KR790001270B1 - Process for production of alkyl pyrimidol(4,5-b)quinolin -4(3h)-one-2-carboxylates - Google Patents

Abstract

Alkyl pyrimido 4,5-b -quinoline-4(3H)-on-2-carboxylate compds were manufd. by reacting 2-amino quinoline-3-carboxamide (I; R1 = H, C1-4 alkyl or phenyl, R2R3R4R5 = H, C1-4 alkyl, C1-4 alkoxy, halo, benzyloxy, methylthio) with dialkyl cxalate having C1-4 alkoxy, in inert solvent at 20-100≰C in the presence of salts, C1-4 sodium amide, sodium 3-amino propylamide or potassium compds.

Description

Method for producing alkylpyrimido [4, 5-b] -quinolin-4- (3H) -one-2-carboxylates

The present invention relates to lower alkyl esters of fused pyrimidin-4 (3H) -one-2-carboxylic acids, in particular alkyl pyrimido [4, 5-b] -quinolin-4 (3H) -one The present invention relates to an improved method for preparing 2-carboxylates.

Various 2-amidoquinoline-3-carboxamides are cyclized with dialkyl oxalates to include alkyl esters of pyrimido [4, 5-b] quinolin-4 (3H) one-2-carboxylic acid. Methods for producing pyrimidines of the attached ring are known. This process involves the removal of byproducts of water and alcohols by condensation at temperatures of 150 ° C-185 ° C. Excess dialkyl oxalate is usually used as a solvent, and bases such as sodium alkoxide or sodium hydride are sometimes used as catalysts. This reaction requires several hours to two days to complete the reaction, depending on the reaction agent. And in most cases the yield of cyclized product is poor. However, it has been reported that in only one case a satisfactory yield is obtained; That is, diethyl to 6-fluoro-2-aminoquinoline-3-carboxamide in the preparation of ethyl 7-fluoro pyrimido [4, 5-b] quinolin-4 (3H) one-2-carboxylate It was a case where the molar ratio of oxalate was 15-1 and reacted at 160 degreeC for 18 hours.

Diethyl oxalate and anthranylamide (2-1 molar ratio) were condensed at 170 ° -180 ° C. for 6 hours in the absence of a base to yield 57% yield of ethyl 4-quinazone-2-carboxylate and bis-substituted as a byproduct. The production of oxamides has been reported by Baker et al. J. Org. Chem. 27, 4, 672-4,674 (1962).

When preparing ethyl 4-quinazolo-2-carboxylate through the process of the present invention, anthranylamide (.05 mol), diethyl oxalate (0.1 mol) and sodium ethoxide ( 0.15 mol) was reacted for 1 hour at 70 ° -75 ° C in ethanol (100 mL) solvent, yielding a 78% yield as compared to 57% yield reported by Baker et al.

In view of the conventional harsh conditions, appropriate 2-aminoquinoline-3-carboxamides are reacted with appropriate dialkyl oxalates under relatively mild temperature and time conditions, yielding alkyl pyrimido [4, 4] as a very satisfactory and economical yield. 5-b] It was unexpectedly surprising that it was possible to prepare quinoline-4 (3H) one-2-carboxylates. It can be easily applied in large scale reactions, does not require special reactors, avoids the formation of bis-substituted oxamides as by-products, and does not require removal of by-product alcohols and water.

The cyclization reaction can be summarized by the following equation:

Of particular interest to the process of the present invention are the following reagents:

Wherein, R is C ₁ - ₄ alkyl and; R ₁ is hydrogen, C ₁ - is one of the ₄ alkyl and phenyl; R _2, R _3, R ₄ and R ₅ are both of hydrogen, C ₁ - is selected from a ₄ alkoxy, halo, benzyloxy, methylthio and _benzylthio-4 alkyl, C _1; The other two are hydrogen, C ₁ - ₄ alkyl, C ₁ - ₄ alkoxy and halo is selected from the; R ₂ and R ₃ and R ₄ , when considered together, are either alkylenedioxy or methylenedioxy or ethylenedioxy.

Cyclization reaction products obtained from these reactants are useful antiallergy agents.

The cyclization reaction involves the presence of a suitable base at a temperature of about 100 ° C. or less in a reaction-inert solvent in a molar ratio of 1: 1 to 1: 3 of the appropriate 2-amino quinoline-3-carboxamide and the appropriate dialkyl oxalate. It is carried out by reaction under. Suitable solvents include alcohols corresponding to the alkyl groups of the dialkyl oxalate reactants, solvents which can be mixed with xylenes, toluene, benzene, dioxane, tetrahydrofuran and other alcohols and dimethylsulfoxide and the alcohols There are combinations of Although the use of a solvent does not appear to be essential for carrying out the reaction, it is very advantageous in terms of reaction rate and yield.

The nature of the dialkyl oxalate is not critical to the success of the process of the present invention. Advantageous dialkyl oxalates, however, are those having the same alkyl group and having 1 to 4 carbon atoms.

They are advantageous as reactants, they are readily available, and the cyclized products they make have useful anti-allergic activity, their overall reaction is easy in this process, and the alkyl moieties of alcohols and alkoxides are dialkyl oxalates. Easily available alcohols that correspond to the alkyl moiety of are used as solvents and sodium alkoxides as cyclization reagents to provide satisfactory yields of cyclized products. The alkyl groups use different dialkyl oxalates to obtain a mixture of esters. For this reason, it is preferable to use dialkyl oxalates with identical alkyl groups in order to obtain a single product which is not a mixture of esters.

Preferred solvents are alcohols. In order to avoid transesterification, it is of course necessary to use the alcohol corresponding to the ester group of the dialkyl oxalate reagent as solvent. However, as soon as a person skilled in this area is immediately aware, transesterification can be avoided or minimized by using it as a solvent for branched alcohols, such as t-butyl alcohol, where the transesterification tends to be very small. have.

The molar ratio of dialkyl oxalate to 2-aminoquinoline-3-carboxamide reagent is not critical but must be at least a ratio of 1: 1. For reasons of yield and economics of cyclized products, it is usually preferred to use about 3 molar equivalents of dialkyl oxalate relative to one mole of 2-aminoquinoline-3-carboxide reagent. Increasing this ratio does not appear to be advantageous.

For this cyclization reaction, various bases can be used. Suitable bases include sodium and potassium alkoxides (particularly the alkoxy moieties correspond to the alcohol moieties of dialkyl oxalates), sodium and potassium hydrides, amides and 3-aminopropyl amides, triphenylmethyl sodium and triphenylmethyl There is a potashium.

This base is preferably used as a ratio of about 2-3 molar equivalents relative to 1 mole of 2-aminoquinoline-3-carboxide reagent. It is preferable to use a 3: 1 molar ratio to obtain an optimum yield. It is shown that even if the molar ratio is further increased, no gain is obtained. Lower molar ratios tend to reduce the yield of cyclized products. Preferred bases are sodium alkoxides where the alkoxy moiety corresponds to the alkyl moiety of the dialkyloxalate.

The reaction proceeds at a temperature lower than 100 ° C. An advantageous reaction range is from about 20 ° C to 100 ° C. For economic reasons, it is advantageous to run the reaction at the lowest temperature, which gives good reaction rates and yields and requires minimal cooling and heating. This is of course easily determined by experiment. Such preferred temperatures are found within the range of about 25 ° C to 50 ° C. The low range is very satisfactory when using dimethyl and diethyl oxalates as reactants. Higher ranges are sometimes advantageous when dibutyl oxalate is used as the reactant.

The products of the present invention and their pharmaceutically usable cationic salts are useful for the control (prophylactic and therapeutic measures) of allergic symptoms and reactions in mammals, and as standalone therapeutic agents or for example theophylline or sympathomimetic amines. And the like as a mixture of therapeutic agents. That is, they may be administered alone, but are generally administered with a pharmaceutical carrier selected based on the chosen route of administration and typical pharmaceutical preparations. For example, they may be tablets, capsules, tablets, troches, candy, powders, aerosol spray water suspensions with inert pharmaceutically acceptable carriers. Or in the form of aqueous solutions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile liquid media and various types of non-toxic organic solvents. Furthermore, the oral administration compositions of the present invention can be suitably sweetened or flavored using various reagents in the form commonly used for this purpose.

The choice of particular carrier and the ratio of active ingredient to carrier are influenced by the solubility and chemical nature of the therapeutic compounds, the route of administration chosen and the need for standard pharmaceutical practice. For example, when the compounds of the present invention are administered orally in the form of tablets, excipients such as lactose, sodium citrate, calcium carbonate and dicalcium carbonate may be used. Various disintegrants such as starch, alginic acid and certain complex silicates can also be used to prepare tablets for oral administration, with lubricants such as magnesium stearate, sodium laurylsulfate and activity. When orally administered in the form of capsules, among the preferred materials which can be used as pharmaceutically usable carriers are lactose and high molecular weight polyethylene glycols. When water suspensions are used for oral administration, the compounds of the present invention may be formulated with emulsions, suspending agents and the like. Diluents such as ethanol, propylene glycol glycerin chloroform and combinations thereof may also be used with other materials.

In addition to the sterile aqueous solutions of the pharmaceutically usable soluble salts described when used for oral and inhalation administration, these compounds may be made into solutions or suspensions dissolved in sesame, peanut oil or propylene glycol aqueous solutions. Such special solutions are particularly suitable for intramuscular and subcutaneous injection purposes. Aqueous solutions, including salts dissolved in distilled water, are also useful for intravenous purposes as long as their pH is adjusted in the event. Such solutions should also be suitably buffered as needed and the liquid diluent first made into isotonic solution as sufficient saline or glucose.

In asthma patients suffering from bronchial constriction, these compounds may be administered by inhaler or other equipment to bring the active substance directly into contact with the contraction of the patient's organs.

When administered by inhalation, the compositions can be administered by (1) a nebulizer, a solution or suspension in which the active ingredient is dissolved in a liquid medium of the type described above, and (2) by a pressurized container. A solution or suspension in which the active ingredient is dissolved in a liquid propellant, such as difluoromethane or chlorotrifluoroethane, or (3) a powder diluent (eg, lactose) for administration via a powder inhalation device. It may be made of a mixture with.

Compositions suitable for inhalation with conventional nebulizers comprise approximately 0.1-1% of active ingredient; When using a pressurized container, it contains about 0.5-2% of the active ingredient. The composition for powder inhalation should have a ratio of about 1: 0.5 to 1: 1.5 of the active ingredient to the diluent.

The active ingredient needs to be able to form such a composition ratio to obtain a suitable dosage unit. As can be clearly seen, several dosage units can be administered simultaneously. In some cases compositions having up to 0.005% active ingredient by weight may be used, but preference is given to using compositions containing at least 0.005% active ingredient; Otherwise the amount of carrier becomes too much. As the concentration of the active ingredient increases, the activity increases. The composition may contain 10, 50, 75, 95, or even more by weight of the active ingredient.

In terms of the dosage regimen of these compounds, the physician will ultimately determine the dosage that is best suited for the individual patient, which may include the nature and extent of the symptom, the particular pharmacological characteristics administered, the route of administration, etc. , Weight and response. In general, the dose is slowly increased until initially a small amount begins to be administered to determine the most appropriate level. When the composition is administered orally, it is often the case that a larger amount of active ingredient is required to achieve the same level as obtained when a small amount is administered parenterally.

Considering all the above factors, the compound of the present invention is orally administered to humans at about 10-1,500 mg daily, preferably at about 10-600 mg at once or divided, or about 0.2-12 mg per kg body weight. Administration can effectively control bronchial contraction in humans. These values are for illustrative purposes and of course higher or lower dosages may be more appropriate for each individual.

When administered intravenously or by inhalation, the effective daily dose is administered once or in divided doses of about 0.5-400 mg per day, preferably 0.25-200 mg or 0.005-4 mg per kg of body weight.

Example 1

Ethyl 7, 8-dimethoxypyrimido [4, 5-b] quinolin-4 (3H) -one-2-carboxylate

2-amino-6,7-dimethoxyquinoline- with stirring in a room temperature solution containing diethyl oxalate (8.8 g, 0.06 mole) and sodium ethoxide (4.0 g, 0.06 mole) in ethanol (160 mL) 3-carboxamide (5.0 g, 0.02 mol) was added. A yellow suspension was produced. Within about 1 hour the reaction mixture became cloudy. After stirring for 2 hours, diatomaceous earth (3.0 g) and charcoal (1.3 g) were added and the mixture was further stirred for 15 minutes. After filtration through diatomaceous earth, the filter cake was washed with ethanol (50 mL). The filtrate was heated to reflux and glacial acetic acid (2.4 mL, 0.04 mol) was added. A yellow solid precipitated out. After refluxing for 30 minutes, the reaction mixture was cooled to room temperature and stirred for another hour. The product was filtered off and dried in vacuo at 70 ° C.

Yield = 6.9 g, 98.9%

Assay: calcd C ₁₆ H ₁₅ N ₃ O ₅ C, 58.35; H, 4.59; N, 12.76%

Found C, 57.81; H, 4.58; N, 12.46%

The procedure was repeated 10 times the amount to obtain 91.7% yield.

Example 2

The reaction was carried out in the same molar ratio as in Example 1 with appropriate 2-aminoquinoline-3-carboxamide, appropriate dialkyl oxalate and sodium alcoholate and alcohols, where the alkyl groups correspond to that of the dialkyl oxalate used. In the course of the procedure of Example 1 was changed to the following compounds were prepared.

Example 3

Following the procedure of Example 1, using the same molar ratio of reactants but using the following bases instead of sodium ethoxide:

Potassium ethoxide

Triphenylmethyl Sodium

Sodium amide

Potassium 3-aminopropylamide

Sodium hydride

In each case the product was obtained at a yield similar to the yield yield in Example 1.

Example 4

Ethyl 7, 8-dimethoxypyrimido [4, 5-b] quinolin-4 (3H) -one-2-carboxylate

Diethyloxalate (DEO), and 6,7-dimethoxy-2-amino quinoline-3-carboxamide (0.02 mole) in the presence of a suitable base using ethanol using the time, temperature, and molar ratio conditions shown in the table below Reacted within. In each case, a substantial cyclization reaction occurred to yield the title product, which was recovered by the procedure of Example 1.

Claims (1)

As described above in detail, the structural formula of 2-amino-3-a-carboxamide, 1-3 mol equivalent weight C ₁ below - of the dialkyl oxalate having an alkyl group of _4, -100 ℃ about 20 ℃ Alkyl pyramido [4,5-b] -quinoline- characterized in that it reacts in the presence of 2-3 molar equivalents of base per mole of 2-aminoquinoline-3-carboxamide in a reaction-inert solvent at a temperature. The manufacturing method of 4 (3H) -one-2-carboxylates.

Wherein, R ₁ is hydrogen, C ₁ - ₄ is one of the alkyl or _{phenyl, R 2, R 3, R} 4 and R ₅ both of a hydrogen, C ₁ - ₄ alkyl, C ₁ - alkoxy ₄ , Halo, benzyloxy, methylthio and benzylthio; The other two are hydrogen, C ₁ - ₄ alkyl, C ₁ - ₄ alkoxy and halo is selected from the; R ₂ and R ₃ and R ₄ when considered together are either alkylenedioxy or methylenedioxy or ethylenedioxy. In addition, the base is C ₁ - is selected from among sodium alkoxide, triphenylmethyl sodium, sodium hydride, sodium amide, sodium amide or the corresponding potassium 3-aminopropyl compound of _4.