EP1165529A1 - A process for the preparation of thiazolidine derivatives - Google Patents

A process for the preparation of thiazolidine derivatives

Info

Publication number
EP1165529A1
EP1165529A1 EP00909666A EP00909666A EP1165529A1 EP 1165529 A1 EP1165529 A1 EP 1165529A1 EP 00909666 A EP00909666 A EP 00909666A EP 00909666 A EP00909666 A EP 00909666A EP 1165529 A1 EP1165529 A1 EP 1165529A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
preparation
mixture
added
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00909666A
Other languages
German (de)
French (fr)
Inventor
Itsuo Fukui Research Institute OKUMOTO
Nobuyuki Minase R.I. Ono Pharm Co Ltd NAKAMURA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ono Pharmaceutical Co Ltd
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.)
Filing date
Publication date
Application filed by Ono Pharmaceutical Co Ltd filed Critical Ono Pharmaceutical Co Ltd
Publication of EP1165529A1 publication Critical patent/EP1165529A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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.

Landscapes

  • 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 )
(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
(wherein R is hydrogen, Cl-4 alkyl, halogen or cyano.) or
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
Scheme 2
alcoholate (VII)
Acid hydrolysis
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)
is given from a compound of formula (II-l)
in about 23% yield.
As an Example for the reaction scheme 2 , a compound of formula (1-2)
is given from a compound of formula (II-2)
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)
(wherein D ring is
(wherein R is hydrogen, Cl-4 alkyl, halogen or cyano.) or
A is C2-6 alkylene.), consisting of subjecting to reaction a compound of formula (II)
(wherein X is halogen and the other symbols are as defined above.) and a compound of formula (V)
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
Among the compounds of formula ( I ) prepared by the present invention, A is preferably C2-3 alkylene. As the compound of formula ( I ) ,
or
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
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
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
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
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)
(wherein D ring is
(wherein R is hydrogen, Cl-4 alkyl, halogen or cyano.) or
and A is C2-6 alkylene) which is characterized by subjecting to reaction a compound of formula (II)
(wherein X is halogen and the other symbols are as defined above.) and a compound of formula (V)
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
and A is ethylene.
4. A method for the preparation, according to claim 1, of a compound of formula (I) wherein D ring is
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.
EP00909666A 1999-03-18 2000-03-16 A process for the preparation of thiazolidine derivatives Withdrawn EP1165529A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP7351999 1999-03-18
JP7351999 1999-03-18
PCT/JP2000/001595 WO2000055146A1 (en) 1999-03-18 2000-03-16 A process for the preparation of thiazolidine derivatives

Publications (1)

Publication Number Publication Date
EP1165529A1 true EP1165529A1 (en) 2002-01-02

Family

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Country Status (12)

Country Link
EP (1) EP1165529A1 (en)
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)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2670731B1 (en) 2011-02-02 2016-05-25 Bionomics Limited Positive allosteric modulators of the alpha 7 nicotinic acetylcholine receptor and uses thereof.

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8919417D0 (en) * 1989-08-25 1989-10-11 Beecham Group Plc Novel compounds
FR2749583B1 (en) * 1996-06-07 1998-08-21 Lipha NOVEL SUBSTITUTED THIAZOLIDINE -2,4- DIONE DERIVATIVES, PROCESSES FOR OBTAINING SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0055146A1 *

Also Published As

Publication number Publication date
TR200102689T2 (en) 2002-01-21
NO20014451D0 (en) 2001-09-13
ZA200107603B (en) 2003-02-26
NZ514177A (en) 2003-04-29
AU3192400A (en) 2000-10-04
HUP0200585A2 (en) 2002-06-29
WO2000055146A1 (en) 2000-09-21
BR0009079A (en) 2002-01-02
CN1350526A (en) 2002-05-22
NO20014451L (en) 2001-11-12
KR20010112328A (en) 2001-12-20
HUP0200585A3 (en) 2004-07-28
CA2368146A1 (en) 2000-09-21

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