HUP0200585A2 - A process for the preparation of thiazolidine derivatives - Google Patents

Description

.··. .-. :·’·73.359/ΒΕ « U-. PUBLICATION COPY .:1. .:1. .sí.

Process for the preparation of thiazolidine derivatives

P02 0 0 5 85

The invention relates to a process for the preparation of thiazolidine derivatives. More specifically, the invention relates to the

A process for preparing compounds of general formula (I) (wherein all symbols are as defined below) which are useful agents for the treatment of non-insulin-dependent diabetes.

WO97/47612 describes that thiazolidine derivatives, including a compound of formula (I), lower blood sugar levels and are thus useful in the treatment of non-insulin-dependent diabetes. The patent describes several processes for the preparation of thiazolidine derivatives. Some of the processes for the preparation of compounds of formula (I) are summarized in Schemes 1 and 2 below.

In Scheme 1, the

D ring meaning

group of general formula, in which

R is hydrogen, C1-C4 alkyl, halogen or cyano, or

group of general formula;

is an alkylene group having 2-6 carbon atoms; and

X represents a halogen atom.

In Scheme 2

R represents an alkyl group, and the other symbols have the meanings defined above.

Reaction scheme 1

Reaction scheme 2

COOR1 \ (VI)

COOR1

Alkali metal alcoholate

Halogenation

COOR1

K \?COOR1 λ

Acid (Vili)

Acid hydrolysis

73,359/IN

However, the processes described in Schemes 1 and 2 give compounds of general formula (I) in low yields, and are therefore not suitable for industrial scale synthesis. For example, as described above, for Scheme 1, the

Compound O is obtained in about 23% yield from compound of formula.

As an example for Scheme 2, (1-2)

Compound F is obtained in approximately 23% yield from

From a compound of formula JL J (II-2).

Therefore, we hoped for a process that would improve chemical yield and be suitable for industrial-scale synthesis.

The inventors have made a thorough investigation to eliminate this problem and have found that the addition of ^an alkali metal in the presence of ammonia greatly increases the yield and toljGSSG tGSzi 3. tcilslnicinyt ·

73.359/BE

The invention relates to a method for

Compounds of general formula (I) — in which the ring has the meaning

group of general formula, in which

R is hydrogen, C1-C4 alkyl, halogen or cyano, or

A represents an alkylene group of 2-6 carbon atoms — for the preparation of which the process comprises:

a compound of general formula (II) — in which

X represents a halogen atom, and the other symbols have the meanings defined above — and a

Compounds of formula (V) are reacted with each other in the presence of an alkali metal in liquid ammonia.

For example, the reaction in which the compound of general formula (I) is prepared from a compound of general formula (II) and a compound of formula (V) is carried out by reacting a compound of general formula (II) with a compound of general formula (V).

The compound of formula 73.359/BE and the compound of formula (V) are reacted with each other in the presence of liquid ammonia, using an alkali metal (lithium, sodium, etc., preferably lithium) and a catalyst (iron (II) nitrate nonahydrate), etc.), in the presence or absence of a solvent (tetrahydrofuran, diethyl ether, dioxane, etc.) at -78°C to -60°C, preferably -70°C to -60°C. [The reaction is described in Synthesis 310, (1971).

Compounds of general formula (II) used as starting materials in the above reaction are known and can be prepared, for example, according to reaction scheme 1 above.

As used herein, the C1-4 alkyl group may be methyl, ethyl, propyl, butyl, and isomers thereof.

In this specification, the alkylene group having 2-6 carbon atoms includes ethylene, propylene, tetramethylene, pentamethylene, hexamethylene and isomers thereof.

The halogen atom is a fluorine, chlorine, bromine, and iodine atom.

In the compounds of formula (I) prepared according to the invention, the D ring is preferably

group with the formula

In the compounds of general formula (I) prepared according to the invention, A preferably represents an alkylene group having 2-3 carbon atoms.

Among the compounds of general formula (I)

73.359/BE or

advantageous.

The present invention provides an excellent process for the preparation of compounds of formula (I), which are the target compounds. The process of the present invention provides compounds of formula (I) in a yield two to three times better than the previously known process [i.e., compounds of formula (I) are obtained in a yield of 60-90% by this process, compared to a yield of 20-30% by the previous process].

Therefore, the process of the invention is superior to the previous process and is suitable for industrial scale synthesis.

The following examples are intended to illustrate the invention in a non-limiting sense. The solvents in parentheses represent the developing or eluting solvents, and the amounts of solvents used are given by volume in the chromatographic separations.

In NMR, the solvents in parentheses refer to the solvents used in the measurement.

Reference example 1

Preparation of 1-(2-Bromoethoxy)-4-cyanobenzene

622 g potassium carbonate and 2.5 liters methylene dibromide suspension

73.359/BE was added dropwise to a solution of 357 g of 4-cyanophenol in 0.7 l of acetonitrile at reflux over a period of 9 hours, 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. 1.5 l of a 1:2 mixture of ethyl acetate:hexane was added to the residue and the mixture was stirred overnight at ambient temperature. The precipitate was filtered off. Approximately half of the solvent of the mother liquor was evaporated under reduced pressure. The crystals were filtered off. The crystals formed were dried under reduced pressure to give 386 g (63%) of the title compound as white crystals.

TLC: Rf 0.55 (hexane:ethyl acetate = 1:1).

NMR (CDCl ₃ ): 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]thiazolidine-2,4-dione

To 2.5 liters of liquid ammonia at a temperature between -70°C and -60°C is added 5.8 g of lithium metal. To the mixture is added 150 mg of iron (III) nitrate nonahydrate. To the mixture is added 23.3 g of lithium metal and the mixture is stirred until the navy blue color disappears. To the mixture is added 150 mg

73.359/BE iron(III) nitrate nonahydrate and the whole is stirred for 20 minutes. To the mixture is added 234 g of 1,3-thiazolidine-2,4-dione over 15 minutes and the mixture is stirred for 30 minutes. To the mixture is added a solution of 348 g of the compound prepared in Reference Example 1 in 420 ml of tetrahydrofuran over 5 minutes. The reaction mixture is stirred for 1 hour at a temperature between -60°C and -50°C. To the mixture is added 269 g of ammonium chloride and allowed to stand overnight at ambient temperature. To the residue are added 2 liters of water and 1.5 liters of a 1:1 mixture of ethyl acetate:diethyl ether and the aqueous phase is separated. Under ice-cooling, the aqueous phase is acidified to pH ⁼ 2-3 by adding 2.5 liters of concentrated hydrochloric acid solution. The crystals that have separated are collected on a filter and washed successively with water and ethanol, and dried under reduced pressure to obtain crude crystals. The crude crystals are dissolved in ethanol while boiling under reflux. Activated carbon is added to the mixture. The mixture is stirred at the same temperature and filtered while heating. The filtrate is stirred for 5 hours at ambient temperature. The crystals that have formed are filtered off and dried under reduced pressure to obtain 303 g (75%) of the compound of the invention, which has the following physical characteristics.

TLC: Rf 0.46 (hexane:ethyl acetate = 1:1).

NMR (DMSO-d ₆ ) : δ 12.20-11.90 (br.s, IH) , 7.5 (d, J = 7.5 Hz, 2H) , 7.10 (d, J = 7.5 Hz, 2H) , 4.70 (dd, J = 5.0, 2.5 Hz, 1H) , 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 .

73.359/BE

Reference example 2

Preparation of 2-(2-Bromoethoxy)naphthalene.

By the same procedure as described in Reference Example 1, using β-naphthol instead of 4-cyanophenol, the title compound was obtained with the following physical characteristics.

TLC: Rf 0.50 (hexane:ethyl acetate = 9:1).

NMR (CDC1 ₃ ) : 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-(2-Naphthyloxy)ethyl]thiazoline-2,4-dione

To 1.5 liters of liquid ammonia were added 1.32 g of lithium metal, 35 mg of iron (III) nitrate nonahydrate and 5.28 g of lithium metal successively at a temperature of -70°C to -60°C, and the mixture was stirred until the navy blue color disappeared. To the mixture was added 35 mg of iron (III) nitrate nonahydrate and stirred for 20 minutes. To the mixture was added 52.7 g of 1,3-thiazolidine-2,4-dione and stirred for 30 minutes. To the mixture was added a solution of 75.4 g of the compound prepared in Reference Example 2 in 250 ml of anhydrous tetrahydrofuran and stirred for 2.5 hours at ambient temperature. The mixture was cooled to -70°C, 50.6 g of ammonium chloride was added, and the mixture was left to stand overnight.

73.359/BE at ambient temperature. The mixture was concentrated under reduced pressure. To the residue were added 500 ml of hexane:ethyl acetate (1:1) and 300 ml of 5M aqueous sodium hydroxide solution. Under ice-cooling, the aqueous phase was acidified by adding concentrated hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with 2M hydrochloric acid solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methylene dichloride:ethyl acetate = 10:1). The residue was recrystallized from 400 ml of ethanol to give 56 g (65%) of the title compound, which had the following physical characteristics.

TLC: Rf 0.33 (methylene chloride:ethyl acetate, 10:1).

NMR (CDCl ₃ +DMSO-d ⁶ ) : 6 10.50 (br, s, 1H) , 7.75 (m, 3H) , 7.44 (m, 1H) , 7.35 (m, 1H) , 7.12 (m, 2H) , 4.51 (m, 1H) , 4.32 (m, 1H) , 4.20 (m, 1H), 2.75 (m, 1H), 2.40 (m, 1H).

IR (KBr): 3171, 3058, 1747, 1688, 1626, 1600, 1259, 1216, 1184, 1030, 839, 52, 6546 cm' ¹ .

73.359/BE

Claims (4)

Patent claims Compounds of general formula (I) — in which formula the D ring meaning R is hydrogen, C1-C4 alkyl, halogen or cyano, or a group of general formula; and A represents an alkylene group of 1-6 carbon atoms — for the preparation of, characterized in that a a compound of general formula (II) — in which X represents a halogen atom, and the other symbols have the meanings defined below — and a Compounds of the formula are reacted with each other in the presence of an alkali metal in liquid ammonia. ² · The method according to claim 1, characterized in that, 73.359/BE that lithium is used as the alkali metal. 3. A process according to claim 1 for the preparation of compounds of general formula (I) in which ring D represents a kepletu group; and A represents an ethylene group. 4. A process according to claim 1 for the preparation of compounds of general formula (I) in which ring D is a group of formula, and A means ethylene group. 5. A process according to claim 1 for the preparation of 5-[2-(4-cyanophenoxy)ethyl]thiazolidine-2,4-dione. 6· The process according to claim 1 for the preparation of 5-[2-(2-naphthyloxy)ethyl]thiazoline-2,4-dione. The authorized person: 73.359/BE