WO2000055146A1 - A process for the preparation of thiazolidine derivatives - Google Patents

A process for the preparation of thiazolidine derivatives Download PDF

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Publication number
WO2000055146A1
WO2000055146A1 PCT/JP2000/001595 JP0001595W WO0055146A1 WO 2000055146 A1 WO2000055146 A1 WO 2000055146A1 JP 0001595 W JP0001595 W JP 0001595W WO 0055146 A1 WO0055146 A1 WO 0055146A1
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Prior art keywords
compound
formula
preparation
mixture
added
Prior art date
Application number
PCT/JP2000/001595
Other languages
French (fr)
Inventor
Itsuo Okumoto
Nobuyuki Nakamura
Original Assignee
Ono Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
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Priority to KR1020017011662A priority Critical patent/KR20010112328A/en
Priority to BR0009079-4A priority patent/BR0009079A/en
Priority to EP00909666A priority patent/EP1165529A1/en
Priority to AU31924/00A priority patent/AU3192400A/en
Priority to CA002368146A priority patent/CA2368146A1/en
Priority to NZ514177A priority patent/NZ514177A/en
Publication of WO2000055146A1 publication Critical patent/WO2000055146A1/en
Priority to NO20014451A priority patent/NO20014451L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members

Definitions

  • the present invention relates to a process for the preparation of thiazolidine derivatives . More particularly, the present invention relates to a process for the preparation of a compound of formula ( I )
  • thiazolidine derivatives including a compound of formula ( I ) reduce blood sugar level and therefore are useful for the treatment of non-insulin dependent diabetes mellitus.
  • many methods for the preparation of thiazolidine derivatives are illustrated. Thereamong some of methods for the preparation of a compound of formula ( I ) are extracted in the following reaction scheme 1 and 2.
  • D ring is
  • A is C2-6 alkylene and X is halogen.
  • R 1 is alkyl and the other symbols are as defined above.
  • the present inventors investigated energetically in order to improve the problem, so that the present inventors found that in the presence of ammonia addition of an alkali metal increased the yield very much and completed the invention.
  • the present invention relates to a process for the preparation of a compound of formula (I)
  • A is C2-6 alkylene.), consisting of subjecting to reaction a compound of formula (II)
  • reaction of preparing a compound of formula ( I ) from a compound of formula (II) and a compound of formula (V) is, for example, carried out by subjecting to reaction a compound of formula (II) and a compound of formula (V) in the presence of liquid ammonia, using an alkali metal (lithium, sodium etc.
  • a compound of formula (II) which is used as a starting material in the above reaction is known and it is , for example , prepared according to the above reaction scheme 1.
  • Cl-4 alkyl is methyl, ethyl, propyl, butyl and isomers thereof.
  • C2-6 alkylene is ethylene, propylene, tetramethylene, pentamethylene, hexamethylene and isomers thereof.
  • halogen is fluorine, chlorine, bromine and iodine.
  • D ring is preferably
  • A is preferably C2-3 alkylene.
  • the present invention gives an excellent method in the preparation of a compound of formula ( I ) which is a target compound.
  • the method of the present invention gives a compound of formula ( I ) in about two or three times as high yield as the previously known method (i.e. A compound of formula ( I ) is given about 60-90% yield by the present method; about 20-30% yield by the previous method. ) .
  • the method of the present invention is more excellent than the previous method and is suitable for industrial mass synthesis.
  • the solvents in parentheses show the developing or eluting solvents and the ratios of the solvents used are by volume in chromatographic separations .
  • the crystal that appeared was gathered and washed by water and ethanol successively, dried under reduced pressure to give a crude crystal.
  • the crude crystal was dissolved in ethanol under refluxing condition.
  • activated carbon To the mixture was added activated carbon.
  • the mixture was stirred at the same temperature and filtrated with heating.
  • the filtrate was stirred at ambient temperature for 5 hours.
  • the crystal that appeared was filtered off and was dried under reduced pressure to give the compound of the present invention (303 g, 75% yield) having the following physical data.
  • the aqueous layer was acidified by adding cone, hydrochloric acid and the mixture was extracted with ethyl acetate.
  • the organic layer was washed by 2N hydrochloric acid, dried over anhydrous magnesium sulfate and was concentrated under reduced pressure.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a process for the preparation of a thiazolidine compound of formula (I): wherein D ring is (i); wherein R is hydrogen; C1-4 alkyl, halogen or cyano; or (ii) and A is C2-6 alkylene. According to the present method, a compound of formula (I) is obtained in higher yield than the previous method.

Description

DESCRIPTION
A process for the preparation of thiazolidine derivatives
Technical Field
The present invention relates to a process for the preparation of thiazolidine derivatives . More particularly, the present invention relates to a process for the preparation of a compound of formula ( I )
Figure imgf000003_0001
(wherein all symbols are as defined hereafter.) which is useful as an agent for non-insulin dependent diabetes mellitus .
Background Art
In W097/47612 specification, it is described that thiazolidine derivatives including a compound of formula ( I ) reduce blood sugar level and therefore are useful for the treatment of non-insulin dependent diabetes mellitus. In the specification many methods for the preparation of thiazolidine derivatives are illustrated. Thereamong some of methods for the preparation of a compound of formula ( I ) are extracted in the following reaction scheme 1 and 2. In the reaction scheme 1 , D ring is
Figure imgf000004_0001
(wherein R is hydrogen, Cl-4 alkyl, halogen or cyano.) or
Figure imgf000004_0002
A is C2-6 alkylene and X is halogen. In the reaction scheme 2, R1 is alkyl and the other symbols are as defined above.
Scheme 1
Figure imgf000004_0003
Scheme 2
Figure imgf000005_0001
Figure imgf000005_0002
alcoholate (VII)
Figure imgf000005_0003
Acid hydrolysis
Figure imgf000005_0004
The methods described in the reaction scheme 1 and 2 , however, gives a compound of formula (I) in low yield, and so they are not suitable for industrial mass synthesis. For example, according to the above specification, as an Example for the reaction scheme 1, a compound of formula (1-1)
Figure imgf000005_0005
is given from a compound of formula (II-l)
Figure imgf000006_0001
in about 23% yield.
As an Example for the reaction scheme 2 , a compound of formula (1-2)
Figure imgf000006_0002
is given from a compound of formula (II-2)
Figure imgf000006_0003
in about 23 % yield.
Therefore, a method to improve chemical yield and applicable to industrial mass synthesis was hoped for.
Disclosure of Invention
The present inventors investigated energetically in order to improve the problem, so that the present inventors found that in the presence of ammonia addition of an alkali metal increased the yield very much and completed the invention.
The present invention relates to a process for the preparation of a compound of formula (I)
Figure imgf000007_0001
(wherein D ring is
Figure imgf000007_0002
(wherein R is hydrogen, Cl-4 alkyl, halogen or cyano.) or
Figure imgf000007_0003
A is C2-6 alkylene.), consisting of subjecting to reaction a compound of formula (II)
Figure imgf000007_0004
(wherein X is halogen and the other symbols are as defined above.) and a compound of formula (V)
Figure imgf000007_0005
in the presence of an alkali metal using liquid ammonia.
The reaction of preparing a compound of formula ( I ) from a compound of formula (II) and a compound of formula (V) is, for example, carried out by subjecting to reaction a compound of formula (II) and a compound of formula (V) in the presence of liquid ammonia, using an alkali metal (lithium, sodium etc. , preferably lithium.) and a catalyst (iron (III) nitrate nonahydrate etc.), in the presence or absence of a solvent (tetrahydrofuran, diethylether, dioxane etc.) at a temperature of from -78 °C to -60 °C, preferably at a temperature of from -70 °C to -60 °C (The reaction is illustrated in Synthesis, 310 (1971).).
A compound of formula (II) which is used as a starting material in the above reaction is known and it is , for example , prepared according to the above reaction scheme 1.
In the present specification, Cl-4 alkyl is methyl, ethyl, propyl, butyl and isomers thereof.
In the present specification, C2-6 alkylene is ethylene, propylene, tetramethylene, pentamethylene, hexamethylene and isomers thereof.
In the present specification, halogen is fluorine, chlorine, bromine and iodine.
Among the compounds of formula (I) prepared by the present invention, D ring is preferably
or
Figure imgf000008_0002
Among the compounds of formula ( I ) prepared by the present invention, A is preferably C2-3 alkylene. As the compound of formula ( I ) ,
Figure imgf000009_0001
or
Figure imgf000009_0002
is preferable.
Industrial Applicability
The present invention gives an excellent method in the preparation of a compound of formula ( I ) which is a target compound. The method of the present invention gives a compound of formula ( I ) in about two or three times as high yield as the previously known method (i.e. A compound of formula ( I ) is given about 60-90% yield by the present method; about 20-30% yield by the previous method. ) .
Therefore, the method of the present invention is more excellent than the previous method and is suitable for industrial mass synthesis. Best Mode for Carrying Out the Invention
The following examples are intended to illustrate, but do not limit, the present invention. The solvents in parentheses show the developing or eluting solvents and the ratios of the solvents used are by volume in chromatographic separations .
Solvents in parentheses of NMR show the solvents used in measurement.
Reference Example 1
Preparation of 1- (2-bromoethyloxy) -4-cyanobenzene
Figure imgf000010_0001
To a suspension of potassium carbonate (622 g) in dibromoethane (2.5 L) under refluxing condition, was added dropwise over a period of 9 hours a solution of 4-cyanophenol (357 g) in acetonitrile (0.7 L) and the mixture was stirred for 2.5 hours . The mixture was cooled to ambient temperature and the precipitate was filtered off. The filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate-hexane mixture (1.5 L, ethyl acetate: hexane = 1:2) and the mixture was stirred at ambient temperature overnight . The precipitate was removed off . Approximately half volume of the solvent of the mother solution was evaporated under reduced pressure. The crystal was filtered off. The crystal that appeared was dried under reduced pressure to give the title compound (386 g, 63% yield) as a white crystal.
TLC : Rf 0.55 (hexane : ethyl acetate = 1:1); NMR (CDC13): δ 7.60 (d, J = 7.5 Hz, 2H) , 7.00 (d, J = 7.5 Hz, 2H), 4.35 (t, J = 5 Hz, 2H) , 3.65 (t, J = 5 Hz, 2H) .
Example 1
Preparation of 5- [2- (4-cyanophenoxy)ethyl] -thiazolidin- 2,4-dione
Figure imgf000011_0001
To liquid ammonia (2.5 L ) was added metal lithium (5.8 g) at a temperature of from -70 °C to -60 °C. To the mixture was added iron(III) nitrate nonahydrate (150 mg) . To the mixture was added metal lithium (23.3 g) and the mixture was stirred until navy blue color disappeared. To the mixture was added iron(III) nitrate nonahydrate (150 mg) and the mixture was stirred for 20 minutes. To the mixture was added 1 ,3-thiazolidin-2,4-dione (234 g) over a period of 15 minutes and the mixture was stirred for 30 minutes. To the reaction mixture was added a solution of the compound prepared in reference example 1 (348 g) in tetrahydrofuran (420 ml) over a period of 5 minutes . The reaction mixture was stirred at a temperature of from -60 °C to -50 °C for 1 hour. To the mixture was added ammonium chloride (269 g) and the mixture was allowed to stand at ambient temperature overnight . To the residue was added water (2 L) and ethyl acetate-diethyl ether mixture (1.5 L ; ethyl acetate : diethyl ether = 1:1) and the aqueous layer was separated. Under cooling with ice, the aqueous layer was acidified to pH 2-3 by adding concentrated hydrochloric acid (2.5 L). The crystal that appeared was gathered and washed by water and ethanol successively, dried under reduced pressure to give a crude crystal. The crude crystal was dissolved in ethanol under refluxing condition. To the mixture was added activated carbon. The mixture was stirred at the same temperature and filtrated with heating. The filtrate was stirred at ambient temperature for 5 hours. The crystal that appeared was filtered off and was dried under reduced pressure to give the compound of the present invention (303 g, 75% yield) having the following physical data. TLC : Rf 0.46 (hexane : ethyl acetate = 1:1); NMR (DMSO-d6) : δ 12.20-11.90 (br.s, IH) , 7.75 (d, J = 7.5 Hz, 2H), 7.10 (d, J = 7.5 Hz, 2H) , 4.70 (dd, J = 5.0, 2.5 Hz, IH), 4.25 (t, J = 5.0 Hz, 2H) , 2.60-2.30 (m, 2H) ; IR (KBr) : 3181, 2229, 1746, 1697, 1606, 1509, 1305, 1257, 1180, 1154, 1029, 829, 669, 549 cm"1.
Reference Example 2 Preparation of 2- (2-bromoethyloxy)naphthalene
Figure imgf000013_0001
By the same procedure as described in reference example 1 using jS -naphthol in place of 4-cyanophenol, the title compound having the following physical data was given. TLC: Rf 0.50 (n-hexane : ethyl acetate = 9:1); NMR (CDC13) : δ 7.80-7.65 (m, 3H) , 7.50-7.05 (m, 4H) , 4.40 (t, 2H, J = 7 Hz), 3.70 (t, 2H, J = 7 Hz).
Example 2
Preparation of 5- [2- (naphthalen-2-yloxy)ethyl] thiazolin- 2, 4-dione
Figure imgf000013_0002
To liquid ammonia (1.5 L) at a temperature of from -70 to -60 °C, were added metal lithium (1.32 g) , iron(III) nitrate nonahydrate (35 mg) and metal lithium (5.28 g) successively and the mixture was stirred until navy blue color disappeared. To the mixture was added iron(III) nitrate nonahydrate (35 mg) and the mixture was stirred for 20 minutes . To the mixture was added 1 , 3-thiazolidin-2 , 4-dione (52.7 g) and the mixture was stirred for 30 minutes . To the reaction mixture was added a compound prepared in reference example 2 (75.4 g) in anhydrous tetrahydrofuran (250 ml) and the mixture was stirred at ambient temperature for 2.5 hours . The mixture was cooled to -70 °C, and thereto was added ammonium chloride (50.6 g) and the mixture was allowed to stand at ambient temperature overnight . The mixture was concentrated under reduced pressure. To the residue were added n-hexane-ethyl acetate mixture (500 ml; n-hexane : ethyl acetate = 1:1) and a 5N aqueous solution of sodium hydroxide (300 ml). Under cooling with ice, the aqueous layer was acidified by adding cone, hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed by 2N hydrochloric acid, dried over anhydrous magnesium sulfate and was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride : ethyl acetate = 10:1). The residue was recrystallized by ethanol (400 ml) to give the compound of the present invention (56 g, 65 %) having the following physical data. TLC: Rf 0.33 (methylene chloride : ethyl acetate = 10:1); NMR (CDCl3+DMSO-d6) : δ 10.50 (br.s, IH) , 7.75 (m, 3H) , 7.44 (m, IH), 7.35 (m, IH) , 7.12 (m, 2H) , 4.51 (m, IH) , 4.32 (m, IH), 4.20 (m, IH), 2.75 (m, IH) , 2.40 (m, IH) ; IR (KBr) : 3171, 3058, 1747, 1688, 1626, 1600, 1259, 1216, 1184, 1030, 839, 752, 656 cm"1.

Claims

1. A method for the preparation of a compound of formula (I)
Figure imgf000015_0001
(wherein D ring is
Figure imgf000015_0002
(wherein R is hydrogen, Cl-4 alkyl, halogen or cyano.) or
Figure imgf000015_0003
and A is C2-6 alkylene) which is characterized by subjecting to reaction a compound of formula (II)
Figure imgf000015_0004
(wherein X is halogen and the other symbols are as defined above.) and a compound of formula (V)
Figure imgf000015_0005
in the presence of an alkali metal in liquid ammonia.
2. A method for the preparation, according to claim 1, which is characterized by using lithium as an alkali metal.
3. A method for the preparation, according to claim 1, of a compound of formula (I) wherein D ring is
Figure imgf000016_0001
and A is ethylene.
4. A method for the preparation, according to claim 1, of a compound of formula (I) wherein D ring is
Figure imgf000016_0002
and A is ethylene.
5. A method for the preparation, according to claim 1 , of 5- [ 2- ( 4-cyanophenoxy)ethyl] -thiazolidin-2,4-dione .
6. A method for the preparation, according to claim 1, of 5- [2- (naphthalen-2-yloxy)ethyl]thiazolin-2,4-dione.
PCT/JP2000/001595 1999-03-18 2000-03-16 A process for the preparation of thiazolidine derivatives WO2000055146A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
KR1020017011662A KR20010112328A (en) 1999-03-18 2000-03-16 A process for the preparation of thiazolidine derivatives
BR0009079-4A BR0009079A (en) 1999-03-18 2000-03-16 Process for the preparation of thiazolidine derivatives
EP00909666A EP1165529A1 (en) 1999-03-18 2000-03-16 A process for the preparation of thiazolidine derivatives
AU31924/00A AU3192400A (en) 1999-03-18 2000-03-16 A process for the preparation of thiazolidine derivatives
CA002368146A CA2368146A1 (en) 1999-03-18 2000-03-16 A process for the preparation of thiazolidine derivatives
NZ514177A NZ514177A (en) 1999-03-18 2000-03-16 A process for the preparation of thiazolidine derivatives
NO20014451A NO20014451L (en) 1999-03-18 2001-09-13 Process for the preparation of thiazolidine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11/73519 1999-03-18
JP7351999 1999-03-18

Publications (1)

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WO2000055146A1 true WO2000055146A1 (en) 2000-09-21

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KR (1) KR20010112328A (en)
CN (1) CN1350526A (en)
AU (1) AU3192400A (en)
BR (1) BR0009079A (en)
CA (1) CA2368146A1 (en)
HU (1) HUP0200585A3 (en)
NO (1) NO20014451L (en)
NZ (1) NZ514177A (en)
TR (1) TR200102689T2 (en)
WO (1) WO2000055146A1 (en)
ZA (1) ZA200107603B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9062013B2 (en) 2011-02-02 2015-06-23 Bionomics Limited Positive allosteric modulators of the α7 nicotinic acetylcholine receptor and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0419035A1 (en) * 1989-08-25 1991-03-27 Beecham Group Plc Thiazolidine dione derivatives
WO1997047612A1 (en) * 1996-06-07 1997-12-18 Merck Patent Gmbh Novel thiazolidone-2 derivatives, 4-diketone substituted, method for obtaining them and pharmaceutical compositions containing same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0419035A1 (en) * 1989-08-25 1991-03-27 Beecham Group Plc Thiazolidine dione derivatives
WO1997047612A1 (en) * 1996-06-07 1997-12-18 Merck Patent Gmbh Novel thiazolidone-2 derivatives, 4-diketone substituted, method for obtaining them and pharmaceutical compositions containing same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TAYLOR J D ET AL: "A New Method for the Preparation of 5-Alkyl- and 2,5-Dialkyl-1,3-thiazolidine-2,4-diones through Dianion Intermediates", SYNTHESIS, 1971, THIEME VERLAG, STUTTGART., DE, pages 310 - 311, XP000909949 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9062013B2 (en) 2011-02-02 2015-06-23 Bionomics Limited Positive allosteric modulators of the α7 nicotinic acetylcholine receptor and uses thereof

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NO20014451L (en) 2001-11-12
ZA200107603B (en) 2003-02-26
CA2368146A1 (en) 2000-09-21
EP1165529A1 (en) 2002-01-02
NO20014451D0 (en) 2001-09-13
AU3192400A (en) 2000-10-04
CN1350526A (en) 2002-05-22
HUP0200585A2 (en) 2002-06-29
TR200102689T2 (en) 2002-01-21
NZ514177A (en) 2003-04-29
BR0009079A (en) 2002-01-02
HUP0200585A3 (en) 2004-07-28
KR20010112328A (en) 2001-12-20

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