U.S. patent number RE36,575 [Application Number 08/948,515] was granted by the patent office on 2000-02-15 for pyridine and thiazolidinedione derivatives.
This patent grant is currently assigned to Takeda Chemical Industries, Ltd.. Invention is credited to Takeshi Fujita, Chitoshi Hatanaka, Kanji Meguro, Satoru Ooi.
United States Patent |
RE36,575 |
Meguro , et al. |
February 15, 2000 |
Pyridine and thiazolidinedione derivatives
Abstract
A compound of the formula: ##STR1## (wherein R.sup.1 is hydrogen
or a lower alkyl) can be produced advantageously by (1) reacting a
compound of the formula: ##STR2## (wherein R.sup.1 has the meaning
given above) with a halogenating agent or sulfonyl halide to give a
compound of the formula: ##STR3## (wherein R.sup.1 has the meaning
given above and X is a halogen or an alkyl- or aryl-sulfonyloxy),
(2) reacting the resulting compound with a compound of the formula:
##STR4## to give a compound of the formula: ##STR5## (wherein
R.sup.1 has the meaning given above), (3) reacting the resulting
compound with a compound of the formula: ##STR6## to give a
compound of the formula: ##STR7## (wherein R.sup.1 has the meaning
given above), and (4) subjecting the resulting compound to
catalytic reduction.
Inventors: |
Meguro; Kanji (Hyogo,
JP), Fujita; Takeshi (Hyogo, JP), Hatanaka;
Chitoshi (Kyoto, JP), Ooi; Satoru (Nara,
JP) |
Assignee: |
Takeda Chemical Industries,
Ltd. (Osaka, JP)
|
Family
ID: |
15975864 |
Appl.
No.: |
08/948,515 |
Filed: |
October 10, 1997 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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073695 |
Jul 14, 1987 |
4812570 |
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Reissue of: |
291782 |
Dec 29, 1988 |
04898947 |
Feb 6, 1990 |
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Foreign Application Priority Data
|
|
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Jul 24, 1986 [JP] |
|
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61-1742178 |
|
Current U.S.
Class: |
546/269.7;
546/340 |
Current CPC
Class: |
A61P
3/08 (20180101); C07D 213/30 (20130101); C07D
417/12 (20130101) |
Current International
Class: |
C07D
417/12 (20060101); C07D 417/00 (20060101); C07D
213/46 (20060101); C07D 213/00 (20060101); C07D
213/46 (); C07D 417/12 () |
Field of
Search: |
;546/340,269.7 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Sohda et al., Chem. Abstracts, vol. 98, No. 19; 160624h (1983).
.
March, J. Adv. Org. Chem., pp. 707-709. Month and Year Not
Available. .
Sohda et al., "Studies on Antidiabetic Agents. III..sup.1)
5-Arylthiazolidine-2,4-diones as Potent Aldose Reductase
Inhibitors", Chem. Pharm. Bull. 30(10)3601-3616(1982)..
|
Primary Examiner: Stockton; Laura L.
Attorney, Agent or Firm: Weneroth, Lind & Ponack
L.L.P.
Parent Case Text
This application is a division of Ser. No. 07/073,695 filed July
14, 1987 now U.S. Pat. No. 4,812,570.
Claims
We claim: .[.1. A compound of the formula: ##STR18##
wherein R.sup.1 is hydrogen or a lower alkyl..].2. A compound of
the formula: ##STR19## wherein R.sup.1 is hydrogen or a lower
alkyl. .Iadd.3. The compound according to claim 2, wherein R.sup.1
is ethyl. .Iaddend..Iadd.4. A compound of the formula ##STR20##
wherein R.sup.1 is hydrogen or a lower alkyl, excluding
4-[2-(6-methyl-2-pyridyl)ethoxy]benzaldehyde and
4-[2-(2-pyridyl)ethoxy]benzaldehyde. .Iaddend..Iadd.5. The compound
according to claim 4, wherein R.sup.1 is ethyl. .Iaddend.
Description
This invention relates to a novel method of producing
thiazolidinedione derivatives having hypoglycemic and hypolipidemic
activities.
Methods for production of various thiazolidinedione derivatives
having hypoglycemic and hypolipidemic actions are described in
Japanese Kokai Tokkyo Koho Sho 55-22636 and Sho 55-64586 and
Chemical & Pharmaceutical Bulletin 30, 3563(1982), 30,
3580(1982), and 32, 2267(1984). These methods invariably comprise
the steps of diazotizing an aniline derivative, condensing it with
an acrylic ester in the presence of a copper catalyst by the
so-called Meerwein arylation reaction to give a haloester, reacting
it with thiourea to give an iminothiazolidine, and finally
hydrolyzing the same. These methods include multi-step reaction
processes. In particular, it is sometimes difficult to control the
Meerwein reaction in an industrial production, since it is an
exothermic reaction accompanied by generation of a large amount of
nitrogen gas and thus could be dangerous. Moreover, because of the
formation of by-products in the step of Meerwein arylation
reaction, this route assures only insufficient yields and calls for
a time-consuming purification procedure. Furthermore, special
measures are required in the Meerwein reaction for elimination of
an extremely bad odor of acrylic acid ester which must be used in
excess and for disposal of the effluent containing a heavy metal.
The above mentioned points make the known route disadvantageous
both technically and commercially.
This invention provides a new commercially profitable method for
the production of thiazolidinedione derivatives which have
hypoglycemic and hypolipidemic activities and are of value as
therapeutic agents for diabetes and hyperlipemia.
This invention relates to:
1. A method for producing a compound of the formula: ##STR8##
(wherein R.sup.1 is hydrogen or a lower alkyl), which comprises
reacting (1) a compound of the formula: ##STR9## (wherein R.sup.1
has the meaning given above) with a halogenating agent or a
sulfonyl halide to give a compound of the formula ##STR10##
(wherein R.sup.1 has the meaning given above and X is a halogen or
an alkyl- or aryl-sulfonyloxy) (2) reacting the resulting compound
with a compound of the formula: ##STR11## to give a compound of the
formula: ##STR12## (wherein R.sup.1 has the meaning given above),
(3) reacting the resulting compound with a compound of the formula:
##STR13## to give a compound of the formula: ##STR14## (wherein
R.sup.1 has the meaning given above), and (4) subjecting the
resulting compound to catalytic reduction.
2. A method for producing a compound of the formula (V) which
comprises reacting a compound of the formula (II) with a
halogenating agent or sulfonyl halide to give a compound of the
formula (III) and then reacting the Compound (III) with a compound
of the formula (IV).
3. A method for producing a compound of the formula (V) which
comprises reacting a compound of the formula (II) with a compound
of the formula: ##STR15## to give a compound of the formula:
##STR16## (wherein R.sup.1 has the meaning given above), and then
reacting the resulting compound with aqueous formic acid in the
presence of Raney nickel alloy.
4. A method for producing a compound of the formula (I) which
comprises reducing a compound of the formula (VII).
5. A compound of the formula (V).
6. A compound of the formula (VII).
Referring to the above general formulas (I), (II), (III), (V),
(VII) and (IX), the lower alkyl group denoted by R.sup.1 is a
straight-chain or branched alkyl group of 1 to 6 carbon atoms, such
as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc. Among them,
lower alkyl groups of 1 to 3 carbon atoms are preferable and ethyl
is the most preferable. Such an alkyl group may be situated in any
position of the pyridine ring. Halogen shown by X in the formula
(III) includes chlorine, bromine and iodine; alkylsulfonyloxy shown
by X includes methylsulfonyloxy, ethylsulfonyloxy and
propylsulfonyloxy; and arylsulfonyloxy shown by X includes
phenylsulfonyloxy and p-tolylsulfonyloxy. Particularly preferable
ones are arylsulfonyloxy groups.
In the method of the present invention, first Compound (II) is
reacted with a halogenating agent or sulfonyl halide to prepare
Compound (III). As the halogenating agent, there may be mentioned
thionyl chloride, phosphorus oxychloride, phosphorus tribromide,
etc. As the sulfonyl halide, there may be mentioned such
alkylsulfonyl halide having 1 to 4 carbon atoms as methylsulfonyl
chloride, ethylsulfonyl chloride, propylsulfonyl bromide, such
arylsulfonyl halide (phenyl or naphthyl which are unsubstituted or
substituted by 1 to 3 alkyl groups of 1 to 4 carbon atoms) as
phenylsulfonyl chloride, p-tolylsulfonyl chloride, p-tolylsulfonyl
bromide. Among them, arylsulfonyl halide is preferable.
When halogenating agent is used, the reaction is carried out in a
solvent such as dichloromethane, dichloroethane, chloroform, carbon
tetrachloride, benzene, toluene, xylene, dimethylformamide, etc.
The reaction temperature is in the range of -20.degree. C. to
80.degree. C., preferably -10.degree. C. to 60.degree. C.
When sulfonyl halide is used, the reaction is carried out in a
solvent. The solvents includes such halogenated aliphatic
hydrocarbon as dichloromethane, dichloroethane, chloroform, carbon
tetrachloride, such aromatic hydrocarbon as benzene, toluene,
xylene, such ether as diethyl ether, dibutyl ether, diisobuthyl
ether, ethyleneglycol diethyl ether, dioxane, tetrahydrofuran,
water, ethyl acetate, dimethylformamide or a mixture of two or more
of these solvents. The reaction is usually carried out in the
presence of an inorganic base (e.g. sodium hydroxide, potassium
hydroxide, potassium carbonate, sodium carbonate, etc.) or an
organic base (e.g. triethylamine, morpholine, N-ethylpiperidine,
etc.). Further the reaction is advantageously carried out in the
presence of a phase transfer catalyst such as benzyl
tributylammonium bromide, benzyl triethylammonium chloride,
tetrabutylammonium bromide, cetyl trimethylammonium chloride. The
sulfonyl halide is used in an amount of 1 to 2 moles, preferably
1.0 to 1.5 moles per mole of Compound (II). The base is used in an
amount of 1 to 3 moles, preferably 1.5 to 2.5 moles per mole of
Compound (II). The phase transfer catalyst is used in an amount of
0.1 to 1.0 mole, preferably 0.2 to 0.5 mole per mole of Compound
(II). The reaction temperature is usually 0.degree. C. to
50.degree. C., preferably 15.degree. C. to 30.degree. C.
The reaction time is usually not less than 2 hours, preferably 3 to
5 hours though it varies with a reaction condition such as reaction
temperature.
The reaction between Compound (III) and Compound (IV) is usually
carried out in the presence of a base in a suitable solvent.
Further, the reaction advantageously proceeds in the presence of a
phase transfer catalyst. As the solvent, the base and the phase
transfer catalyst, those used in the reaction between Compound (II)
and the sulfonyl halide can be used. Compound (IV) is used in an
amount of 1 to 3 moles, preferably 1 to 1.5 mole, per moles of
Compound (III). The base is used in an amount of 1 to 3 moles,
preferably 1.5 to 2.5 moles, per mole of Compound (III). When a
phase transfer catalyst is used in the reaction, the amount of the
catalyst is usually 0.1 to 1.0 mole, preferably 0.2 to 0.5 mole,
per mole of Compound (III). The reaction temperature is usually
20.degree. C. to 90.degree. C., preferably 50.degree. C. to
65.degree. C. The reaction time is usually not less than 5 hours,
preferably 10 to 20 hours. It is advantageous, from the industrial
point of view, to use a sulfonyl halide in the reaction to convert
Compound (II) to Compound (III) since the reaction mixture
containing Compound (III) can be used, without isolating the
Compound (III), for the next reaction to give Compound (V).
Compound (III) can also be converted to Compound (V), for example,
by the following processes. ##STR17## [wherein R.sup.1 has the
meaning defined hereinbefore]
The conversion of Compound (II) to Compound (IX) is effected by
condensing (II) with (VIII) in the presence of, for example, sodium
hydride. This reaction can be conducted in a solvent such as
dimethylformamide, dimethyl sulfoxide, tetrahydrofuran,
dimethoxyethane, etc. at -10.degree. C. to 30.degree. C. The
subsequent conversion of Compound (IX) to Compound (V) is effected
by heating (IX) together with Raney nickel alloy in aqueous formic
acid. The reaction between Compound (V) and Compound (VI) is
usually carried out in a suitable solvent in the presence of an
appropriate base. As such solvent-base system, there may be
employed a suitable combination of a solvent such as alcohols (for
example, methanol, ethanol, propanol, 2-propanol, butanol, isobutyl
alcohol, 2-methoxyethanol, etc.), dimethylformamide, dimethyl
sulfoxide, sulfolane, acetronitrile, dioxane, dimethoxyethane,
acetic acid, etc. with a base such as amines (for example, ammonia,
methylamine, ethylamine, n-butylamine, pyrrolidine, piperidine,
morpholine, piperazine, diethylamine, diisopropylamine,
triethylamine, etc.), sodium alkoxides (for example, sodium
methoxide, sodium ethoxide, etc.), potassium carbonate, sodium
carbonate, sodium hydroxide, sodium acetate, potassium acetate, and
so on. Compound (VI) is generally used in a proportion of 1 to 4
moles and preferably 1 to 2.5 moles per mole of Compound (V). The
base is generally used in a proportion of 0.05 to 1.0 mole and
preferably 0.3 to 0.5 mole per mole of Compound (V). This
condensation reaction is conducted generally at 40.degree. C. to
reflux temperature and preferably at 60.degree. C. to reflux
temperature. The reaction time is generally 0.5 to 50 hours.
Then, Compound (VII) is reduced to produce Compound (I). In this
step, Compound (VII) is subjected to catalytic reduction in a
suitable solvent in the presence of a catalyst. As the solvents,
there may be employed, among others, alkanols such as methanol,
ethanol, propanol, etc., ethers such as dioxane, dimethoxyethane,
tetrahydrofuran, etc., ethyl acetate, acetic acid,
dimethylformamide, N-methylpyrrolidone, etc., either alone or in
combination. As the catalyst, there can be employed palladium
black, palladium on carbon, palladium or barium sulfate, palladium
on barium carbonate, platinum oxide, platinum on carbon and so on.
The reaction temperature is usually 0.degree. C. to 180.degree. C.,
preferably 50.degree. C. to 120.degree. C. Though the reaction
proceeds under atmospheric pressure, it may be conducted under a
pressure of not more than 150 kg/cm.sup.2, preferably 30
kg/cm.sup.2 to 100 kg/cm.sup.2.
The resulting thiazolidinedione derivative (I) can be easily
separated and purified by known isolation and purification
procedures. Particularly, the Compound (I) can be isolated in high
quality either by recrystalizing from dioxide, acetic acid-acetone,
acetic acid-water or acetic acid-ethanol or by dissolving Compound
(I) in hydrochloric acid, aqueous sulfuric acid or aqueous methane
sulfonic acid followed by neutralizing the solution with sodium
hydrogencarbonate, ammonia, etc. to crystalize Compound (I).
Further, as (I) forms salts with bases, it can be isolated in the
form of a salt. As examples of such salt, there can be mentioned
the sodium salt, potassium salt, magnesium salt, ammonium salt,
triethylammonium salt, piperidinium salt, morpholinium salt,
phenylethylammonium salt, and so on.
The Compound (I) produced by the method of this invention or a
pharmaceutically acceptable salt thereof exhibits blood-glucose and
blood-lipid lowering action with lower toxicity, and may be safely
administered, orally or parenterally, as it is or advantageously as
a pharmaceutical composition comprising an effective amount of the
compound (I) or its pharmacologically acceptable salt and a
pharmacologically acceptable carrier, excipient or diluent
therefor, in the form of, for example, powder, granule, tablet,
hard capsule, soft capsule, dry syrup, suppository, injection or
the like.
The composition for oral administration such as powder, granule,
tablet, hard capsule, soft capsule and dry syrup may be prepared by
a per se known conventional manner, and may comprise carriers,
excipients or diluents conventionally used in the pharmaceutical
art. For example, suitable carriers or excipients include lactose,
starch, sugar, magnesium stearate, etc. As the excipients in the
preparation of soft capsules, there my be used nontoxic,
pharmaceutically acceptable oils and fats of animal, vegetable or
mineral origin. The essential active ingredients are generally
dissolved in these oils and fats before filling soft capsules
therewith.
The compositions for parenteral administration may, for example, by
injections, and suppositories. The injectable preparations may be
prepared in the form of solutions or suspensions. Injectable
preparations in the form of aqueous solutions may be prepared by a
conventional manner. The suppositories for rectal administration
can be prepared by incorporating the compound (I) or its
pharmacologically acceptable salt with a conventional suppository
base. The pharmaceutical composition of the present application can
be used as an antidiabetic agent for mammals including man.
Oral administration to an adult patient is 0.05-10 mg/kg body
weight/day, preferably 0.5-5 mg/kg body weight/day, and
parenterally 0.01-10 mg/kg body weight/day, preferably 0.01-1.0
mg/kg body weight/day once daily or divided into 2-4 times a
week.
The method of the present invention involves only four steps to
produce the desired Compound (I) from Compound (II) which is
commercially available. Further in the present method, it is
unnecessary to use either acrylic acid ester which has a bad smell,
or a heavy metal which should not be dumped together with waste
fluid from the viewpoint of environmental pollution. The present
method can avoid the Meerwein reaction which is difficult to
conduct on an industrial scale. Thus the present method is
advantageous from the industrial point of view.
EXAMPLE 1
[Production of Compound (V) from Compound (II) via Compound
(III)]
(a) To a solution of sodium hydroxide (5 g) in water (30 ml), were
added methylene chloride (100 ml), 5-ethyl-2-pyridineethanol (15 g)
and benzyltributylammonium chloride (50% aqueous solution, 6 g),
p-toluenesulfonyl chloride (23 g), and the mixture was stirred at
room temperature for 2 hours. To the reaction mixture were added
p-hydroxybenzaldehyde (12 g), water (100 ml) and sodium hydroxide
(8 g) and the mixture was stirred at 40.degree.-50.degree. C. for
12 hours. The reaction mixture was separated into two phases and
the methylene chloride layer was dried (MgSO.sub.4) and
concentrated to give 28.6 g of crude
4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde as oil. This oil was
purified by silica gel chromatography to give 15.8 g (62%) of pure
4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde as oil.
NMR (CDCl.sub.3) .delta.: 1.15 (t, 3H), 2.6 (q, 2H), 3.2 (t, 2H),
4.4 (t, 2H), 6.89-8.35 (m, 7H), 9.88 (s, 1H).
(b) To a mixed solution of 5-ethyl-2-pyridine ethanol (6.0 kg),
benzyltributylammonium chloride (6.2 kg of 50% aqueous solution),
1,2-dichloroethane (30 l) and p-toluenesulfonylchloride (9.2 kg)
was added dropwise 8N aqueous solution (10 l) of sodium hydroxide
at 25.degree. C. After the solution was stirred at 22.+-.3.degree.
C. for 4 hours, p-hydroxybenzaldehyde (5.9 kg) and 3N solution (16
l) of sodium hydroxide, were added, and the mixed solution was
stirred at 57.+-.3.degree. C. for 15 hours. After the solution was
cooled, water (70 l) was added. The aqueous layer was separated and
subjected to extraction with 1,2-dichloroethane (20 l). The organic
layers were combined and the combined layer was washed three times
with 0.1N aqueous solution of sodium hydroxide and three times with
water (30 l). The organic layer was concentrated at not higher than
45.degree. C. under a reduced pressure, whereby
4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde was obtained as an oil.
Quantitative analysis by HPLC (high performance liquid
chromatography) showed that 5.98 kg (59.0%) of
4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde was included in this
crude product.
(c) By a similar manner to Example (1-a), the reaction was carried
out by using benzyltriethylammonium chloride as a phase transfer
catalyst, whereby 8.3 g (32.5%) of
4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde was obtained as an
oil.
(d) In a similar manner to Example (1-b), the reaction was carried
out by using carbontetrachloride as a solvent and 30 g of
5-ethyl-2-pyridinethanoi. Quantitative analysis by HPLC showed that
55.3% of 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde was included
in the crude product obtained in the above.
EXAMPLE 2
[Production of Compound (VII) from Compound (V)]
(a) A mixture of 4-[2-(6-methyl-2-pyridyl)ethoxy]benzaldehyde (1.21
g), 2,4-thiazolidinedione (0.59 g), ethanol (50 ml) and piperidine
(0.33 g) was heated under reflux for 16 hours. The reaction mixture
was poured into ice-water and acidified with acetic acid. The
resulting crystals were collected by filtration to give
5-{4-[2-(6-methyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione.
Yield: 1.34 g (78.5%). Recrystallization from methanol gave pale
yellow prisms. m.p.: 180.5.degree.-182.degree. C.
Elemental analysis, for C.sub.18 H.sub.16 N.sub.2 O.sub.3 S Calcd.:
C, 63.51; H, 4.74; N, 8.23. Found: C, 63.40; H, 4.84; N, 8.30.
(b) A mixture of 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde (2.40
g), 2,4-thiazolidinedione (1.66 g), ethanol (40 ml) and piperidine
(0.2 ml) was heated under reflux for 8 hours. The resulting
crystals were recrystallized form ethyl acetate to give 2.14 g
(64%) of
5-{[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione
as colorless crystals. m.p.: 165.5.degree.-167.degree. C.
Elemental analysis, for C.sub.19 H.sub.18 N.sub.2 O.sub.3 S Calcd.:
C, 64.39; H, 5.12; N, 7.90. Found: C, 64.29; H, 5.19; N, 7.64.
(c) A mixture of 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde (5.56
kg), 2,4-thiazolidinedione (6.7 kg), piperidine (1.4 l) and ethanol
(80 l) was refluxed for 5 hours. The reaction mixture was gradually
cooled and resulting crystals were collected by filtration. The
crystals were washed with ethanol (20 g), dried, and subjected to
recrystallization from 1,2-dichloroethane (120 l). The resulting
crystals were collected by filtration. The crystals were washed
with 1,2-dichloroethane (15 l) and dried under reduced pressure
whereby 4.87 kg (63.1%) of crystals of
5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione
were obtained.
(d) A mixture of 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde (27
g), ethanol (300 ml), 2,4-thiazolidinedione (33 g) and concentrated
aqueous ammonia (14 ml) was heated under reflux for 5 hours. The
precipitated crystals were separated. Recrystallization from
1,2-dichloroethane gave 21.6 g (57.6% of crystals of
5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione.
EXAMPLE 3
[Production of Compound (I) from Compound (VII)]
(a) To a solution of
5-{4-[2-(6-methyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione
(400 mg) in dioxane (60 ml) was added 5% palladium on carbon (1.2
g) and catalytic reduction was carried out at atmospheric pressure
for 6 hours. The catalyst was filtered off and the filtrate was
concentrated. The residue was recrystallized from 70% ethanol to
give
5-{4-[2-(6-methyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione as
crystals. Yield: 218 mg (54.2%); m.p.: 156.degree.-157.degree.
C.
Elemental analysis, for C.sub.18 H.sub.18 N.sub.2 O.sub.3 S Calcd.:
C, 63.14; H, 5.30; N, 8.18. Found: C, 63.03; H, 5.19; N, 8.41.
(b) To a dimethylformamide solution of
5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione
(1.0 g) was added palladium black (0.2 g) and catalytic reduction
was carried out at 50.degree. C. and 50 kg/cm.sup.2 for 5 hours.
The catalyst was filtered off and the filtrate was concentrated to
dryness. The residue was dissolved in 6N-hydrochloric acid and the
solution was neutralized with sodium hydrogen carbonate to give
5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione as
crystals. Yield: 650 mg (64.8%); m.p.: 173.degree.-174.degree.
C.
Elemental analysis, for C.sub.19 H.sub.20 N.sub.2 O.sub.3 S Calcd.:
C, 64.02; H, 5.66; N, 7.86. Found: C, 63.73; H, 5.65; N, 7.84.
(c) To a solution of
5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione
(600 g) in dimethylformamide (1.2 l) was added palladium on carbon
(600 g). The mixture was heated at 50.degree. C. to 55.degree. C.
under 50 kg/cm.sup.2 for 2 hours. The catalyst was filtered off and
water was added to the filtrate. The resulting crystals were
collected by filtration and washed with water. Recrystallization
from dioxane (8.5 l) gave crystals of
5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione.
Yield: 380.9 g (63.1%).
(d)
5-{4-[2-(5-Ethyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione
(10 g) was dissolved in acetic acid (200 ml). To the solution was
added 5% palladium on carbon (50% wet, 20 g). The mixture was
hydrogenated at 55.degree. C. to 60.degree. C. under 40 to 50
kg/cm.sup.2 for 2 hours. After removing the catalyst by filtration,
the filtrate was concentrated to about 80 ml. To the concentrate
was added acetone (800 ml). The resulting crystals of
5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione was
collected by filtration. Yield: 6.81 g (67.7%).
(e) To a solution of
5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione
(10 g) in dioxane (200 ml) was added 5% palladium on carbon (5 g).
The mixture was heated at 100.degree. C. under 50 kg/cm.sup.2 for 2
hours. The catalyst was filtered off, and the filtrate was
concentrated to about 70 ml under reduced pressure. The resulting
crystals were collected by filtration and dried at 50.degree. C.
under a reduced pressure to give 7.2 g of crude crystals.
Recrystallization from acetic acid-water gave crystals of
5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione.
Yield: 6.42 g (63.8%).
(f) The crude produce of
5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione
obtained by a similar manner to Example (3-e) was subjected to
recrystallization by using acetic acid-ethanol as a
recrystallization solvent to yield a pure sample. Yield: 5.85 g
(58.2%).
REFERENCE EXAMPLE 1
[Production of Compound (IX) from Compound (II)]
To a mixture of 6-methyl-2-pyridineethanol (97.2 g),
p-fluorobenzonitrile (85.8 g) and dry tetrahydrofuran (600 ml) was
added 60% sodium hydride in oil (29.0 g) in small portions with
ice-cooling and stirring and the mixture was further stirred for 2
hours. The reaction mixture was poured in ice-water and extracted
with ethyl ether. The ethyl ether layer was washed with water,
dried (MgSO.sub.4) and concentrated, and the residue was
crystallized from hexane to give
4-[2-(6-methyl-2-pyridyl)ethoxy]benzonitrile. Yield: 85.9 g
(50.1%); m.p.: 66.degree.-67.degree. C.
REFERENCE EXAMPLE 2
[Production of Compound (V) from Compound (IX)]
A mixture of 5-[2-(6-methyl-2-pyridyl)ethoxy]benzonitrile (9.62 g),
Raney nickel alloy (10.0 g) and 75% formic acid (150 ml) was heated
under reflux for 1 hour. The reaction mixture was filtered and the
filtrate was concentrated. The residue was diluted with water,
alkalinized with 4N-KOH, and extracted with ethyl ether. The ethyl
ether layer was washed with water and dried (MgSO.sub.4) and the
solvent was distilled off. The residue was recrystallized from
ethyl etherhexane to give
4-[2-(6-methyl-2-pyridyl)ethoxy]benzaldehyde.
Yield: 6.20 g (63.6%); m.p.: 53.degree.-55.degree. C.
* * * * *