JPS61268679A - Production of 2-thiochromenylidene acetoacetic ester - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for producing 2-thiochromenylideneacetoacetate, which is partially known and can be used for the production of pharmaceutically active compounds.

3-oxo-1-(4-oxo-2-7enyl-4H-
Thiochromen-8-yl)-1-butene-2-carboxylic acid ester is
gttl ) is known to be obtained from 4-oxo-2-phenyl-4M-thiochromene-8-carbaldehyde and its corresponding acetoacetate by a condensation reaction (see European Patent Specification No. 123112). However, due to the poor solubility of aldehydes, this method is very complicated and results in low yields.

It is also known that 1-722-2-nitrobut-1-en-6-one and its sieve conductor with a substituent in the phenyl position can be obtained by reacting nitroacet/ with the corresponding thick base. [Ni Dornak (A, Dor)
now), Daplu Sasenberg (F, Saa
aenberg), Liebigs Ann.

Chetn, 602, 14-23 (1957)]
.

Furthermore, it is also known that the desired pensolidene compound cannot be obtained in one step by reacting acetoacetate with aromatic azomethine in the presence of an acid or base catalyst [
Chemical Abs'
tracta) 79, 126.279.85.7
7829].

This formula (I) in which R1 represents straight-chain or branched alkyl with up to 4 C atoms and R2 has up to 4 C atoms and optionally halogen or up to 7 A 2-thiochromenylideneacetoacetate ester of the general formula (2), representing a straight-chain or branched alkyl optionally substituted by acyloxy having a C atom, is a 2-thiochromenylideneacetoacetate of the general formula (2), in which R3 has up to 6 C atoms. represents a straight chain or branched alkyl having the general formula (iD , if appropriate in the presence of an inert organic diluent, by reaction with an acylating agent.

Surprisingly, the process according to the invention gives the final product (I) in one step. From the knowledge of the prior art, it was completely unexpected that pensolidene compounds could be obtained with little effort and in good yields. Furthermore, it was completely unexpected that azomethine would react so easily with the bulky thiochromenyl group.

The method according to the invention has the advantage that it is a single step reaction and can therefore be carried out easily and conveniently. Furthermore, the finishing and purification of the final product is technically easy to carry out.

Compounds prepared by the process according to the invention generally have the formula (
I). In this formula, Rt preferably represents a straight-chain or branched alkyl having up to 4 C atoms;
and R1 preferably represent straight-chain or branched alkyl having up to 4 C atoms, bromomethyl or chloromethyl or acetoxymethyl or benzyloxymethyl.

Using R3-n-butyriminomethyl-4-oxo-2-phenyl-4H-thiochromene and methyl acetoacetate as starting materials, the reaction process can be performed using the following formula: %Formula% Acetoacetic acid of formula (A) used as starting materials Esters are known or can be prepared by known methods [D. Borr-mann
), HoubexJFeryl
), 1 Methods of Organic Chemistry (Mathodan der O
rganischttnOhmjoze#)”■74,25
0<1968), Varnish ry (S, Gejin) p
・, pallet 5ynth, Comtmbx.

1980.805; and tetrahuman o y (Tgt
ra-hydros) 34, 145! 1 (1978)].

The Schiff base of formula (2) used as starting material is new. This compound is prepared at a temperature of 0°C to 60°C, preferably at room temperature.
8-carbaldehyde is combined with an amine of 2M Rh -Nll, (V1 in which Rs has the meanings given above) and an alcohol such as methanol, ethanol or propatool, or a chlorinated hydrocarbon such as methylene dichloride, chloroform or tetrachloride. carbon chloride, or an aromatic hydrocarbon in an organic solvent such as benzene, toluene or xylene, preferably in a solvent such as methylene dichloride or chloroform, if appropriate with sodium sulfate, potassium carbonate, magnesium sulfate or molecular sieves. It can be prepared by adding a water-absorbing substance such as, and reacting. After the additives have been removed and the solvent or solvent-water mixture has been removed, the Schiff base is crystallized.

Acylating agents suitable in the process according to the invention are all customary acylating agents. These are preferably carboxylic acid anhydrides such as acetic anhydride or propionic anhydride,
or carboxylic acid halides such as acetyl chloride, acetyl bromide, propionyl chloride or propionyl bromide. Particularly suitable as acylating agent is acetic anhydride.

This reaction can be carried out with or without a diluent. If appropriate, suitable diluents are customary inert solvents. These suitably include aromatic hydrocarbons such as benzene, toluene or xylene, or carboxylic acids such as formic acid, acetic acid or globionic acid, and halodanated hydrocarbons such as methylene dichloride, chloroform or carbon tetrachloride. The reaction is carried out at a temperature of 0°C to 200°C, preferably 10°C to 150°C.

This reaction can be carried out under normal pressure, but can also be carried out under high pressure. Generally, the reaction is carried out under normal pressure.

In carrying out the process according to the invention, acetoacetate values of from 0.1 to 10, preferably from 1 to 5 mol per mole of thick base are used. Acylating agents are generally used in amounts of 1 to 10 moles, preferably 2 to 6 moles per mole of thick base. It is particularly preferred to carry out the reaction using acetic anhydride in an excess of up to 6 molar, so that acetic anhydride is both a solvent and an acylating agent.

Compounds of formula (I) can be converted into 1,4-dihydropyridines in a simple and known manner with enamines or with acetoacetate and amines [Nie-Handzig (A.)].

Hantzsch), Littbigs Ann,
Chetn, 2 j 5.

1.1982 and Nie Eisner (11, p: 1sn
er), Soei Kuzay (7, Kuthan),
Chetn, Rev.

72, (1972)].

These dihydropyridines constitute valuable pharmaceutically active compounds used as cardiotonic agents to improve myocardial contractility. In addition, they increase the influx of calcium into cells and can therefore be used as antihypotensive agents to lower blood sugar levels, to reduce swelling of mucous membranes and to influence salt and fluid balance. (European Patent No. 12
3112 and European Patent No. 123095).

The following examples serve to illustrate the invention without limiting it.

Production Examples Example 1 α) B-n-butyriminomethyl-4-oxo-2-
4-okino-2-phenyl-4H-thiochromene-8-carbaldehyde of 4.25 phenyl-4H-thiochromene 7521 (2.83 mol)
Partially dissolved in 1 liter of methylene chloride, 420 m
1-(4.25 mol) of n-butylamine is added. A complete solution was obtained after stirring for several hours, and some reaction water had settled out. The mixture is then concentrated under vacuum and then evaporated for 6 mouthfuls after adding in each case 2 liters of methylene chloride in order to completely remove any residues of butylamine. The oil crystallizes on cooling.

b) 4-acetoxy-6-okine-1-(4-oxo-2-phenyl-4H-thiochrome/-8-ik>-
Ethyl 1-butene-2-carboxylate followed by 92Of<
2.85 mol) of crude butylimino compound (1α) was added to 58
5f (511 mol) of ethyl acetoxyacetate and 52
Mix vigorously with 5d (5.66 mol) of acetic anhydride. With external cooling, a rise in temperature is obtained after a few minutes. Cooling is interrupted as soon as the temperature drops. Seed is added and the mixture is allowed to crystallize with stirring. Stir the crystal mass well and suction it through a glass filter, first 1:
Wash with 1 toluene/petroleum ether and then with petroleum ether.

Yield near 5 ar (61.5% of theory) Melting point: below 135°C (cis/trans mixture) was also prepared in a similar manner to this reaction procedure.

Example 2 3-oxo-1-(4-okino-2-phenyl-4H-
Methyl thiochrome/-8-yl)-1-butene-2-carboxylate Yield: 73% of theory Melting point: 155°C (cis/trans mixture) Example 3 4-chloro-3-oxo-1-(4 -oxo-2-phenyl-4H-thiochromen-8-yl)-1-butene-
Isopropyl 2-carboxylate yield: 67% of theory Melting point near 6°C (cis/trans mixture) Example-4 4-chloro-3-oquin-1-(4-oxo-2-phenyl-4H-f ochromene- 8-yl)-1-butene-
Ethyl 2-carboxylate Yield: 61% of theory Melting point = 89°C (cis/trans mixture) Example 5 2-Methyl-4-(4-oxo-2-phenyl-4H-
thiochromen-8-yl)-5-oxo-1,4,5,
7-Titrahydrofuro(3,4-b)-pyridine-3-
9 (2,94 mol) of 4-acetoxy- to 1.283 ethyl carboxylate
3-oxo-1-(4-oxo-2-7enyl-4H-
Ethyl thiochromen-8-yl)-1-butene-2-carboxylate (Example 1b) was suspended in 2.3 liters of ethanol and 579.7 f (2.94 mol) of β-aminocrotonic acid Add chill. The mixture is heated at reflux temperature for 8 hours.

After addition of 150-saturated ethanolic MCI, heating at reflux temperature is continued for an additional 3 hours. The mixture is left to crystallize at room temperature and the crystal mass is suctioned off through a glass filter. Dilute the filter cake with 1.5 liters of ethanol.
Extracted by double boiling, separated in a suction oven, and then dried in a vacuum drying cabinet at 120° C. and lmHg for 48 hours.

Yield: 990? (75% of theory) Melting point: 266℃ (decomposition)

Claims (1)

[Claims] 1. Formula (I) ▲Mathical formula, chemical formula, table, etc.▼(I) In the formula, R^1 represents a straight chain or branched alkyl having up to 4 C atoms, and 2-thiochromeni of In the production of lydenacetoacetic acid ester, the general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) where R^3 represents a straight chain or branched alkyl having up to 6 C atoms, The Schiff base of is expressed by the general formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) In the formula, R^1 and R^2 have the above meanings, and an acetoacetic acid ester of and, if appropriate, an inert A method characterized in that the reaction is carried out together with an acylating agent in the presence of an organic diluent. 2. In formula (I), R^1 represents a straight-chain or branched alkyl having up to 4 C atoms, and R^2 represents a straight-chain or branched alkyl having up to 4 C atoms, bromomethyl or chloromethyl or acetoxymethyl or benzyloxymethyl. 3. The method according to claim 1 or 2, wherein the reaction is carried out at a temperature of 0 to 200°C. 4. The method according to claim 1 or 2, wherein the reaction is carried out at a temperature of 10 to 150°C.