-butyl acetoacetate, 0.17 g of piperidine and 0.6 ml
of acetic acid in 20 ml of benzene was heated under reflux
for 6 hours using an apparatus for azeotropic dehydration.
.~
After cooling the system, 10 ml of water were added thereto
and the benzene layer was fractioned. After washing the
benzene layer successively with a saturated aqueous solution
of sodium hydrogen carbonate and a saturated aqueous
solution of sodium chloride, the benzene layer was dried
over anhydrous magnesium sulfate. After the solvent was
removed by distillatior- under reduced pressure, the
resulting residue was subjected to silica gel column
chromatography. The crystals obtained from a portion eluted
with n-hexane:ethyl acetate (5:1 volume ratio) were washed
with n-hexane to obtain 5.82 g of a mixture of geometric
isomers of tert-butyl 2-(m-nitrobenzylidene)acetoacetate as
colorless crystals.
Melting point: 33 - 36C
(2) A mixture of 3.56 g of t-butyl 2-(m-nitrobenzyli-
dene)acetoacetate obtained in (1) and 1.41 g of methyl 3-
aminocrotonate in 7 ml of tert-butanol was heated under
reflux for 20 hours. The solvent was removed by
distillation under reduced pressure. The thus obtained oily
residue was treated with n-hexane to obtain 4.6 g of the
aimed 2,6-dimethyl-4-(m-nitro phenyl)-1,4-dihydropyridine-
3,5-dicarboxylic acid-3-tert-butyl ester-5-methyl ester.
Melting point: 120 - 122C
(3) To 5 ml of a 25% ice-water cooled solution of
hydrogen bromide in acetic acid, a solution of 2.5 g of
2,6-dimethyl 4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-
r~7~
39~
dicarboxylic acid-3-tert-butyl ester-5-methyl ester obtained
in (2) in 5 ml of toluene was dropwise added. After
stirring the mixture for 5 minutes under ice cooling, the
mixture was poured into 50 ml of ice water. After the
mixture was made alkaline with a 10% aqueous solution of
sodium hydroxide, the mixture was extracted with toluene.
The aqueous layer was made acidic with conc. hydrochloric
acid and the precipitated crystals were collected by
filtration. The crystals were washed with ether to obtain
1.24 g of aimed 5-methoxycarbonyl-2,6-dimethyl-4-(m-
nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid
(racemate).
Melting point: 203 - 204C (decomposed)
Reference Example 2
A solution of 7.55 g of m-nitrobenzaldehyde, 5.75 g of
methyl 3-aminocrotonate and 7.90 g of tert-butyl
acetoacetate in 25 ml of tert-butanol was heated under
reflux for 22 hours. After the solvent was removed by
distillation under reduced pressure, the resulting residue
was dissolved in 150 ml of toluene. After washing the
solution successively with 10% hydrochloric acid, a
saturated aqueous solution of sodium hydrogen carbonate and
a saturated aqueous solution of sodium chloride, the
solution was dried over anhydrous magnesium sulfate. The
solvent was removed by distillation under reduced pressure
to obtain 19.62 g of an oily substance. The
oily substance was dissolved in 20 ml of toluene and the
solution was dropwise added to 20 ml of a 25% hydrogen
bromide in acetic acid under ice cooling. After stirring
the mixture for 5 minutes at the same temperature, the
rnixture was poured in-to 200 ml of ice water. After adding
250 ml of a 10~ sodium hydroxide solution to the mixture to
make it alkaline the mixture was washed with 100 ml of
toluene. The aqueous layer was acidified with conc.
hydrochloric acid and the precipitated crystals were taken
by filtration to obtain 4.51 g of the aimed 5-methoxy-
carbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-
3-carboxylic acid (racemate).
Each optical isomer of said racemate can be obtained
according to a process of T. Shibanuma et al, Chem. Pharm.
Bull., 28, 2809 (1980).
Reference Example 3
(1) In 66 ml of acetone, 17.7 g o~ dl-l-benzyl-3-
hydroxypyrrolidine and 15.2 g of D-(-)-mandelic acid were
dissolved by heating. The solution was allowed to stand at
4C overnight and, 8.5 g of the precipitated crystals were
recrystallized from 26 ml of acetone to obtain 5.1 g of (D)-
(-)-mandelate of (S)-(-)-1-benzyl-3-hydroxypyrrolidine.
Specific rotation [~] 20 + 45.5 (C=1, methanol).
D
Recrystallization was further repeated but no change was
noted in the specific rotation.
Melting point: 101 - 102C
Nuclear magnetic resonance spectrum of N-CH2-Ph was
observed at 4.03 ppm (singlet, 2H) but quartet (J=12.5Hz) of
`` ~739~
ll
AB type of (R)-(-) form at 4.01 ppm was not observed.
(2) In 50 ml of chloroform, 22 g of (D)~ mandelate
of (S)-(-)-l-benzyl-3-hydroxypyrrolidine were dissolved.
The chloroform layer was washed with a solution of 14.4 g of
anhydrous sodium carbonate in 90 ml of water and dried over
anhydrous magnesium sulfate. After chloroform was removed
by distillation, the residue was distilled under reduced
pressure to obtain 11.5 g of S-(-)-1-benzyl-3-hydroxypyrro-
lidine. ~oiling point 109C/0.65 mmHg. [a] 20 -3.77 (C=5,
methanol).
Reference Example 4
(S)-(-)-malic acid, 75 g, was reacted with 75 ml of
benzyl amine at 170C for 3 hours to obtain 52.7 g of (S)-
(-)-1-benzyl-3-hydroxysuccinic imide (melting point, 99-
101 C; specific rotation [a] 20 -51.1 (C=1, methanol)). In
340 ml of absolute tetrahydrofuran, 9.73 g of lithium
aluminum hydride were suspended and, a solution of 20.5 g of
the imide in 200 ml of absolute tetrahydrofuran was dropwise
added to the suspension under ice cooling. After heating
under reflux for 3 hrs, the mixture was cooled and 100 g of
sodium sulfate decahydrate were added thereto. The mixture
was stirred overnight under ice cooling. The insoluble
matter was removed by filtration and the solvent was removed
by distillation under reduced pressure. The residue was
~'
12
distilled under reduced pressure to obtain 13.8 g of
(S)-(-)-l-benzyl-3-hydroxypyrrolidine having a boiling point
of 109 - 115 C/0.8 mmHg and a specific rotation of [a] 20
-3Ø The thus obtained (S)-(-) form contained 10% of
R-(~) form, based on the nuclear magnetic resonance spectrum
of the hydrogen of the 3-position using a shift reagent
(Eu-TFMC (III) ). The (S)-(-) form was converted into
D-(-)-mandelate as in Reference Example 3, which was
recrystallized from a 3-fold volume of ethanol and then from
a 6-fold volume of ethanol-toluene (1:5). The thus obtained
mandelate ([a] 20 -45.2) was treated as mentioned above to
obtain 8.6 g of (S)~ l-benzyl-3-hydroxypyrrolidine
(boiling point, 115-120C/1.2-1.5 mmHg, [a] 20 -3.77 (C=5,
methanol) ).
Reference Example 5
To 50 ml of 9-borobicyclo 3.3.1 nonane (0.5M tetra-
hydrofuran solution), 3.4 g of 2-(+)-pinene was added and
the mixture was stirred for 5 hours of 60C. The mixture
was cooled to room temperature and 1.75 g of 1-benzyl-3-
pyrrolidinone was added thereto. After stirring the mixture
at room temperat~re for 4 days, 1.3 ml of acetoaldehyde was
added to the mixture at 0C. The solvent was removed by
distillation under reduced pressure and 20 ml of ether was
added to the residue. The mixture was cooled to 0C and 1.5
ml of 2-aminoethanol was added thereto. The mixture was
13
stirred. The formed precipitates were removed by distilla-
tion. The ethereal solution was extracted with lN hydro-
chloric acid. The hydrochloric acid layer was rendered
alkaline with sodium carbonate and ex~racted with dichloro-
methane. The extract was dried over anhydrous magnesium
sulfate and concentrated to obtain 1.1 g of the crude
product. The crude product was distilled under reduced
pressure to obtain 0.6 g of the pure product. Boiling
point, 106-C/0.9 mmHg. The thus obtained (S)-( )-1-benzyl-
3-hydroxypyrrolidine was 30% enantio excess (e.e.), based on
the nuclear magnetic resonance spectrum of the hydrogen at
the 3-position after adding a shift reagent (Eu-TFMC (III)).
~xample 1
In 3 ml of dichloromethane, 332 mg of 5-
methoxycarbonyl-2,6-dimethyl-~-(m-nitrophenyl)-1,4-
dihydropyridine-3-carboxylic acid was dissolved and 250 mg
of phosphorus pentachloride was added to the solution while
stirring under ice cooling. The mixture was stirred for an
additional 1 hour at the same temperature. The reaction
mixture was cooled to -30C and 177 mg of (S)-1-benzyl-3-
hydroxypyrrolidine was added thereto. After stirring at
-30C for two hours, -the reaction mixture was washed with
water and then with a saturated aqueous solution of sodium
hydrogen carbonate. The solvent was removed by distillation
to obtain an oily substance. The oily substance was
subjected to silica gel column chromatography eluting with
ethyl acetate-acetic acid (5:1 v/v) to obtain the dextroro-
tatory optical isomer (I) of diastereomer A of YM-09730
~ r r
~2~3~3~
1~
showing retention time of 28 minutes in a high speed
liquid chromatographic system [column: Nucleosil
S C18 4.6 mm ~ x 300 mm, column temperature: 30C,
mobile phase: 0.05 mol dihydrogen potassium phosphate
(pH 3)-acetonitrile ~80:20 v/v) including tetra-n-
pentylammonium bromide, flow rate: 0.9 ml/min., UV
detector (~ 254 nm)]. In chloroform, the thus obtained
isomer was treated with a saturated aqueous solution of
hydrogen sodium carbonate and then with dilute hydro-
chloric acid to obtain 161 mg of the hydrochloride of
the dextrorotatory optical isomer of diastereomer A
of YM-09730.
Melt-ing point: 228 - 230C ~decomp.)
Specific rotation: ~]20 +116.3 (C=0.5, methanol)O
Example 2
In 3 ml of dichloromethane, 332 mg of (-)-5-methoxy-
carbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydro-
pyridine-3-carboxylic acid was dissolved and 250 mg of
phosphorus pentachloride was added to the solution while
stirring under ice cooling. The mixture was further
stirred for 1 hour at the same temperature. The reaction
mixture was.cooled to -30-C-~and 1-77 mg of (S)-l-benzyl-
3-hydr~xypyrrolidine was added thereto. After stlrring
at -30C for 2 hours, the Teaction mixture was diluted
with 5 ml of dichloromethane and washed successively with
water and a saturated aqueous solution of sodlum hydroge~
carbonate twice in a portion of 5 ml. The solvent was
was removed by distillation under reduced pressure to obtain
an oily substance. The oily substance was subjected to
silica gel (15 g) column chromatography eluting with
toluene-acetic acid ~4:1 v/v). The fraction containing the
desired isomer was concentrated under reduced pressure, and
the resultant residue was dissolved in 5 ml of chloroform.
~fter adding 1 ml of a solution of 0.8 N hydrogen chloride
in ethanol to said chloroform solution, the solution was
again concentrated under reduced pressure. The residue was
dissolved in 2 ml of methanol and the solution was allowed
to stand overnight under ice cooling. The precipitated
crystals were collected by filtration and dried to obtain
350 mg of the hydrochloride of the dextrorotatory optical
isomer of diastereomer A of YM-09730.
Melting point: 226 - 228C (decomp.)
Specific rotation: ([o~] 20 +116.4(C=1, methanol)
NMR (in CD30D, TMS internal standard, ~ppm):
1.80-2.70 (2H, broad m, C4--H2)
2.32, 2.34 (6H, s, C2,6--CH3)
3.0-4.0 (4H, m, C2lsl-H2)
3.64 (3H, s, -COOCH3)
4.42 (2H, s, --CH2~)
5.08(lH, s, C4-H)
5.30(lH, m, C3--H)
7.30-8.20 (9H, m, benzene ring-H)
16
Example 3
In 6 ml of dichloromethane and N,N-dimethylformamide
(4:1 v/v), 840 mg of (-)-5-methoxycarbonyl-2,6-dimethyl-4-
(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was
suspended and 0.2 ml of thionyl chloride was added to the
solution under ice cooling. The mix~ure was stirred for 1
hour at the same temperature. To the reaction mixture was
dropwise added 450 mg of (S)-1-benzyl-3-hydroxy-pyrrolidine
in 3 ml of dichloromethane under ice cooling, the resultant
mixture was further stirred for 15 hours under ice cooling,
and then the reaction mixture was diluted with 10 ml of
dichloromethane. After washing the obtained solution
successively with 10 ml of water and 10 ml of a saturated
aqueous solution of sodium hydrogen carbonate, the solution
was dried over anhydrous magnesium sulfate. The solvent was
removed by distillation under reduced pressure to obtain an
oily substance. The oily substance was subjected to silica
gel (40 g) column chromatography eluting with toluene-acetic
acid (4:1 v/v, followed by 1:1 v/v). The fraction
containing the desired isomer was concentrated under reduced
pressure to obtain 990 mg of a concentrated oily substance,
the oily substance was dissolved in 10 ml of chloroform.
After adding 2.6 ml of a solution of 0.8 N hydrogen chloride
in ethanol, the solution was again concentrated under
reduced pressure. The obtained residue was dissolved in
5 ml of methanol, the solution was allowed to stand
overnight under ice cooling. The precipitated crystals
'~
17
were taken by filtration and dried to obtain 850 mg of
the hydrochloride of the dextrorotatory, optical iSOmer
of diastereomer A of YM-09730.
Melting point: 226 - 228C (decomp.)
Specific rotation: [c~]D +116.4 (c=l, methanol)
N~R spectra were consistent with those of the product
prepared by Example 2.
Example 4
1) The concentrated oily substance (990 mg)
obtained by following the Example 3 procedure
was dissolved in 10 ml of ethanol, the solution was again
concentrated under reduced pressure. The resulting
residue was dissolved in--5- ml--of--ethanol, the solution
was allowed to stand overnight undeT ice cooling. The
precipitated crystals were collected by filtration and
dried to obtain 730 mg of the free base of the dextro-
- - - rotatory, -opitical isomer -of diastereomer A of YM-09730D
Melting point: 137 - 139C
Specific rotation: [U]D -~64.8 (c-l, methanol)
NMR (in CDC13, TMS internal standard9 ~ppm)
1.4 - 3.0 (6H, m, C2"4,~5, H2
2.34, 2.36 (6H, s, C2 6~CH3)
3.65 (5H, s, -COOCH3 and -CH2~)
5.10 (lH, s, C4-H)
-- - - 5.12 (lH, m, C3,-H)
5.78 ~lH, broad s, NH)
7.16 - 8.24 ~9H, m, benzene ring-H)
~3~
18
2) The free base (700 mg) obtained above was dissolved
in 10 ml of chloroform and 1.8 ml of a solution of 0.8 N
hydrogen chloride in ethanol, the solution was concentrated
under reduced pressure. The obtained residue was dissolved
in 3.5 ml of methanol, the solution was allowed to stand
overnight under ice cooling. The precipitated crystals were
collected by filtration and dried to obtain 630 mg of the
hydrochloride of the dextrorotatory, optical isomer of
diastereomer A of YM-09730.
Melting point: 228-230 C (decomp.)
Specific rotation: ([~] 20 +116.7 (c=1, methanol)
NMR spectrum were consistent with those of the product
prepared by Example 2).
'~ '
