KR810000557B1 - Manufacturing Process of Chiochroman Derivatives - Google Patents

Abstract

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Description

Manufacturing Process of Chiochroman Derivatives

The present invention relates to a process for producing a cheochrome derivatives, and provides a process for preparing a cheochrome derivative, such as the formula (I).

Wherein A is a hydrogen atom or a halogen atom, R ₁ is a hydrogen atom or a straight or branched chain alkyl group having 1 to 5 carbon atoms, R ₂ is an alkyl group having 1 to 7 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms .

In British Patent No. 1,308,191, some of these compounds are introduced, and as a preparation method, 1-chloro-2,3-epoxypropane is reacted with a hydroxythiochrome such as formula (II). A process consisting of condensing (2,3-epoxypropoxy) -thiochroman), such as formula (III), with a primary amine, such as formula (IV), is addressed.

R ₂ is an alkyl group having 1-5 carbon atoms or a cycloalkyl group having 3-6 carbon atoms.

The present invention can reduce the excessive amount of the amine, such as the formula (IV) used in the previous process, the time required in each process of the process can be significantly reduced, the previous process requires an extra decomposition process On the other hand, optically active compounds such as formula (I) are based on the viewpoint that they can be prepared from amino compounds with optical activity.

Therefore, in the present invention, by reacting only hydroxychirochloro as the formula (II) with 1-halogen 2,3-dihydroxy propane in a basic medium, it is possible to react with (2,3-dihydroxypropyloxy) as in the formula (V). The process provides a process for the selective conversion of an aminoalcohol, such as Formula (I), to produce only a chemokine and to react the glycol with an amine of the formula (IV) in the presence of an aminophosphonium halide, such as formula (VI).

In the formula (VI), R ₁ ′ and R ₂ ′ are lower alkyl or phenyl groups and X is a halogen atom, generally an iodine atom.

Another advantage of the process according to the invention is that the limited use of amines such as formula (IV) allows selective amination of the primary alcohol groups without affecting the secondary alcohol groups.

Amino, such as formula (IV), is alkylamine or cycloalkylamine. Their hydrocarbyl chains may include one or more substituents, such as lower alkyl groups, or aromatic heterocycles, such as pyrrolidinyl or pyridine rings.

Use of an amine as an optically active form yields a compound of formula (I) in an optically active form. Optically active amines include secondary butylamine, (N-ethylpyrrolidinyl-2-) methylamine, 2-methylcycloproclamine, 3,3-dimethyl-2-aminobutane and 2-amino-3 -Methyl hexane and the like can be used.

According to the general nature of the invention:

(1) The reaction between the hydroxythiochroman of formula (II) and 1-halo-2,3-dihydroxy propane is carried out with alkali metal hydroxides such as sodium or potassium hydroxide, sodamide or sodium hydride. In the presence of the same strong base.

(2) The reaction is carried out in the presence of a polar aprotic solvent, such as dimethyl formamide, dimethyl acetamide, or dimethyl sulfoxide.

(3) The reaction is carried out at a temperature between 50-150 ° C., generally 75-125 ° C.

(4) Phosphonium halide is N-methyl-N-phenylamino-triphenylphosphonium halide, generally N-methyl-N-phenylamino-triphenylphosphonium iodine.

(5) Condensation takes place in an inert solvent, usually a highly polar solvent. Suitable solvents include aromatic hydrocarbons such as benzene and toluene, polar solvents such as dimethylformamide, dimethyl sulfoxide and hexamethylphosphoamide.

Chiochroman derivatives of formula (I) can be chlorided by adding inorganic or organic acids, in particular pharmaceutically acceptable inorganic or organic acids.

Chiochroman derivatives of structural formula (I) and their medically acceptable salts, which have essential pharmacological and therapeutic properties, particularly for the cardiovascular system, are beta-adrenergic receptors of the heart in the form of nontoxic inert pharmaceutical compositions. Can also be used as a blocker of.

The amination reaction of the present invention is generally used. It may also be applied to any glycol to produce the corresponding aminoalpha-hydroxy derivatives.

Hydroxy compounds of formula (II) used as starting materials are described in British Patent Nos. 1,308, 191 and 1,261,111.

Phosphonium halide can be obtained according to a known process (Tanigawa, Tetraheadon Letter # 1975: 471-472). The following examples illustrate the invention. The temperature is in degrees Celsius.

Example 1

[dl 8- (3-tert-butylamino-2-hydroxypropoxy) -thiochromen]

[Step A]

In a cedar flask, 4 g of sodium hydroxide and 20 ml of water are added and dissolved. Then, 16.6 g of 8-hydroxythiochrome in 200 ml ethanol is added thereto.

Stir and heat at 50 ° C. for 15 minutes, then add 12.1 g of 1-chloro-2,3-dihydroxypropane in drops. Hold at 50 ° C. for 3 hours and add 1-chloro-2,3-dihydroxypropane every hour.

The reaction medium is finally heated to 50 ° C. over time, cooled to room temperature and evaporated to dryness. Grab the residue with water and stir quickly. Insoluble materials are filtered off, washed with water until neutral and dried. The residue weighed 16 g (yield = 68%). It consists essentially of only 5- (2,3-dihydroxypropoxy) thiok which dissolves at 115 ° -120 ° C. The purity can be further increased by recrystallization from ethyl acetate tape.

Pure compounds dissolve at 118-120 ° C.

[Step B]

Only 2.4 g of 8- (2,3-dihydroxypropoxy) -thiochrome is dissolved in 10 ml of dimethylformamide and 0.24 g of sodium hydroxide are added. After heating at 80 ° C. for 30 minutes, a solution containing 4.95 g of N-methyl-N-phenylaminotriphenylphosphonium iodine dissolved in dimethylformamide and 1.46 g of tertiary butylamine in dimethylformamide were added thereto. give. The reaction mixture is heated to 80 ° C. for about 2 hours and then cooled to room temperature. The solvent is distilled off under reduced pressure and then the residue is dissolved in chloroform. The organic solution is extracted with N / 10 hydrochloric acid solution. The acid portion is collected and made basic with sodium hydroxide and extracted three times with ether. The ether solution is washed with water, dried over magnesium sulfate, filtered and evaporated. The oily residue weighs 2.4g. It was purified by chromatography on silica and eluted with benzene-methanol (1: 1). Distillation of the solvent gives only the desired dl 8- (tert-butylamino-2-hydroxypropoxy) -chiroch in 60% yield.

It dissolves at 70-72 ° C.

Example 2

[Dextrorotatori 8- (3-tert-Butylamino-2hydroxypropoxy) -thiochromo]

Using the process of Example (I), starting 8- (2,3-dihydroxypropoxy) -thiochroman and (+) secondary butylamine obtained in step (A) of Example (I) As a material, only the dextrose rotator 8- (3-tert-butyl amino-2-hydroxypropoxy) -thioke was obtained in a yield of 55%. It dissolves at 80-88 ° C.

Example 3

[Reborotatori 8- (3-tert-Butylamino-2-hydroxypropoxy) -thiochromo]

Levorottori 8- (3-tert-Butylamino-2-hydroxypropoxy) -thiochrome only with a yield of 55% starting from (-) secondary butylamine by the manner described in Example (II) Obtained.

[Production of Starting Material]

300 g of polyphosphoric acid is slowly heated in a water bath until it reaches 40 ° C. and when this temperature is reached, 30 g of (orzo methoxyphenyl) chioff is added within 90 minutes. All viscous mixture is left to stir for 2 hours and then spilled on crushed ice. The excess reactant is hydrolyzed and the resulting cheochromemann derivative is isolated by filtration, dried, washed with water and further dried in an oven. This yields 21.9 g of 8-methoxy thiochroman 4-one as a yellow powder, which is easily oxidized by oxygen in the atmosphere. Pure compound is dissolved at 98-110 ° C. (yield = 80%). 23.96 g of 8-methoxy thiochroman 4-one is charged into a flask with a mixture of 27.4 ml of hydrazine hydrate and 112 ml of ethylene glycol. Heat this mixture to room temperature.

Next, 15.8 g of caustic potassium is added with vigorous stirring. Once the alkaline reagent is dissolved, the mixture is heated to reflux while the resulting water is removed by distillation. The temperature was gradually increased to 205-210 ° C. and then heated again at 2 ° C. for 6 hours, then the reaction mixture was returned to room temperature, 10 ml of hydrazine hydrate was added and heated again for 6 hours, then the reaction mixture was poured into cold water. Let's do it. The suspension is acidified by adding hydrochloric acid, and the aqueous suspension is extracted three times with chloroform. The chloroform solution layer is combined, washed with water, dried and evaporated. Dry residue is purified by fractionation.

Pure compounds are recovered from the main fraction at 104-106 ° / 0.1 mmHg. The yield is about 13.61 g, that is, the yield is 67%.

8-hydroxy thiochroman is a colorless compound that dissolves at 86-88 ° C. Only the chelates are further recovered from the distillate water-glycol.

The distillate is extracted with chloroform. The chloroform solution is washed with dilute hydrochloric acid and water, then dried and evaporated to recover 3.11 g of 8-methoxy thiol as a viscous liquid.

Boiling point = 115-118 ° / 0.06 mmHg.

+1,16110

+1,16110

8-methoxy thiochromen is converted to 8-hydroxythiochrome by demethylation by complex borontrifluoride-acetic acid in methylene chloride.

This gives only a second 8-hydroxythioke.

Claims (1)

In preparing a cheiochroman derivative, only hydroxy chichrochrome of the formula (II) is reacted with 1-halogen 2,3-dihydroxypropane in the presence of a basic medium to (2,3-dihydroxypropyl of the formula (V). Oxy) only to cheochromo, and the glycol is reacted with an amine of formula (IV) in the presence of the amino phosphonium halide of formula (VI) to selectively convert to an amino alcohol of formula (I) Preparation of Derivatives.

Wherein A is hydrogen or a halogen atom, R ₁ is hydrogen or a straight or branched chain alkyl group having 1-5 carbon atoms, R ₂ is an alkyl group having 1-7 carbon atoms or a cycloalkyl group having 3-6 carbon atoms, R ₁ ' And R ₂ ′ is a lower alkyl group or a phenyl group, and X is a halogen atom and is generally an iodine atom.