CN85100796A - The preparation method of qualone derivative - Google Patents

Abstract

A method for producing quinolinone derivatives of chemical formula (I) or acceptable pharmaceutical salts thereof, wherein "Het", R, R ¹ , R ² , Y are as specification, as defined in the claims.

The derivative is used for the treatment or prevention of heart diseases such as weak heart.

Description

The preparation method of quinolinone derivative

The present invention relates to substituted quinolinone cardiac stimulants, which can selectively increase myocardial contractility without increasing heart rate, and these compounds can be used for the treatment or prevention of heart disease, especially heart failure .

The present invention has the compound of formula (I)

And its pharmaceutically acceptable salts, wherein "Het" is any substituted 5- or 6-membered carbon atom connected to the 5-, 6-, 7-, or 8-position of the quinolinone Monocyclic aromatic heterocyclic group; R attached to the 5-, 6-, 7- or 8-position, is oxygen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkane Thio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ sulfonyl, halo, CF ₃ , hydroxyl, hydroxymethyl, or cyano; R ¹ is hydrogen, cyano, (C ₁ -C ₄ ) Alkoxy, carbonyl, C ₁ -C ₄ alkyl, nitro, halo, -NR ³ R ⁴ or CONR ³ R ⁴ , wherein R ³ and R ⁴ are H or C ₁ -C ₄ alkyl, respectively, Or connect with nitrogen to form a saturated 5- or 6-membered heterocyclic ring, which contains a heteroatom or group selected from O, S and NR ⁵ (R ⁵ is hydrogen or C ₁ -C ₄ alkyl); R ² is hydrogen, C ₁ -C ₄ alkyl or 2-hydroxyethyl; Y is H or C ₁ -C ₄ alkyl; the dotted line between the 3- and 4-positions indicates that it may or may not be a bond.

Especially R is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkanesulfinyl, C ₁ -C ₄ alkanesulfonyl , halo; CF ₃ or hydroxyl; and Y is H.

Furthermore, the present invention also provides intermediates of compounds of formula (I) having formula (II):

Wherein Het, R, R ¹ , Y and the dotted line are as defined in the chemical formula (I).

The special direction of the present invention is that "Het" is any substituted 5- or 6-monocyclic aromatic nitrogen-containing heterocyclic ring with a carbon atom connected to the 5-, 6-, 7- or 8-position of the quinolinone ; R connected to the 5-6-, 7- or 8-position, is hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; R ¹ is hydrogen, cyano, (C ₁ -C ₄ Alkyl) carbonyl, C ₁ -C ₄ alkyl, -NR ³ R ⁴ or -CONR ³ R ⁴ , wherein R ³ and R ⁴ are H or C ₁ -C ₄ alkyl respectively, or connected with nitrogen to form A saturated 5- or 6-membered heterocyclic group, which can optionally contain a heteroatom or group selected from O, S and NR ⁵ (R ⁵ is hydrogen or C ₁ -C ₄ alkyl); R ² is Hydrogen, C ₁ -C ₄ alkyl or 2-hydroxyethyl; Y is H; and the dotted line between the 3- and 4-positions indicates whether or not it is a bond.

唑基，异

唑基，噻唑基，异噻唑基，三氮唑基，呋喃基，噻吩基，二氮唑基，及含氮时，其N-氧化物，所有任意被1或2取代者，其中取代基系选自：例如C₁-C₄烷基，C₁-C₄烷氧基，C₁-C₄烷硫基，氰基，CF₃，卤基，-NR³R⁴或-CONR³R⁴，其中R³和R⁴之定义如化学式（Ⅰ），羟甲基和（C₁-C₄烷氧）羰基。Examples of the "Het" group include: pyridyl, pyrazinyl, pyrimidinyl, imidazolyl, pyrazolyl,

Azolyl, iso

Azolyl, thiazolyl, isothiazolyl, triazolyl, furyl, thienyl, diazolyl, and when nitrogen-containing, their N-oxides, all of which are optionally substituted by 1 or 2, wherein the substituent is selected from: e.g. C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, cyano, CF ₃ , halo, -NR ³ R ⁴ or -CONR ³ R ⁴ , wherein R ³ and R ⁴ are as defined in formula (I), hydroxymethyl and (C ₁ -C ₄ alkoxy) carbonyl.

A preferred N-oxide is pyridyl-N-oxide.

"Halo" means F, Cl, Br and I, C ₃ and C ₄ alkyl and alkoxy can be straight chain or branched.

When R ³ and R ⁴ are joined together with a nitrogen atom to form a so-called saturated 5- or 6-membered heterocyclic group, examples of the heterocyclic group are 1-pyridyl, piperidyl, morpholino and 4- Methylpiperazinyl.

Although the compound of formula (I) is denoted as 2-(1H)-quinolinone, it can be appreciated that when ^R is H, the following tautomerism will occur:

The ketone formula is a relatively stable tautomer, and the final product is named and assigned as quinolinone, and those who are familiar with this art know that both tautomers exist, and even some special compounds are called hydroxyl tautomers. The existence of T is preferred, but the following disclosures combine all tautomeric forms to prove it.

基，咪唑基，三氮唑基，四氮唑基，嘧唑基，草二唑基，噻吩基或呋喃基，所有随意经选自C₁-C₄烷基，C₁-C₄烷氧基，氰基，胺基和胺基甲酰基之1或2取代基取代者为较佳。Preferred compounds, "Het" is pyridyl, its N-oxide, pyrimidinyl, pyridyl

Base, imidazolyl, triazolyl, tetrazolyl, pyrimazolyl, oxadiazolyl, thienyl or furyl, all are optionally selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy One or two substituents of cyano group, cyano group, amino group and carbamoyl group are preferred.

基，（e）吡

基，（f）三氮唑基或N-甲基三氮唑基，（g）四氮唑基或N-（正-丁基）-四氮唑基，（h）N-甲基咪唑基，（i）氧二氮唑基，（j）噻唑基，（k）噻嗯基，及（l）呋喃基。More preferably: "Het" is selected from (a) pyridyl substituted by 1 or 2 methyl groups, or by a single methoxy, cyano, amino or carbamoyl group, (b) pyridyl- N-oxide, (c) pyrimidine, (d) dat

base, (e)pyridine

base, (f) triazolyl or N-methyltriazolyl, (g) tetrazolyl or N-(n-butyl)-tetrazolyl, (h) N-methylimidazolyl , (i) oxydiazolyl, (j) thiazolyl, (k) thianthyl, and (l) furyl.

More preferably, "Het" is pyridin-3-yl, pyridin-4-yl, 2-,6-dimethylpyridin-3-yl, or 1-methyl-(1H)-1,2,4- Triazol-5-yl.

"Het" is preferably connected to 5-, 6-, 7-position, more preferably 6-position.

R is represented by H, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkanesulfinyl, C ₁ -C ₄ alkanesulfonyl, halogen Base, hydroxy, or hydroxymethyl are preferred; H, C ₁ -C ₄ alkyl, methoxy, methylthio, methylsulfinyl, methylsulfonyl, bromo, hydroxy and hydroxymethyl For more base.

When R is a substituent, it is preferably at the 7- or 8-position, more preferably at the 8-position, more preferably at the 8-position, especially 8-methyl.

^R1 is preferably H, cyano, C ₁ -C ₄ alkoxycarbonyl, nitro, halo or amine, preferably H, cyano, methoxycarbonyl, nitro, halo or amine Good; H is the best.

R ² is preferably H or CH ₃ , most preferably H.

Y is preferably H or CH ₃ , and H is the best.

A double bond between the 3- and 4-positions of quinolinone is preferred.

Preferred compounds are those having the structure (IA):

Where Het and R are as defined above, and "Het" is preferably 2,6-dimethylpyridin-3-yl or 1-methyl-(1H)-1,2,4-triazol-5-yl, R is preferably methyl.

Pharmaceutically acceptable salts of compounds of formula (I) are non-toxic and include: acid addition salts such as hydrocyanide, hydrobromide, hydroiodide, sulfate or hydrogensulfate, phosphate or hydrogenphosphate , acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, methanesulfonate, and p-toluene phosphate, including metal salts, especially acid Metal salts and alkaline earth metal salts, especially sodium or potassium salts.

The cardiostimulant activity of the compound of chemical formula (I) can be demonstrated by the effectiveness of one or more of the following tests: (a) the increase in the contractility of the "Starling" dog heart-lung model measured by left heart catheterization, (b) The increase in myocardial contractility (dp/dt max of the left ventricle) in anesthetized dogs was measured via left heart catheterization. (c) Increased myocardial contractility in dogs implanted with left ventricular electrical power transmitters (dp/dt max) or embodied carotid coils (systolic time interval).

In test (a), the positive inotropic effect of the test compound on heart-lung specimens of "Starling" dogs was measured after bolus treatment to obtain the selectivity of the increase in inotropic force of the test compound versus frequency.

In test (b), the positive inotropic effect of the test compound on anesthetized dogs was measured after intravascular injection to obtain the magnitude and persistence of the effect, the selectivity of inotropic force increase versus frequency, and the peripheral effects, For example, the effect on blood vessels.

In test (c), after intravascular injection, the positive inotropic effect was measured in dogs implanted with left ventricular electrical power transmitters (dp/dt max), or embodied carotid coils (systolic time intervals), to obtain test compound systolic The magnitude of the effect, the selectivity of the increase in contraction force to the frequency, and the duration of the contraction effect.

The compound of formula (I) can be used alone, but is usually administered in admixture with a pharmaceutical carrier selected by the intended use and standard pharmaceutical practice, for example in oral administration in the form of tablets containing excipients such as starch and lactose; or in capsules , can be used alone, or mixed with excipients; or in the form of elixirs or suspensions, containing flavoring or coloring agents, which can also be used for parenteral injection, such as intravenous injection, intramuscular injection, or subcutaneous injection. In the injection method, it is preferably in the form of a sterile aqueous solution, which may also contain other solutes, such as sufficient salts or glucose, to make the solution equal.

For the treatment and prevention of heart disease, such as congestive heart failure, when administered to human body, the oral dose of the compound of the present invention is: based on the average adult dosage (70kg), 10mg to 1g per day, 2 to 4 times a day. The dosage for intravenous injection is: when necessary, such as the treatment of acute heart failure, each single dose is 1 to 100 mg, typical adult patients, each tablet or capsule contains 5 to 100 mg of active compound, together with pharmaceutically acceptable excipients. excipient or carrier. Depending on the condition and body weight of the treated body, the dosage can be changed according to medical practice.

The present invention also provides a pharmaceutical composition, comprising the compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent and carrier.

The invention also provides a method of stimulating the heart of animals, including humans. Including: sufficient amount of the compound of chemical formula (I) or its salts for animals to stimulate the animal's heart, or the pharmaceutical composition defined above.

The present invention further provides a compound of chemical formula (I), or a pharmaceutically acceptable salt thereof, for use in medicine, especially for the heart of congestive heart failure.

The compounds of this invention can be produced in several ways, including the following:

Method A

This method is used to manufacture compound (I) in which ^R2 is H, and the description is as follows:

Wherein R, R ¹ , Y, dotted line and "Het" are defined as chemical formula (I), demethylated in aqueous solution of inorganic acid, preferably in aqueous solution of HCl or HBr, typically in 48% HBr or 5M HCl aqueous solution, Heating methoxy-quinoline (II) to reflux concentration for 0.5-4 hours, or heating to reflux temperature in ethanol containing catalytic amount (generally 5-15% by volume) of 48% HBr solution, to carry out better. The resulting product can be isolated and purified by conventional methods.

A typical reaction using 48% HBr aqueous solution is illustrated as follows:

A typical reaction using ethanol containing a catalytic amount of 48% HBr is illustrated below:

This method can replace 48% HBr with 5M HCl aqueous solution, and carry out under the same conditions. The typical reaction using 5M HCl is described as follows:

In those cases where ^R1 is an alkoxycarbonyl group (e.g. _-COOCH3 ), dealkylation can convert this group to -COOH, in which case the carbonyl group can conventionally be re-esterified, e.g. using sulfuric acid Methanol.

The raw materials of chemical formula (II) can be remanufactured by traditional methods, and the typical manufacturing methods of these materials are described in detail as follows:

Wherein Q is a free group, such as C ₁ -C ₄ alkoxy, preferably methoxy or ethoxy.

This reaction involves the cyclization of an acrylamide derivative, typically 3-ethoxyacrylamide, using concentrated (typically 98%) sulfuric acid. The reaction is typically carried out by stirring the reactants at room temperature for 8-48 hours, and the product can be isolated and purified by conventional methods.

Typical reactions are as follows:

The raw materials are known or can be narrowly obtained by known methods.

Method C:

The method is described in general form as follows:

wherein Q is a suitable free group such as Cl, Br or I. It involves the substitution of neocyclic arylzinc chlorides, catalyzed by tetrakis(triphenylphosphine)palladium(O), to replace the ion group. The reaction is typically performed by heating the reactants to reflux temperature in an organic solvent such as THF.

Typical responses are as follows:

Neocycloarylmagnesium chloride can also be used instead of zinc chloride, and other suitable transition metal catalysts (eg, nickel-based) can be used.

The raw material is either a known compound or can be obtained by a traditional method. The new cycloylzinc chloride is reacted in THF at -70 to -100°C with an appropriate halogenated heterocycle and 2 equivalents of tertiary butyllithium. , to obtain lithium derivatives, followed by reaction with anhydrous zinc chloride solution in THF. The heterocyclic zinc chloride can also be prepared by reacting a corresponding Grignard reagent and zinc chloride solution in THF. The desired end product is typically warmed from the reaction mixture to room temperature. Then add the appropriate halogenated quinolinone and tetrakis(triphenylphosphine)palladium(O) in THF, and then heat under reflux until the reaction is complete, usually 1 to 48 hours. The product can be recovered and purified by known methods.

The raw materials of this method can be prepared by traditional methods, and the typical preparation methods of these materials are as follows:

Method D:

This law states as follows:

The reaction involves reduction of the nitro group, preferably using stannous chloride dihydrate in ethanol. The reaction typically heats the reactants to reflux temperature for 1-8 hours.

Typical reactions are as follows:

Method E:

R ¹ is Cl, Br, or the chemical formula (I) compound of I can also be prepared by conventional halogenation of the compound of R ¹ being H, and the typical reaction is as follows:

Method F:

"Het" is an N-oxide compound of formula (I), which can be produced by oxidation of a corresponding original nitrogen-containing heterocyclic ring, generally using a peroxyacid oxidizing agent, such as m-chloroperbenzoic acid, or peroxyacid, and Manufactured under normal reaction conditions. Typical reactions are as follows:

Method G:

R ² is a C ₁ -C ₄ alkyl or 2-hydroxyethyl compound of formula (I), which can also be prepared by N-alkylation of an equivalent compound in which R ² is H. The typical method is: N-unsubstituted The reaction of quinolinones with sodium hydride or other strong bases to form anions, followed by e.g. C ₁ -C ₄ alkyl halides, di(C ₁ -C ₄ alkyl) sulfates, or 2-hydroxyethyl nitrogen compounds, react in a conventional manner, a typical reaction is as follows:

Method H:

The general form of this Law is as follows:

The reaction involves the catalytic hydrogenation of 3,4-bisammonium over a suitable catalyst, such as a transition metal catalyst, typically in ethanol at 25-100°C and 15-5000 psi of hydrogen. The material was heated for 1-7 days at 10% palladiumized active base.

Typical reactions are as follows:

Method I:

The general form of this method is as follows:

(X=Cl, Br or I)

The reaction involves electrophilic halogenation of the 8-position of the raw material 3,4-dihydroquinolinone in concentrated (preferably 98%) sulfuric acid in the presence of silver sulfate (X=Cl, Br, I) . The reaction is usually carried out at 0-70° for 1-16 hours, and the product can be purified by conventional methods.

Typical reactions are as follows:

Method J:

The general form of this Act is as follows:

The reaction involves bromination of the 3-position of the starting material, followed by dehydrobromination to produce a 3,4-double bond. The reaction is generally carried out in acetic acid by mixing the starting material 3,4-dihydroquinolinone and bromine And sodium acetate - heated to 25-120 ° C, 1-2 hours.

The product can be purified by known methods.

Typical reactions are as follows:

Method K:

The general form of this method is as follows:

Wherein R ⁶ is C ₁ -C ₄ alkyl, and Q ¹ is a free group.

This reaction involves the nucleophilic substitution reaction of a free group Q ¹ (such as F, Cl, Br, I) with a C ₁ -C ₄ alkanethiol metal salt (such as an alkali metal salt) in the presence of copper (I) metal . Generally, sodium salt is used in a high-boiling organic solvent, such as N-methylpyrrolidone, and heated to reflux temperature (for example, 160°C (about 0.5-48 hours). The product can be isolated and purified by conventional methods.

Typical reactions are as follows:

Method L:

The general form of this method is as follows:

Wherein R ⁶ is C ₁ -C ₄ alkyl.

The reaction involves the partial oxidation of the sulfide to the equivalent sulfoxide or sulfone species with an appropriate oxidant, such as an organic peroxyacid or sodium metaperiodate. Typically in an organic solvent such as dichloromethane at -70° to +30° for 1-24 hours.

Typical reactions are as follows:

Method M:

The general form of this method is as follows:

Wherein R ⁶ is C ₁ -C ₄ alkyl.

Demethylation is preferably carried out in an aqueous mineral acid solution, preferably 48% HBr, by heating alkoxyquinoline, or by treating it with other demethylating agents, such as boron tribromide or pyridine hydrogen chloride.

Typical reactions are as follows:

Method N:

The general form of this method is as follows:

The reaction involves displacement of the halogen atom "X" (X = Cl, Br or I) by lithium derived from _C1 - _C4 alkyllithium, followed by chlorination of the resulting Organometallic substances are quenched. The reaction is generally carried out in a suitable organic solvent (such as tetrahydrofuran) at -75° to 0°C. When R ² is hydrogen, at least 2 equivalents of C ₁ -C ₄ alkyllithium should be used. A preferred alkyllithium is n-butyllithium.

Typical responses are as follows:

Salts of the compounds of formula (I) may be prepared by entirely conventional methods, for example by reacting the free base in an organic solvent with a suitable acid in an organic acid to form an acid addition salt, or by reacting the free base with a suitable acid such as a base Metal or alkaline earth metal hydroxides (preferably aqueous sodium hydroxide solution) react to form pharmaceutically acceptable metal salts.

The compounds of the present invention contain one or more asymmetric centers and thus the present invention includes isolated enantiomers and diastereomers, or mixtures thereof, which are obtainable in isolated form by conventional methods.

The following examples illustrate the preparation of compound (I). (All concentrations are at 0°C):

Example 1

Preparation of 6-(3-pyridyl)-2-(1H)-quinolinone

A stirred solution of 2-methoxy-6-(3-pyridyl)quinoline (1.83 g) in aqueous HBr (6 cm ³ ) was heated to 100° for about 1.5 hours and then cooled in an ice bath to 5M The NaOH solution was adjusted to pH 8, extracted continuously with chloroform for 6 hours, and the organic extract dried (MgSO ₄ ) was evaporated to obtain a solid, which was recrystallized with methanol-ethyl acetate to obtain 6-(3-pyridine base)-2-[1H]-quinolinone, mp 217-218° (0.62 g).

analyze(%):

Actual value: C, 75.9H4.8N12.2

Value calculated from C ₁₄ H ₁₂ N ₂ O: C, 75.7H4.5N12.6

Example 2-11:

The following compounds were prepared in a similar manner to Example 1 starting from the appropriate 6-substituted-2-methoxyquinoline and 48% HBr.

Examples 12 and 13

The following compounds were prepared from the appropriate 3,6-disubstituted-2-methoxyquinolines in a manner similar to Example 1 but substituting 5M HCl for 48% HBr.

Example 14

3-Methoxycarbonyl-6-(3-pyridyl)-2-[1H]-quinolinone hemihydrate

2-Methoxy-3-methoxycarbonyl-6-(3-pyridyl)-quinoline (0.50 g) was dissolved in a solution of 5M HCl (30 cm ³ ), heated under reflux for 20 minutes, and the cooled mixture Filtration and washing of the solid with methanol gave the hydrochloride salt of the crude intermediate 6-(3-pyridyl)-2-[1H]-quinolinone-3-carboxylic acid, mp 350-352°, (0.45 g) , the material was placed in methanol (50cm ³ ), heated under reflux with acetic acid (1cm ³ ) for 1 hour, the mixture was concentrated in vacuo, and the residue was partitioned between chloroform (100cm ³ ) and aqueous sodium bicarbonate Then, the aqueous phase was further extracted with chloroform (3 x 25 cm ³ ), the organic extracts were added together, dried (MgSO ₄ ) and evaporated to give 3-methoxycarbonyl-6-(3-pyridyl)-2-[ 1H]-Quinolinone hemihydrate, mp 223-225°, (0.32 g).

analyze%:

Actual values: C, 66.9; H, 4.3; N, 9.4.

Calculated for C ₁₆ H ₁₂ N ₂ O ₃ , 0.5H ₂ O.

C, 66.5; H, 4.5; N, 9.7.

Example 15

Using 2-methoxyl-3-methoxycarbonyl-6-(4-pyridyl)quinoline as raw material, 3-methoxycarbonyl-6-(4-pyridyl)-2 -[1H]-Quinolinone hemihydrate, m.p. 246-248°.

analyze%:

Actual values: C, 66.7; H, 4.2; N, 9.4.

Calculated for C ₁₆ H ₁₂ N ₂ O ₃ , 1/2H ₂ O:

C, 66.4; H, 4.5; N, 9.7.

Example 16:

Preparation of 8-methyl-6-(3-pyridyl)-2-(1H)-quinolinone

A stirred solution of 2-methyl-8-methyl-6-(3-pyridyl)-quinoline (1.07 g) in 5M HCl (10 cm ³ ) was heated at reflux for 2.5 hours and then cooled to obtain The cooled solution was basified to pH 9 with 2M NaOH aqueous solution, extracted with chloroform:methanol at a ratio of 9:1 (4×100cm ³ ), and the combined and dried (MgSO ₄ ) extracts were vacuum Concentrate to give a solid. Recrystallization from ethyl acetate-methanol gave 8-methyl-6-(3-pyridyl)-2-(1H)-quinolinone, mp 235.5-236.5°, (0.63 g).

analyze%:

Actual values: C, 76.0; H, 5.1; N, 11.6

Calculated value of C ₁₅ H ₁₂ N ₂ O:

C, 76.2; H, 5.1; N, 11.9

Examples 17-56:

In a similar manner to Example 16, the appropriate substituted 2-methoxyquinoline and 10% by volume of 48% HBr aqueous solution in ethanol (Examples 37, 42, 46 and 51), or 5M HCl Aqueous Solutions (Other Examples) The following compounds were prepared.

In Example 43, the starting material was 2-methoxy-6-(1-tributyltinyltetrazol-5-yl)quinoline which was removed under acidic reaction conditions.

In Example 37, part of -CN was hydrolyzed into -CONH ₂ , and the resulting mixture could be analyzed by chromatography on silica gel, with the volume ratio of chloroform:methanol:ammonia (SG0.880) being 94:5:1 Punch to separate it. See Example 51 for aminomethylthio compounds.

Example 57

In a similar manner to Example 16, with 6-[1-methyl-1,2,4-triazol-5-yl]-2-methoxy-4,8-dimethylquinoline and 5MHCl as Raw materials for the manufacture of 6-[1-methyl-1,2,4-triazol-5-yl],4,8-dimethyl-2-(1H)-quinolinone 0.75H ₂ O, mp as 327°.

analyze%:

Actual values: C, 62.8; H, 5.3; N, 20.6.

Calculated for C ₁₄ H ₁₄ N ₄ O, 0.75H ₂ O:

C, 62.8; H, 5.8; N, 20.9.

Example 58

Preparation of 8-methyl-6-[2,6-dimethylpyridin-3-yl]-2-(1H)-quinolinone, 3H ₂ O sodium salt

8-Methyl-6-[2,6-dimethylpyridin-3-yl]-2-(1H)quinolinone (94.7 g) and 5M NaOH solution (379 ^cm3 ) were slurried for 4 hours and the solids were filtered Wash with water (380cm ³ ), add isopropanol (600cm ³ ), evaporate volatile materials to obtain a solid, dissolve it in boiling methanol (1620cm ³ ), filter the hot solution, concentrate in vacuo (270cm ³ ), and cool to 0°, the precipitate was filtered and dried in vacuo at 50° to give the title compound, mp > 220° (dec) (60.4 g).

analyze%:

Actual values: C, 59.8; H, 5.5; N, 7.9.

_{Calcd for C17H15N2ONa} , _3H2O :

C, 60.0; H, 6.2; N, 8.2.

Example 59

Preparation of 8-Hydroxymethyl-6-[2,6-dimethylpyridin-3-yl]-2-(1H)-quinolinone, 0.1H ₂ O

At -70°, a solution of n-butyllithium (1.04 cm ³ dissolved in 1.6 M solution in n-hexane) was added to 8-bromo-6-[2,6-dimethyl-pyridine-3- [H]-2-(1H)-quinolinone (0.25 g) was dissolved in a stirred solution of 20 ^cm³ of THF. After 2 hours, gaseous formaldehyde [produced by paraformaldehyde (0.3 g) per liter] was put into the solution, stirred for a further 10 minutes, the mixture was heated to room temperature, saturated NH ₄ Cl solution (10 cm ³ ) was added, followed by chloroform (3× 50 cm ³ ) of the extraction mixture, the combined and dried (MgSO ₄ ) organic extracts were evaporated and washed on silica gel (MK 60.9385, a trade name from Merck) with dichloromethane:methanol in a ratio of 19:1. Chromatographic analysis of the appropriate fractions was added together and evaporated to give 3-hydroxymethyl-6-[2,6-dimethylpyridin-3-yl]-2-(1H)-quinolinone , 0.1H ₂ O, mp 218.5-221°C (0.094 g).

analyze%:

Actual values: C, 72.1; H, 5.8; N, 9.9.

Calculated for C ₁₇ H ₁₆ N ₂ O ₂ , 0.1 H ₂ O:

C, 72.4; H, 5.7; N, 9.9.

Example 60

Preparation of 6-(3-pyridyl)-2-(1H)-quinolinone

Sulfur-3-[4-(3-ethoxyacryloyl)phenyl]pyridine (1.43 g) was stirred in 98% H ₂ SO ₄ (4.0 cm ³ ) for 16 hours, the mixture was added to ice (50 g), and the resulting solution Basify to pH 8 with 2.5M NaOH solution and extract the mixture with chloroform:methanol 9:1 (10 x 100 cm ³ ). The combined and dried (MgSO ₄ ) extracts were concentrated in vacuo to give a solid which was recrystallized from isopropanol to give 6-(3-pyridyl)-2-(1H)-quinolinone, mp228- 230° (0.39 g).

analyze%:

Actual values: C, 75.3; H, 4.5; N, 12.5

Calculated for C ₁₄ H ₁₂ N ₂ O:

C, 75.7; H, 4.5; N, 12.6

Example 61

Preparation of 6-(2-methoxypyridin-5-yl)-2-(1H)-quinolinone

A solution of 5-bromo-2-methoxypyridine (1.50 g) dissolved in tetrahydrofuran (THF) (10 cm ³ ) was added at -70° under nitrogen, and tertiary butyllithium (8.0 cm ³ dissolved in pentyl (2.0 M solution in alkanes) was stirred. After 10 minutes, a solution of anhydrous zinc chloride (1.09 g) in THF (10 cm ³ ) was added and the mixture was allowed to warm to room temperature for 1 hour. A suspension of 6-bromo-2-(1H)-quinolinone (0.813 g) and tetrakis(triphenylphosphine)palladium(0) (0.03 g) in THF (10 cm ³ ) was added, refluxed and heated for 3 hours, and the Saturated NH ₄ Cl solution (1 cm ³ ) was added to the cooled mixture, followed by a solution of ethylenediaminetetraacetic acid disodium salt (6.0 g) in water. Chloroform (100cm ³ ) and methanol (30cm ³ ) were added and the mixture was warmed until all solid material had dissolved. The phases separated and the aqueous phase was extracted with 9:1 chloroform:methanol (3 x 50cm ³ ). The combined and dried (MgSO ₄ ) extracts were concentrated in vacuo to give a solid which was recrystallized from isopropanol to give 6-(2-methoxypyridin-5-yl)-2-(1H)-quinolinone, mp248-252°, (0.56 g).

analyze%:

Actual values: C, 71.4; H, 4.9; N, 11.2

Calculated for C ₁₅ H ₁₂ N ₂ O ₂ :

C, 71.4; H, 4.8; N, 11.1

Examples 62-72:

In a similar manner to the previous examples, from the appropriate substituted 6-bromo- or 6-bromo-2-(1H)-quinolinone and the appropriate heterocyclic arylzinc chloride, and tetrakis(triphenylphosphine ) palladium(O) as a catalyst to prepare the following compounds.

In Examples 69-72, 2,6-lutidine-3-ylzinc chloride was prepared from the appropriate magnesium Grignard reagent (which is a known compound) rather than from the appropriate lithium derivative.

In a similar manner to Example 61, 6-bromo-3,4-dihydro-2-(1H)-quinolinone, or 6-bromo-4-methyl-3,4-dihydro-2-(1H )-quinolinone, and appropriate pyridylzinc chloride as starting materials and tetrakis(triphenylphosphine)palladium(O) as catalyst to prepare the following compounds.

Example 76:

Preparation of 3-amino-6-(3-pyridyl)-2-(1H)-quinolinone 2/3 hydrate

Add stannous chloride dihydrate (1.27 g) to 3-nitro-6-(3-pyridyl)-2-(1H)-quinolinone (0.30 g) in ethanol (10 cm ³ ). In the stirred solution, the mixture was heated at reflux for 1.5 hours and allowed to cool. The cooled mixture was partitioned between chloroform (100 cm ³ ) and aqueous Na ₂ CO ₃ (50 cm ³ ), the mixture was filtered, the layers were separated and the aqueous phase was further extracted with 9:1 chloroform:methanol (2 x 50 cm ³ ). The combined and dried ( _MgSO₄ ) extracts were concentrated in vacuo. The resulting solid was powdered with hot isopropanol, filtered and dried to give 0.093 g of 3-amino-6-(3-pyridyl)-2-(1H)-quinolinone, 0.66 H ₂ O, mp 298-300° (decomposed).

analyze%:

Actual values: C, 67.8; H, 4.7; N, 16.8.

Calculated for C ₁₄ H ₁₁ N ₃ O, 0.66H ₂ O:

C, 67.5; H, 4.9; N, 16.9.

Example 77

Preparation of 3-bromo-6-(3-pyridyl)-2-(1H)-quinolinone

A mixture of 6-(3-pyridyl)-2-(1H)-quinolinone monohydrochloride (0.50 g), bromine (3.2 g), acetic acid (10 cm ³ ) and triethyleneamine (0.195 g) , Heated at reflux for 24 hours, then cooled. Diethyl ether ( ^20cm³ ) was added to cool the reaction mixture and the resulting yellow solid was filtered and purified by preparative gel chromatography. Elute it with 15:1 chloroform:methanol (elution 4 times) to get 3-bromo-6-(3-pyridone)-2-(1H)-quinolinone, mp is 297-300 °, ( 0.11 g)

analyze%:

Actual values: C, 55.7; H, 3.1; N, 9.2

Calculated for C ₁₄ H ₉ N ₂ OBr:

C, 55.8; H, 3.0; N, 9.3

Example 78:

6-(1-Oxypyridin-3-yl)-2-(1H)-quinolinone 1/4 hydrate

p-Chloroperbenzoic acid (3.74 g) was added to a stirred solution of 6-(3-pyridyl)-2-(1H)-quinolinone (1.49 g) in chloroform (50 cm ³ ) and methanol (50 cm ³ ). After 16 hours, a solution of NaOH (0.90 g) dissolved in water (5 cm ³ ) was added, followed by silica gel (manufactured by Merck, trade name "MK 60.9385", 30 g), and the mixture was evaporated to dryness in vacuo to obtain a powder Place it on top of a silica gel column (Merck "Mk 60.9385") and elute with 9:1 chloroform:methanol. Fractions containing product were added together and evaporated to give a solid. Recrystallization from isopropanol gave 6-(1-oxopyridin-3-yl)-2-(1H)-quinolinone, 0.25H ₂ O, mp 280° (dec.), (0.44g).

analyze%:

Actual values: C, 60.4; H, 4.4; N, 11.3

Calculated for C ₁₄ H ₁₀ N ₂ O ₂ , 0.25H ₂ O:

C, 69.3; H, 4.4; N, 11.5

Example 79:

Using 8-methyl-6-(3-pyridyl)-2-(1H)-quinolinone as raw material, prepare 8-methyl-6-(1-oxopyridine-3- base)-2-(1H)-quinolinone, 0.35H ₂ O, mp 290° (decomposition).

analyze%:

Actual values: C, 69.3; H, 4.8; N, 10.6

Calculated for C ₁₅ H ₁₂ N ₂ O, 0.35H ₂ O:

C, 69.7; H, 4.9; N, 10.8

Example 80

1-Methyl-6-(3-pyridyl)-2-(1H)-quinolinone 1/4 hydrate

A stirred solution of 6-(3-pyridyl)-2-(1H)-quinolinone (0.05 g) in DMF (0.5 cm ³ ) was treated with NaH (0.012 g in a 50% oil dispersion) at room temperature 1 Hour. A solution of dimethylsulfuric acid (0.016g) in DMF ( ^0.2cm³ ) was added. The mixture was stirred for 1.5 hours. The mixture was concentrated in vacuo. Water (5 cm ³ ) was added to extract the mixture with ethyl acetate (3 x 10 cm ³ ). The combined organic extracts were dried (MgSO ₄ ), concentrated in vacuo, and chromatographed on silica gel (“MK 60.9385” from Merck). , extracted with chloroform to obtain a solid, which was powdered with ether to obtain 1-methyl-6-(3-pyridyl)-2-(1H)-quinolinone 0.25H ₂ O, mp 116-118 ° (0.02 grams).

analyze%:

Actual values: C, 75.2; H, 5.3; N, 11.6

Calculated for C ₁₅ H ₁₂ N ₂ O, 0.25H ₂ O:

C, 74.8; H, 5.2; N, 11.6

Example 81:

8-Methyl-6-[2,6-dimethylpyridin-3-yl]-3,4-dihydro-2-(1H)-quinolinone

8-methyl ^- 6-(2,6-lutidine-3- A solution of ]-2-(1H)quinoline (0.30 g) was hydrogenated and the cooled solution was filtered from "Solkafloc", a trade name for a cellulose-based filter aid). Evaporate to dryness in vacuo and chromatograph the residue on silica gel ("MK 60.9385" from Merck), eluting with 49:1 chloroform:methanol. The appropriate fractions were added together and evaporated to give a solid, which was recrystallized from ethyl acetate/methanol to give 8-methyl-6-(2,6-dimethylpyridin-3-yl)-3,4-di Hydrogen-2-(1H)-quinolinone, mp 255-258°, (0.110 g).

analyze%:

Actual values: C, 76.2; H, 6.8; N, 10.4

_{Calcd for C17H18N2O} : C, 76.7; H, 6.8; N, 10.5

Examples 82-88

In a similar manner to the previous examples, starting from the appropriate substituted quinolinone and _H2 /Pd-C, the following compounds were prepared:

Example 89

In a similar manner to Example 81, using 4,8-dimethyl-6-[2,6-dimethylpyridin-3-yl]-2-(1H)-quinolinone and H ₂ /Pd- C as raw material, preparation of 4,8-dimethyl-6-[2,6-dimethylpyridin-3-yl]-3,4-dihydro-2-(1H)-quinolinone, 0.25H ₂ O, mp is 177-179°.

analyze%:

Actual values: C, 76.3; H, 7.3; N, 10.0

Calculated for C ₁₈ H ₂₀ N ₂ O, 0.25H ₂ O:

C, 75.9; H, 7.3; N, 9.8

Example 90

8-Bromo-6-[2,6-dimethylpyridin-3-yl]-3,4-dihydro-2-(1H)-quinolinone

Bromine (0.46 cm ³ ) was added to 3,4-dihydro-6-[2,6-dimethylpyridin-3-yl]-2-(1H)-quinolinone (1.5 g) at room temperature , and silver sulfate (1.4 g) in a stirred solution of 98% H ₂ SO ₄ (25 cm ³ ), warmed to 50° for about 16 hours, the cooled mixture was poured into ice (100 g), and dissolved in 5M NaOH The solution was neutralized to pH 7. Chloroform (100cm ³ ) was added, two phases were separated and the aqueous phase was further extracted with chloroform (2 x 100cm ³ ). The combined and dried extracts were evaporated in vacuo to give 1.9 g of solid, a small amount of this material was recrystallized from ethyl acetate/methanol to give 8-bromo-6[2,6-lutidine-3-yl ]-3,4-Dihydro-2-(1H)-quinolinone, mp 194-195°.

analyze%:

Actual values: C, 57.7; H, 4.4; N, 8.7

Calculated for C ₁₆ H ₁₅ N ₂ OBr:

C, 58.0; H, 4.6; N, 8.5.

Example 91

In a similar manner to the previous examples, 6-[1-methyl-1,2,4-triazol-5-yl]-3,4-dihydro-2-(1H)-quinolinone, bromo and silver sulfate in H ₂ SO ₄ as raw materials to prepare 8-bromo-6-[1-methyl-1,2,4-triazol-5-yl]-3,4-dihydro-2-( 1H)-Quinolinone, mp 160-163°.

analyze%:

Implemented values: C, 46.8; H, 3.6; N, 18.3.

Calculated for C ₁₂ H ₁₁ BrN ₄ O:

C, 46.9; H, 3.6; N, 18.2.

Example 92

8-Bromo-6-[2,6-dimethylpyridin-3-yl]-2-(1H)-quinolinone

Bromine (0.33 cm ³ ) was added to -bromo-6-[2,6-dimethylpyridin-3-yl]-3,4-dihydro-2-(1H)-quinolinone (1.9 g) at room temperature and sodium acetate (1.06 g) in acetic acid (50 cm ³ ), heated to 100° for about 18 hours, the cooled solution was evaporated in vacuo, and the residue was distributed among 10% Na ₂ CO ₃ solution (50 cm ³ ) and chloroform (100cm ³ ). The aqueous phase was extracted with chloroform (3 x 100 cm ³ ), and the combined and dried (MgSO ₄ ) extracts were concentrated in vacuo to give a solid which was chromatographed on silica gel ("MK 60.9385" from Merck). Analysis, eluting with chloroform, adding appropriate fractions together and evaporating to give 0.80 solid, recrystallized from ethyl acetate/methanol to give 8-bromo-6-[2,6-dimethylpyridin-3-yl] -2-(1H)Quinolinone, mp 212-215° (0.55 g).

analyze%:

Actual values: C, 58.2; H, 4.0; N, 8.5

Calculated for C ₁₆ H ₁₂ BrN ₂ O:

C, 58.4; H, 4.0; N, 8.5

Example 93

In a similar manner to the previous examples, 8-bromo-6-[1-methyl-1,2,4-triazol-5-yl]-3,4-dihydro-2-(1H)-quinone Linone, bromine and CH ₃ COONa, and CH ₃ COOH are raw materials for the preparation of 8-bromo-6 [1-methyl-1,2,4-triazol-5-yl]-2-(1H)-quinone Linone, mp is 257-259°.

analyze%:

Actual values: C, 47.0; H, 3.0; N, 18.2

Calcd _{for C12H9BrN4O} : C, 47.2; H, 3.0; _N , 18.4

Example 94

6-[2,6-Dimethylpyridin-3-yl]-8-thiomethyl-2-(1H)-quinolinone, 1/4 hydrate

A solution of CH ₃ SN _a (15 cm ³ of 2.0 M CH ₃ OH solution) was added to 8-bromo-6-[2,6-dimethylpyridin-3-yl]-2-(1H)- In a solution of quinolinone (0.50 g) and CuI (0.15 g) in N-methyl-2-pyrrolone (12 cm ³ ), after heating to 160° for about 48 hours, add CHCl ₃ (100 cm ³ ) and water ( 50cm ³ ) to dilute the cooled mixture. The separated aqueous phase was re-extracted with CHCl ₃ (3 x 50 cm ³ ), and the CHCl ₃ phases added together and dried (MgSO ₄ ) were evaporated in vacuo to give an oil which was washed on silica gel ("MK 60.9385" from Merck). ) for chromatographic analysis and extraction with CHCl ₃ . The appropriate fractions _were added together and evaporated to give _a solid which was recrystallized from _CH3COOC2H5 to give 6-[2,6-dimethyl-pyridin-3-yl]-8-thiomethyl-2- (1H)-Quinolinone 0.25H ₂ O, mp 146.5-148.5°, (0.04g).

analyze%:

Actual values: C, 67.9; H, 5.6; N, 9.4

Calculated _{for C18H16N2OS , 0.25H2O} :

C, 67.9; H, 5.5; N, 9.3

Example 95

In a similar manner to the previous examples, 8-bromo-6-[1-methyl-1,2,4-triazol-5-yl]-2-(1H)-quinolinone, CH ₃ SNa, And CuI as raw material to produce 6-(1-methyl-1,2,4-triazol-5-yl]-8-thiomethyl-2-(1H)-quinolinone.

analyze%

Actual values: C, 56.1; H, 4.5; N, 19.7

_{Calculated for C13H2N4OS} , _0.25H2O :

C, 56.1; H, 4.5; N, 20.1

Example 96

8-Methylsulfinyl-6-[1-methyl-1,2,4-triazol-5-yl]-2-(1H)-quinolinone

At 0°, m-chloroperbenzoic acid (0.14 g) was added to 6-[1-methyl-1,2,4-triazol-5-yl]-8-thiomethyl-2-(1H )-quinolinone in CH ₂ Cl ₂ (10cm ³ ) stirred solution. After 0.5 h, the solution was concentrated in vacuo and the residue was chromatographed on silica gel ("MK 60.9385" from Merck), eluting with 19:1 _CHCl3 : _CH3OH , adding the appropriate fractions together and evaporating. , to obtain a solid, recrystallized with CH ₃ COOC ₂ H ₅ to obtain 0.86 g of 8-methylsulfinyl-6-[1-methyl-1,2,4-triazol-5-yl]-2- (1H)-Quinolinone, mp 224-227°.

analyze%:

Actual values: C, 53.8; H, 4.3; N, 19.3

Calculated for C ₁₃ H ₁₂ N ₄ O ₂ S:

C, 54.2; H, 4.2; N, 19.4

Example 97

8-Methylsulfonyl-6-[1-methyl-1,2,4-triazol-5-yl]-2-(1H)-quinolinone

0.97 g of 8-methylsulfinyl-6-[1-methyl-1,2,4-triazol-5-yl]-2-(1H)-quinolinone, and 0.088 g of m-chloro A mixture of perbenzoic acid in 10 cm ³ CHCl ₃ was stirred at room temperature for 18 hours, then the mixture was concentrated in vacuo, and the residue was analyzed by chromatography on silica gel ("MK 60.9385" from Merck) with 19:1 CH ₃ COOC ₂ Extract it with H ₅ /CH ₃ OH, collect and evaporate the fraction to give a solid, which is recrystallized with CH ₂ Cl ₂ /C ₆ H ₁₄ to give 8-methylsulfonyl-6-[1-methyl-1 , 2,4-Triazol-5-yl]-2-(1H)-quinolinone, mp 226-232°, (0.051 g).

analyze%:

Actual values: C, 51.0; H, 4.2; N, 17.6

_{Calcd for C13H12N4O3S} : C, 51.3; H, 4.0; _N , 18.4

Example 98

8-Hydroxy-6-[2,6-dimethylpyridin-3-yl]-2-(1H)-quinolinone

A mixture of 0.15 g of 8-methoxy-6-[2,6-dimethylpyridin-3-yl]-2-(1H)-quinolinone and 48% HBr aqueous solution (5cm ³ ) was heated under reflux After 19 hours, it was diluted with water (20cm ³ ), basified to pH 7 with 5M NaOH solution, and extracted with CHCl ₃ (3 x 50cm ³ ). The concentrated and dried (MgSO ₄ ) CHCl ₃ extracts were evaporated in vacuo to give a solid which was recrystallized from CH ₃ COOC ₂ H ₅ to give 0.132 g of 8-hydroxy-6-[2,6-lutidine- 3-yl]-2-(1H)-quinolinone, mp 276-277°.

analyze%:

Actual values: C, 71.8; H, 5.4; N, 10.3

Calculated for C ₁₆ H ₁₄ N ₂ O ₂ :

C, 72.2; H, 5.3; N, 10.5

Example 99

In a similar manner to the previous examples, 8-methoxy-6-[2,6-dimethylpyridin-3-yl]-3,1-dihydro-2-(1H)-quinolinone was used, and 48% HBr as raw material to produce 8-hydroxy-6-[2,6-dimethylpyridin-3-yl]-3,4-dihydro-2-(1H)-quinolinone, m.p.178-185° .

analyze%:

Actual values: C, 69.8; H, 6.3; N, 9.4

Calculated for C ₁₆ H ₁₆ N ₂ O ₂ , 0.5H ₂ O:

C, 71.6; H, 6.0; N, 10.4

Example 100

In a similar manner to Example 98, with 8-methoxy-6-[1-methyl-1,2,4-triazol-5-yl]-2-(1H)-quinolinone, and 48 %HBr as raw material to produce 3-hydroxy-6-[1-methyl-1,2,4-triazol-5-yl]-2-(1H)-quinolinone, m.p.312-313°.

analyze%:

Actual values: C, 59.2; H, 4.1; N, 23.4

Calculated for C ₁₂ H ₁₀ N ₄ O ₂ :

C, 59.5; H, 4.2; N, 23.1

In the next preparation, the synthesis of new raw materials is described, and all temperatures are 0°C.

preparation 1

2-methoxy-6-bromoquinoline

A mixture of 2.90 g of 6-bromo-2-( _1H )-quinolinone and 2.10 g of trimethylzinctetrahydroboric acid was stirred under _nitrogen for 48 hours in 50 cm3 of ^CH2Cl2 . Add 10% NaOH aqueous solution (20cm ³ ), extract the aqueous phase with CH ₂ Cl ₂ (2×40cm ³ ), evaporate the dried (MgSO ₄ ) extract, and wash the residue with petroleum ether

(b.p. 60-80°) crystallization gave 2.16 g of 2-methoxy-6-bromoquinoline, m.p. 90-94°.

analyze%:

Actual values: C, 50.7; H, 3.5; N, 6.0

Calculated for C ₁₀ H ₈ NOBr:

C, 50.4; H, 3.4; N, 5.9

preparation 2

2-Methoxy-6-bromoquinoline (Alternative to Preparation 1)

A solution of 4.0 g of 2-nitrogen-6-bromoquinoline in methanol (20 cm ³ ), and CH ₃ ONa (prepared from 0.5 g of sodium and 20 cm ³ of methanol) were heated at reflux for 16 hours. The solvent was removed in vacuo and the residue partitioned between water (20cm ³ ) and CHCl ₃ (2 x 3cm ³ ) to extract the aqueous phase. The dried ( _MgSO₄ ) extract was evaporated to give a solid which was recrystallized from petroleum gas ether (bp 60-80°) to give 3.0 g of 2-methoxy-6-bromoquinoline, mp 93-96°.

analyze%:

Actual values: C: 50.4; H, 3.4; N, 6.0

Calculated for C ₁₀ H ₈ NOBr:

C, 50.4; H, 3.4; N, 5.9

Preparation 3-9

In a similar manner to Preparation 2, using the appropriate substituted 2-chloroquinoline derivatives, and CH ₃ ONa in methanolic methyl as starting materials, the following compounds were prepared:

Prepare 10

In a similar manner to Preparation 2, starting from 6-bromo-2-chloro-4,8-dimethylquinoline and CH ₃ ONa in methanol, 6-bromo-4,8-dimethyl-2- Methoxyquinoline, 0.25H ₂ O, mp 105°.

analyze%:

Actual values: C, 53.1; H, 4.4; N, 5.2

Calculated _{for C12H12BrNO} , _0.25H2O :

C, 53.2; H, 4.5; N, 5.2

Preparation 11

2-methoxy-8-methyl-6-(3-pyridyl)quinoline

At -70°, under nitrogen, tertiary butyllithium (8.0 cm ³ in 2.0 M solution in pentane) was gradually added to 2.0 g of 6-bromo-2-methoxy-8-methylquinoline in 20 cm ³ After 10 minutes in a stirred solution in THF, the mixture was treated with a solution of anhydrous _ZnCl₂ (1.09 g) in THF (10 ^cm³ ), and the resulting solution was warmed to 0°. A solution of 1.26 g of 3-bromopyridine and 0.05 g of palladium(triphenylphosphine)palladium(0) in THF (10 cm ³ ) was added and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled, concentrated in vacuo, and dissolved in CHCl _{3 .} (100cm ³ ) and a solution of ethylenediaminetetraacetic acid disodium salt (6 g) in water (100cm ³ ). The aqueous phase was re-extracted with CHCl ₃ (3 x 50 cm ³ ), and the pooled and dried (MgSO ₄ ) extracts were concentrated in vacuo to an oil. The oil was chromatographed on silica gel ("MK 60.9385" from Merck ₎ , extracted with _CH3COOC2H5 , pooled and _evaporated to give a solid, which was recrystallized from hexane to give 1.12 g 2-Methoxy-8-methyl-6-(3-pyridyl)quinoline, mp 117-118.5°.

analyze%:

Actual values: C, 76.5; H, 5.7; N, 11.0

Calculated for C ₁₆ H ₁₄ N ₂ O:

C, 76.8; H, 5.6; N, 11.2

Prepare 12-40

In a similar manner to the previous preparation, starting from the appropriate bromo-substituted heterocyclic moiety and the appropriate substituted 2-methoxyquinoline, the following compounds were prepared:

Preparation 41 (Alternative to Preparation 20)

8-methyl-6-(2,6-dimethylpyridin-3-yl]-2-methoxyquinoline 0.33H ₂ O

A solution of 0.935 g of 3-bromo-2,6-lutidine in 5 cm ³ THF was added dropwise to a stirred suspension of 0.133 g of magnesium wood and 0.05 g of iodine in 5 cm ³ THF under reflux. After 1 hour of heating, the magnesium was completely consumed. Cool to 0° while adding anhydrous ZnCl ₂ (0.680 g) in 4 cm ³ THF. After half an hour, a solution of 1.25 g of 6-bromo-8-methyl-2-methoxyquinoline and 0.05 g of tetrakis-(triphenylphosphine)palladium(0) in 10 ^cm THF was added and the mixture was refluxed Heat for 4 hours. The cooled mixture was partitioned between 100 cm ³ CHCl ₃ and a solution of 4 g of ethylenediaminetetraacetic acid disodium salt dissolved in 80 cm ³ water, the aqueous phase was extracted with CHCl ₃ (2×50 cm ³ ), pooled and dried Extraction (MgSO ₄ ) was evaporated in vacuo to give an oil which was chromatographed on silica gel ("MK 60.9385" from Merck) and extracted with chloroform CHCl ₃ . Concentration and evaporation of the appropriate fractions gave 1.04 g of an oil which was crystallized from hexane and powdered to give 8-methyl-6-[2,6-dimethylpyridin-3-yl]-2-methoxyquinoline _0.33H2O , mp 74-76°.

analyze%:

Actual values: C, 76.5; H, 6.4; N, 9.7

Calcd. for _C18H13N2 , _0.33H2O : C, 76.0 _; H, 6.6; N, _9.8

Preparation 42 (Alternative to Preparation 12)

2-methoxy-6-(3-pyridyl)-quinoline

At -100°, under nitrogen, tertiary butyllithium (7.7cm ³ of 2.6M solution in pentane) was added dropwise to a stirred solution of 1.44cm ³ 3-bromopyridine in 2525cm ³ THF within 5 minutes middle. After stirring for 10 minutes, a solution of 2.05 g of anhydrous _ZnCl2 dissolved in 20 ^cm3 of THF was added slowly, and the mixture was allowed to warm to room temperature for 1 hour. A solution of 2.38 g of 2-methoxy-6-bromoquinoline and 0.08 g of tetrakis(triphenylphosphine)palladium(0) in 10 ^cm³ of THF was added and the mixture was heated at reflux for 9 hours. Then 20 cm ³ of NH ₄ Cl solution was added, the mixture was concentrated in vacuo, the aqueous phase was extracted with CHCl ₃ (3 x 50 cm ³ ), and the dried (MgSO ₄ ) extract was evaporated in vacuo to give a solid which was deposited on silica gel (Merck "MK 60.9385") chromatographic analysis, eluting with 1:1 CH ₃ COOC ₂ H ₅ :C ₆ H ₁₄ to obtain a residue, which was recrystallized with petroleum ether (bp60-80°) ether to obtain 0.35 g 2-methoxy-6-(3-pyridyl)quinoline. mp89-91°.

analyze%:

Actual values: C, 76.4; H, 5.1; N, 11.6

Calculated for C ₁₅ H ₁₂ N ₂ O:

C, 76.2; H, 5.1; N, 11.9

Preparation 43-46

In a similar manner to the previous preparation, the appropriate bromopyridine and 6-bromo-3-cyano-2-methoxyquinoline (Preparations 43 and 44), or 6-bromo-2-methoxycarbonylquinoline ( Starting from Preparations 45 and 46), the following compounds were produced.

^* Preparations 43 and 45 produced stable complexes containing zinc chloride, whose structures were not clearly determined, and these substances were directly used in Examples 12 and 14.

Preparation 47

2-methoxy-6-(4-pyrimidinyl)quinoline

(2) pyrimidine

(3) KMnO ₄ /acetone

Add n-butyllithium (2.7cm ³ 1.5M solution in hexane) at -70°, under nitrogen oxygen, dropwise add 0.95 g of 2-methyl-6-bromoquinoline in 5cm ³ ether and stir in suspension. When all the solids had dissolved, a solution of 0.32 g of pyrimidine dissolved in 1 cm ^of diethyl ether was added dropwise to the resulting solution and allowed to warm to room temperature. Add 5 cm ³ of saturated NH ₄ Cl solution, extract the aqueous phase with CHCl ₃ (3 x 10 cm ³ ), and concentrate the dried (MgSO ₄ ) extract in vacuo to give an oil. Put the residue into acetone, add 0.63 g of _KMnO dissolved in acetone dropwise to treat it until a persistent purple color appears, filter it with "Solkafloc" (trade name), and concentrate it in vacuo to obtain an oily substance. It was analyzed by chromatography on silica gel (MK 60.9385 from Merck, and extracted _with 1:1 _CH3COOC2H5 / _C6H14 to _{obtain a solid} , which was _{recrystallized} with _CH3COOC2H5 to obtain 0.54 Grams of 2-methoxy-6-(4-pyrimidinyl)quinoline, mp 164-165°.

analyze%:

Actual values: C, 70.5; H, 5.0; N, 17.9

Calcd _{for C14H11N3O} : C, 70.9; H, 4.7; N, _17.7

Preparations 48 and 49

基）喹啉之混合物，以矽胶（Merck之“MK 60.9385”色层分析，以CH₃COOC₂H₅冲提之。Starting from 2-methoxy-6-lithium quinoline, the following compounds were prepared in a similar manner to the previous preparations. In this case, 2-methoxy-6-(4-pyrazinyl)quinoline and 2-methoxy-6-(3-pyrazinyl

Base) quinoline mixture, chromatographic analysis on silica gel (Merck "MK 60.9385" and extraction with CH ₃ COOC ₂ H ₅ .

Prepare 50

2-Methoxy-6-(pyrazin-2-yl)quinoline 1/4 hydrate

基）喹啉， 1/4 H₂O，m.P.130-132°。With tertiary butyllithium (4.6cm ³ , 2.6M solution in pentane) at -70°, under nitrogen, add 1.43 g of 2-methoxy-6-bromoquinoline dropwise in 10cm ³ THF and stir solution, after 20 minutes, add pyridine (0.43 g) in 5 ^cm³ of THF. After stirring for 20 minutes, a stream of dry air was bubbled through the solution at -70° for 0.5 hours and then allowed to warm to room temperature for 1 hour. Add 50 cm ^{3 of} CHCl ₃ , wash with 10 cm ³ of water, dry (MgSO ₄ ) and concentrate in vacuo to give a residue which is chromatographed on silica gel (Merck "MK 60.9385") and mixed with 1:1 CH ₃ COOC ₂ H ₅ : C ₆ H ₁₄ was extracted to obtain a solid, which was recrystallized with CH ₃ COOC ₂ H ₅ to obtain 0.22 g of 2-methoxy-6-(2-pyridine

base) quinoline, 1/4 H ₂ O, mP130-132°.

analyze%:

Actual values: C, 69.9; H, 4.6; N, 17.1

Calculated for C ₁₄ H ₁₁ N ₃ O, 1/4 H ₂ O:

C, 69.6; H, 4.8; N, 17.4

Preparation 51

3-cyano-6-bromo-2-(1H)-quinolinone

At room temperature, with a solution of 4.1 cm ³ dissolved in CH ₃ COOH (10 cm ³ ), treat a suspension of 13.3 g of 3-cyano-2-(1H)-quinolinone in 130 cm ³ of acetic acid, and heat it under reflux for 4 hours , the mixture was cooled to room temperature, filtered, and the solid was washed with ethanol to give 33-cyano-6-bromo-2-(1H)-quinolinone (14.63 g), which was recrystallized in a small amount from ethanol, mp308-311° .

analyze%:

Actual values: C, 48.6; H, 2.1; N, 11.4

Calculated for C ₁₀ H ₅ NOBr:

C, 48.2; H, 2.0; N, 11.3

Preparation 52

6-Bromo-3-cyano-2-methoxyquinoline

Under nitrogen, a suspension of 1.46 g of 6-bromo-3-cyano-2-(1H)-quinolinone in 150 cm ³ CH ₂ Cl ₂ , and 10.55 g of trimethylzinc tetrafluoroborate The mixture was stirred for 2 days. Add 2M NaOH solution (100cm ³ ), extract the aqueous phase with CH ₂ Cl ₂ (3×200cm ³ ), concentrate the dried (MgSO ₄ ) extract in vacuo, and analyze the residue by chromatography on silica gel (Merck "MK 60.9385") , extracted with 4:1 C ₆ H ₁₄ /CH ₃ COOC ₂ H ₅ to obtain a solid, which was recrystallized with CH ₃ COOC ₂ H ₅ to obtain 1.96 g of 6-bromo-3-cyano-2-methoxy Quinoline, mp169-172°.

analyze%:

Actual values: C, 50.4; H, 2.8; N, 10.8

_{Calcd for C11H7N2OBr2} : C, 50.2; H, 2.7; N _, 10.7

Preparation 53

2-Chloro-6-bromo-3-cyano-quinoline

6-Bromo-3-cyano-2-(1H)-quinolinone (142 g) was heated at reflux in 500 cm ³ of phosphorus cyanide chloride for 1.5 hours, the evaporation was removed in vacuo, and the remaining solid was taken up in CHCl ₃ ( 400cm ³ ), the resulting slurry was poured into ice, the mixture was neutralized with aqueous NH ₃ (SG0.880), the aqueous phase was extracted with CHCl ₃ (2×150cm ³ ), and the dried (MgSO ₄ ) organic The extract, the residue was chromatographed on silica gel (Merck "MK 60.9385"), eluting with toluene to give a solid, which _{was recrystallized} with _CH3COOC2H5 to give 80 g of 2-chloro-6-bromo-3 -Cyano-quinoline, mp 228-230°.

analyze%:

Actual values: C, 44.6; H, 1.5; N, 10.6

Calculated for C ₁₀ H ₅ ClBrN ₂ :

C, 44.9; H, 1.5; N, 10.5

Preparation 54 (Alternative to Preparation 52)

6-Bromo-3-cyano-2-methoxyquinoline

A solution of 1.2 g of 6-bromo-2-chloro- ^3- cyano-quinoline in 30 cm of methanol and CH ₃ ONa (prepared from 0.116 g of sodium and ²⁰ cm of methanol) was heated under reflux for 16 hours, and the mixture was cooled to 0°C. The solid was filtered to give 0.60 g of 6-bromo-3-cyano-2-methoxyquinoline, mp 172-174°.

analyze%:

Actual values: C, 49.8; H, 2.8; N, 10.4

Calculated for C ₁₁ H ₇ N ₂ OBr:

C, 50.2; H, 2.7; N, 10.7

Preparation 55

6-Bromo-2-methoxy-3-methoxycarbonyl-quinoline was prepared from 6-bromo-2-chloro-3-methoxycarbonylpyridine in a similar manner to the previous preparation, m.p.

analyze%:

Actual values: C, 49.0; H, 3.5; N, 5.1

Calculated for C ₁₂ H ₁₀ BrNO ₃ :

C, 48.7; H, 3.4; N, 4.7

Preparation 56

6-Bromo-2-(1H)-quinolinone-3-carboxylic acid

A stirred solution of 4.5 g of ³ -ethoxycarbonyl-2-(1H)-quinolinone in 50 cm of acetic acid was treated with a solution of 16 g of bromine in 20 cm ^of _CH3COOH at room temperature, and the mixture was heated at reflux for 24 hours and cooled. And filtered to obtain 3.42 g of 6-bromo-2-(1H)-quinolinone-3-carboxylic acid as a crude solid, mp > 300°.

Preparation 57

6-Bromo-2-chloro-3-methoxycarbonylquinoline

A stirred suspension of phosphorus oxychloride ( ^40cm³ ) in 6-bromo-2-(1H)-quinolinone-3-carboxylic acid (3.4g) was heated at reflux for 2 hours. The mixture was cooled and evaporated to dryness in vacuo. Treat the solid residue with methanol (50cm ³ ) at 0°, and after stirring at room temperature for 2 hours, filter the mixture and wash the solid with methanol to give 6-bromo-2-chloro-3-methoxycarbonylquinoline, mp176-177 ° (1.82 grams).

analyze%:

Actual values: C, 44.0; H, 2.3; N, 4.7

Calcd _{for C11H7BrClNO2} : C, 44.0; H, 2.3; N _, 4.7

Preparation 58

6-iodo-2-(1H)-quinolinone

A solution of 2.0 g of 2-(1H)-quinolinone and _2.14 g of _Ag₂SO₄ in 15.0 cm of ^concentrated sulfuric acid was stirred at room temperature during the addition of iodine (3.5 g). After heating to 50° for 24 hours, the mixture was poured into ice, the solution was neutralized with Na ₂ CO ₃ solid, the solid was filtered, chromatographed on silica gel (Merck, MK 60.9385) and extracted with CHCl ₃ , to obtain a residue, which was recrystallized from methanol to give 6-iodo-2-[1H]-quinolinone, mp 261°, (0.8 g).

analyze%:

Actual values: C, 41.0; H, 2.4; N, 5.5

Calculated value for C ₉ H ₆ INO:

C, 39.9; H, 2.2; N, 5.2

Preparation 59

6-Bromo-2-chloro-8-methylquinoline

A mixture of 12.0 g of 6-bromo-8-methyl-2-(1H)-quinolinone in POCl ₃ (100 cm ³ ) was heated at reflux for 2 hours, the evaporated material was removed in vacuo and the residue was dissolved in CHCl ₃ (200 cm ³ ). , the resulting solution was poured into 200 g of ice, basified with NH ₃ aqueous solution (SG0.88) to pH 10, the aqueous phase was extracted with CHCl ₃ (2×100 cm ³ ), the concentrated and dried (MgSO ₄ ) extract The product was concentrated in vacuo to obtain 10.7 g of solid, which was recrystallized from ethanol to obtain 6-bromo-2-chloro-8-methyl-quinoline, mp 114-116°.

analyze%:

Actual values: C, 47.2; H, 2.7; N, 5.8

Calculated for C ₁₀ H ₇ BrClN:

C, 46.8; H, 2.7; N, 5.5

Prepare 60-65

In a similar manner to the previous preparations, a 1.0:1.7 mixture of 5-bromo-2-(1H)-quinolinone and 7-bromo-2-(1H)-quinolinone (preparations 60 and 61); and 1.0 : 2.3 mixture of 6-bromo-5-methyl-2-(1H)-quinolinone and 6-bromo-7-methyl-2-(1H)-quinolinone (preparation 62), 6-iodo- 8-Ethyl-2-(1H)-quinolinone (Preparation 63), 6-iodo-8-[propan-2-yl]-2-(1H)-quinolinone (Preparation 64), and 6- Bromo-8-methoxy-2-(1H)-quinolinone (Preparation 65), and starting from _POCl3 , the following compounds were prepared:

Preparation 66

Starting from 6-bromo-4,8-dimethyl-2-(1H)-quinolinone and POCI ₃ in an analogous manner to that of 59, 6-bromo-2-chloro-2,4-dimethyl Quinoline, mp 182°.

analyze%:

Actual values: C, 48.3; H, 3.3; N, 5.3

Calculated for C ₁₁ H ₉ BrClN:

C, 48.3; H, 3.3; N, 5.2

Preparation 67

6-Bromo-8-methyl-2-(1H)-quinolinone

Trans-N-(4-bromo-2-methylphenyl)-3-ethoxypropenylamine (2.0 g) was added little by little to 98% H ₂ SO ₄ (15 cm ³ ) at room temperature, and After stirring, it was poured into ice (100 cm ³ ) for 16 hours and the resulting precipitate was filtered, dried (1.5 g) and recrystallized from CH ₃ COOC ₂ H ₅ /CH ₃ OH to give 6-bromo-8 -Methyl-2-(1H)-quinolinone, mp 272-274°.

analyze%:

Actual values: C, 50.4; H, 3.4; N, 6.1

Calcd _{for C10H8NOBr} : C, 50.4; H, 3.4; N, 5.9

Preparation 68-75

In a similar manner to the previous preparation, trans-N-(3-bromophenyl)-3-ethoxyacrylamide (Preparations 68 and 69), trans-N-(4-bromo-3-methylphenyl)- 3-Ethoxy-acrylamide (Preparations 70 and 71), trans-N-(4-iodophenyl)-3-ethoxyacrylamide-Preparation 72), trans-N-iodo-2-ethylphenyl )-3-ethoxyacrylamide (Preparation 73), trans-N-(4-iodo-2-[propan-2-yl]-phenyl)-3-ethoxyacrylamide (Preparation 74), and Trans-N-(4-bromo _- 2-methoxyphenyl)-3-ethoxyacrylamide (Preparation 75), and 98% _H2SO4 as starting materials, the following compounds were prepared:

Preparation 76

6-Bromo-4,8-dimethyl-2-(1H)-quinolinone

N-[ ₄ -Bromo-2-methylphenyl]-acetylacetamide (18 g) was heated and stirred at 100°C in 98% H ₂ SO 4 . The cooled mixture was poured into 200 g of ice, the solid was filtered and dried in vacuo at 100° for 2 hours to give 15.0 g of crude product. A small amount (1.5 g) of the product was recrystallized from CH ₃ COOC ₂ H ₅ /CH ₃ OH The material yielded 1.1 g of 6-bromo-4,8-dimethyl-2-(1H)-quinolinone, mp>300°.

analyze%:

Actual values: C, 52.0; H, 4.1; N, 5.5

Calculated for C ₁₁ H ₁₀ BrNO:

C, 52.4; H, 4.0; N, 5.6

Preparation 77

N-[4-bromo-2-methylphenyl]-acetylacetamide

A mixture of 25 g of 4-bromo-2-methylaniline and 11.8 cm ³ dienone in 100 cm ³ was stirred and heated under reflux for 5 hours, cooled to room temperature, and the precipitated solid was filtered and washed with C ₆ H ₁₄ /CH ₃ COOC ₂ Recrystallization from _H5 gave 14.0 g of N-[4-bromo-2-methylphenyl]-acetylacetamide, mp 109°.

analyze%:

Actual values: C, 48.5; H, 4.4; N, 5.4

Calculated for C ₁₁ H ₁₂ BrNO ₂ :

C, 48.9; H, 4.5; N, 5.2

Preparation 78

trans-N-(4-bromo-2-methylphenyl)-3-ethoxyacrylamide

At 0°, trans-3-ethoxyacryloyl chloride (0.74 g) was added to 0.93 g of 4-bromo-2-methylaniline in a stirred solution dissolved in 10 cm ³ of pyridine, and 40 cm ³ of water was added after 5 hours. The solid was filtered, washed with water (30cm ³ ) and dried, recrystallized from CH ₃ COOC ₂ H ₆ to obtain 1.3 g of trans-N-(4-bromo-2-methylbenzene)-3-ethoxyacrylamide, mp163-164°.

analyze%:

Actual values: C, 50.7; H, 5.0; N, 5.1

Calculated for C ₁₂ H ₁₄ NO ₂ Br:

C, 50.7; H, 5.0; N, 4.9

Preparation 79-85

Starting from the appropriate substituted aniline and trans-3-ethoxyacryloyl chloride, the following compounds were prepared analogously to the previous preparations:

Preparation 86

4-iodo-2-[propan-2-yl]-aniline

ICI (12.9 cm ³ ) was added to a stirred solution of 27.0 g 2-[prop-2-yl]aniline and 16.4 g CH ₃ COONa in 250 cm ³ CH ₃ COOH at room temperature. After 1 hour, the volatiles were removed in vacuo, the residue was partitioned between 200 cm ³ CHCOOC ₂ H ₅ and 50 cm ³ of 10% Na ₂ CO ₃ solution, filtered through the dried (MgSO ₄ ) organic extract, and evaporated in vacuo. The resulting oil was analyzed by chromatography on silica gel (Merck "MK 60.9385") and extracted with hexane. Fractions containing product were pooled and evaporated to give the crude product (38 g) as a dark unstable oil which was not fully characterized but was used directly in the preparation of 84.

Preparation 87

Starting from 2-ethylaniline, 4-iodo-2-ethylaniline (crude oil) was prepared similarly to the previous preparation (4-bromo-2-methoxyaniline is a known compound).

Preparation 88

6-cyano-2-methoxyquinoline

A mixture of 0.476 g of 6-bromo-2-methoxyquinoline, 0.26 g of KCN, 0.05 mg of KOH and 0.067 g of ( _CH3COO ) _2Pd in ^2.0cm3 of DMF was heated at 135° for 3 hours, and the cooled solution Partition between 20 cm ³ water and 50 cm ³ CHCl, extract the aqueous phase with CHCl ₃ (2 x 25 cm ³ ), evaporate the pooled and dried (MgSO ₄ ) extracts in vacuo, and dissolve on silica gel (Merck "MK 60.938"). Layer analysis, eluting with toluene, collecting and evaporating appropriate fractions gave 0.216 g of 6-cyano-2-methoxyquinoline, mp 163-165°.

analyze%:

Actual values: C, 71.7; H, 4.4; N, 14.8

Calculated for C ₁₁ H ₈ N ₂ O:

C, 71.4; H, 4.4; N, 15.2

Preparation 89

2-methoxy-6-(1-tributyltinyl-(1H)-tetrazol-5-yl)quinoline

6-cyano-2-methoxyquinoline (0.368 g) and 0.73 g of tri-n-butyltin azide were heated together at 110° for 18 hours to give crude oil 2-methoxy-6-(1-tri Butylstannyl-(1H)-tetrazol-5-yl)quinoline, which was used directly without further purification to prepare 6-(tetrazol-5-yl)-2-(1H)-quinolinone (see Implementation Example 43).

Prepare 90

2-methoxy-6-(1-butyl-(1H)-tetrazol-5-yl)quinoline and

2-methoxy-6-(2-butyl-(2H)-tetrazol-5-yl)quinoline

0.368 gram of 6-cyano-2-methoxyquinoline and 0.73 gram of tri-n-butyltin azide were heated together for 18 hours at 120°, the mixture was cooled to 100°, 0.42 gram of n-butyl iodide was added, and the reaction mixture was stirred After 3 hours, the residue was partitioned between 20 cm ³ CH ₃ CN and 20 cm ³ C ₆ H ₁₄ , and the CH ₃ CN layer was concentrated in vacuo to give an oil, which was chromatographed on silica gel (Merck MK 60.9385) to obtain _CH2Cl2 was extracted first ( _CHCl3 / _CH3OH 19:1, R _F 0.75;) as 2-methoxy-6-(2-butyl-(2H) _- Tetrazol-5-yl)quinoline (0.087 g), the second (CHCl ₃ :CH ₃ OH 19:1, _RF 0.62) was 2-methoxy-6-(1 -Butyl-(1H)-tetrazol-5-yl)-quinoline (0.30 g) These compounds were used in Examples 44 and 45 without further purification.

Preparation 91

6-Bromo-4-methyl-3,4-dihydro-2-(1H)-quinolinone

A solution of 0.08 cm ³ bromine in 1 cm ³ CH ₃ COOH was added to a stirred solution of 0.5 g 4-methyl-3,4-dihydro-2-(1H)-quinolinone in 4.0 cm ³ acetic acid at room temperature for 2 hours Volatiles were removed in vacuo, the residue was then partitioned between 50 cm ³ CHCl ₃ and 20 cm ³ water, the organic phase was extracted with CHCl ₃ (2 x 20 cm ³ ), the pooled and dried (MgSO ₄ ) organic extracts were vacuum Evaporation and recrystallization of the residue from CH ₃ COOC ₂ H ₅ gave 0.35 g of 6-bromo-4-methyl-3,4-dihydro-2-(1H)-quinolinone, mp 190°.

analyze%:

Actual values: C, 50.2; H, 4.2; N, 6.0

Calculated for C ₁₀ H ₁₀ BrNO:

C, 50.0; H, 4.2; N, 5.8

6-Bromo-3,4-dihydro-2-(1H)-quinolinone is a known compound.

Preparation 92

6-iodo-3-nitro-2-(1H)-quinolinone

In o-xylene, a stirred mixture of 2.0 g of 2-amino-5-iodobenzaldehyde, 4.2 g of ethyl nitroacetate, and 0.7 g of piperidine was heated at reflux for 1.5 hours, and the cooled solution was concentrated in vacuo and washed with chloroform The residual solid was recrystallized from isopropanol to give 1.14 g of 6-iodo-3-nitro-2-(1H)-quinolinone, m.p. 279-282°.

analyze%:

Actual values: C, 34.6; H, 1.7; N, 8.6

Calculated for C ₉ H ₅ INO ₃ :

C, 34.2; H, 1.6; N, 8.9

Preparation 93

2-Amino-5-iodobenzaldehyde hemihydrate

0.044 g of MnO ₂ was added to a solution of 0.125 g of 2-amino-5-bromobenzyl alcohol in 10 cm ³ CH ₂ CI ₂ . The mixture was stirred for 16 hours, and then 0.44 g of _MnO2 was added. Stirring was continued for 16 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel (Merck "MK 60.9385"), eluting with _CH3COOC2H5 , and the _necessary fractions were collected and condensed by vacuum filtration to yield 0.1 g _of 2-amino -5-iodobenzaldehyde 0.5H ₂ O intermediate, m, p, 105°.

analyze%:

Actual values: C, 33.0; H, 2.4; N, 6.1

Calculated for C ₇ H ₆ INO ₂ , 0.5H ₂ O:

C, 32.8; H, 2.5; N, 5.5

Preparation 94

2-Amino-5-silylbenzyl alcohol

At -30°, under nitrogen, diisobutylaluminum hydride (210cm ³ dissolved in THF 1.5M solution) was added to 28.0 g-2 amino-5-iodobenzoic acid ester dissolved in 100cm ³ THF stirring solution, the The mixture was warmed to room temperature, stirred for 16 hours and treated with 35 cm ³ methanol, 500 cm ³ CH ₃ COOC ₂ H ₅ was added, the mixture was filtered to remove inorganics, and the filtrate was concentrated in vacuo to give a solid, which was dissolved in silica gel (Merck "MK60, 9385" ) chromatography, eluting with 49:1 (volume ratio) of CHCI ₃ :CH ₃ OH, collecting the necessary fractions and evaporating in vacuo to give 19.0 g of 2-amino-5-iodobenzyl alcohol, m, p, 125°.

Sub-fold%:

Actual values: C, 34.4; H, 3.2; N, 6.0

Calcd _{for C17H8NO} : C, 33.8; H, 3.2; N, 5.6

Equipment value:

2-Methoxyquinoline-6-carboxylic acid

Under hydrogen at -70°, n-butyllithium (63cm ³ dissolved in 1.6M solution in hexane) was added dropwise to a stirred solution of 20 g of 6-bromo-2-methoxyquinoline dissolved in 250cm ³ THF, 0.5 hours later. Add 50 g of dry ice, warm the solution to room temperature, remove volatiles in vacuo, partition the residue between 100 cm ³ CHCl ₃ and 100 cm ³ water, separate the aqueous phase, and acidify to pH 3.5 with 5M HCl, filter the precipitated solid and dried (14.2 g), a small amount of which was recrystallized from isopropanol to give 2-methoxyquinoline-6-carboxylic acid,

m, p, 220-222°.

Sub-fold%:

Actual values: C, 65.1; H, 4.5; N, 7.9

_{Calcd for C11H9NO3} : C, 65.0; 4.5; N, 6.9

Preparation 96-100

From appropriately substituted 6-bromo- or 6-iodo-2-methoxyquinolines, n-BuLI and _CO2 , the following compounds were prepared in a similar fashion.

Preparation 101

2-Methoxyquinoline-6-carboxylic acid amide

Oxalyl chloride (10.3 cm ³ ) was added dropwise at 0° to a stirred solution of 12.0 g of 2-methoxyquinoline-6-carboxylic acid dissolved in 100 cm ³ CH ₂ CI ₂ and 0.1 g of DMF, and the mixture was heated to room temperature, After 2 hours, the volatile substrate was removed in vacuo, the residue was placed in 100 cm ³ CH ₂ CI ₂ , cooled to 0°, carefully treated with 30 cm ³ aqueous NH ₃ (SC 0.88), and the mixture was vacuum filtered after 2 hours. . The solid residue was recrystallized from isopropanol, yielding 7.9 g of 2-methoxyquinoline-6-carboxylic acid amide, m, p, 212-214.

Sub-fold%:

Actual values: C, 65.0; 5.0; N, 13.8

_{Calcd for C11H10N2O2} : C, 65.3; H _, 5.0; N, 13.9

Preparation 102-106

From oxalyl chloride, suitably substituted 2-methoxyquinoline-6-carboxylic acids and nitrogen, the following compounds were prepared in analogy to the previous preparations:

Preparation 107

2-Methoxyquinoline-6-[dimethylaminomethylene]carboxamide

胺，m，p，192-195°。A mixture of 3.0 g of 2-methoxyquinoline-6-carboxylic acid amide and 6.0 cm ³ of N,N-dimethylamine dimethyl acetal was heated at 120° for 1.5 hours. After standing at room temperature for 16, the crystalline product was filtered, washed with hexane and dried to give 3.78 g of 2-methoxyquinoline-6-(N-[dimethyl-aminoylidene)carboxylic acid

Amines, m, p, 192-195°.

Sub-fold%:

Actual values: c, 65.5; H, 5.9; N, 16.2

_{Calcd for C14H15N3O2} : C, 65.4; _H , 5.8; N, 16.3

Preparation 108-112

From the appropriate substituted 2-methoxyquinoline-6 carboxylic acid amide and N'-dimethylformamide aldehyde in analogy to the previous preparation, the following compounds were prepared:

Preparation 113

2-methoxy-6-[(1H)-1,2,4-triazol-5-yl]quinoline

A mixture of 1.0 g of 2-methoxyquinoline-6-(N-[dimethylaminomethylene])carboxamide and hydrazine hydrate (0.208 cm ³ ) was stirred at 90° in glacial acetic acid After 1.5 hours, the volatiles were removed in _vacuo , and the residue was chromatographed on silica gel (Merck "MK 60.60.9385"), eluting with _CH3COOC2H5 : _{CH3OH 49} :1 (volume ratio) , pooled and evaporated the desired fractions to give 0.811 g of 2-methoxy-6-[(1H)-1,2,4-triazol-5-yl]quinoline, mp 198-200°.

analyze%:

Actual values: C, 63.8; H, 4.5; N, 24.8

Calculated for C ₁₂ H ₁₀ N ₄ O:

C, 63.7; H, 4.4; N, 24.8

Preparation 114-122

In a similar manner to the previous preparation, from the appropriate substituted 2-methoxyquinoline-6-(N-[dimethylaminomethylene])carboxylic acid amide, and hydrazine hydrate (Preparation 114), or methyl Hydrazine (Preparations 115-122) to prepare the following compounds:

The resulting mixture of regioisomers in preparations 116 and 117 was chromatographed on silica gel (Merck "MK 60.9385") and separated by eluting with ether. The major isomer, with an R _F in ethyl acetate of 0.8, was first eluted (Preparation 116) and a minor product with an R _F of ethyl acetate of 0.28 was subsequently eluted (Preparation 117).

The mixture of regioisomers obtained in preparations 118 and 119 was separated by chromatography on silica gel (Merck "MK 60.9385") and eluted with 1:1 hexane:ether to give the major isomer ( Preparation 119), a small amount of product was extracted from Guan Gui with CH ₃ COOC ₂ H ₅ .

Preparation 123

2-methoxy-6-(1,2,4-oxadiazol-5-yl)piperoline

5M NaOH solution (0.94 cm ³ ) was added to a solution of 0.325 g of hydroxylamine chloride in 3 cm ³ of water and 7 cm ³ of CH ₃ COOH. Add 1.0 g of 2-methoxyquinoline-6-N-([dimethylaminomethylene]) carboxylic acid amide, stir the mixture for 10 minutes, add 10 ^cm of water, keep the solution at 0 ° for 1 hour, and the precipitate Filter, place in dioxane (5cm ³ ) and acetic acid (5cm ³ ), heat at 90° for 1.5 hours, treat the cooled solution with 10cm ³ of water, filter the precipitate, and put it on silica gel (Merck "MK 60.9385") Chromatography, eluting with _CH2Cl2 , pooling and evaporating the desired fractions in vacuo gave 0.537 g of _a solid. A small amount of solid was recrystallized from CH ₃ COOC ₂ H ₅ to give 2-methoxy-6-(1,2,4-oxadiazol-5-yl)quinoline, mp 150-152°.

analyze%:

Actual values: C, 63.3; H, 4.0; N, 18.6

Calculated for C ₁₂ H ₉ N ₃ O ₂ :

C, 63.4; H, 4.0; N, 18.5

Preparation 124

6-[1-methyl-(1H)-imidazol-2-yl]-2-methoxyquinoline

Under -45° nitrogen, add n-butyllithium (9cm ³ 1.6M solution in hexane) to 1.03cm ³ 1-methyl-(1H)-imidazole in 30cm ³ THF stirring solution, 1.25 After 1 hour, a solution of 1.95 g of anhydrous ZnCl ₂ dissolved in 30 cm ³ THF was added dropwise over 5 minutes to obtain a white precipitate. The mixture was heated to room temperature, 3 g of 6-bromo-2-methoxyquinoline and 0.2 g of tetrakis(triphenylphosphine) palladium (O) dissolved in 20 ^cm THF were added, and heated under reflux for 16 hours, and ² cm saturated NH ₄ Cl solution, the reaction mixture was concentrated in vacuo, and the residue was partitioned between 100 cm ³ CHCl ₃ and a solution of 10 g of ethylenediaminetetraacetic acid disodium salt dissolved in 100 cm ³ water, CHCl ₃ (2×50 cm ³ ) The aqueous phase was extracted and the pooled and dried (MgSO ₄ ) extract was evaporated in vacuo to give a solid which was chromatographed on silica gel (Merck "MK 60.9385") with CHCl ₃ :CH 19:1 (volume ratio). ₃ OH was extracted, and the required fraction was concentrated and evaporated in vacuo to obtain a foam, which was recrystallized from CH ₃ COOC ₂ H ₅ /C ₆ H ₁₄ to obtain 0.517 g of 6-[1-methyl-(1H)- Imidazol-2-yl]-2-methoxyquinoline, mp 116.5-118.5°.

analyze%:

Actual values: C, 70.3; H, 5.5; N, 17.4

Calculated for C ₁₄ H ₁₃ N ₃ O:

C, 70.3; H, 5.5; N, 17.5

Preparation 125

Similar to the previous preparation, using 1-methyl-(1H)-imidazole, tetrakis(triphenylphosphine)palladium(O) and 6-bromo-2-methoxy-8-methylquinoline as starting materials, synthesized 6-(1-Methyl-(1H)-imidazol-2-yl)-2-methoxy-8-methylquinoline hemihydrate, m.p. 158-161°.

analyze%:

Actual values: C, 68.4; H, 5.8; N, 15.8

Calculated for C ₁₅ H ₁₅ N ₃ O, 1/2 H ₂ O:

C, 68.7; H, 6.1; N, 16.0

Preparation 126

6-[1-methyl-(1H)-imidazol-5-yl]-2-methoxy-3-methylquinoline

At -70°, under nitrogen, add tert-butyllithium (11.9cm ³ 2.0M solution in pentane) to 0.95cm ³ 1-methyl-(1H)-imidazole in 3cm ³ THF stirring solution . After 10 minutes, the mixture was heated to 0°, continued to stir for 1 hour, then added a solution of 6.25 g of anhydrous ZnCl ₂ dissolved in 45 cm ³ THF, stirred for another 1 hour, added 1.0 g of 6-bromo-2-methoxy- 8-Methylquinoline, and 0.04 g of tetrakis(triphenylphosphine) palladium (O), the mixture was heated under reflux for 18 hours, and the cooled mixture was concentrated in vacuo and distributed between 200 cm ³ CHCl ₃ and 50 g of ethylenediamine Dissodium tetraacetate was dissolved in 250 cm ³ of water, the aqueous phase was extracted with CHCl ₃ (2 x 100 cm ³ ), the concentrated and dried (MgSO ₄ ) extract was evaporated to give a solid, which was deposited on silica gel (Merck "MK 60.9385") chromatographic analysis, eluting with CHCl ₃ , collecting and evaporating the appropriate fractions gave ( _Rf 0.32 in CHCl ₃ ) 0.37 g of 6-[1-methyl-(1H)-imidazole-2- Base] -2-methoxy-8-methylquinoline, mp160-162°. Add the same product as the preparation 125, the second one (R _f in _CHCl3 is 0.26) is 6-[1-methyl-(1H)-imidazol-5-yl]-2-methoxy-8-methylquinone Phenoline, mp 174-175°.

analyze%:

Actual values: C, 71.2; H, 6.0; N, 16.2

Calcd _{for C15H15N3} : C, 71.1; _H , 6.0; N, 16.6

Claims (17)

1, a kind of manufacture chemical formula (I)

or acceptable salts thereof, wherein "Het" is any substituted 5- or 6-membered carbon atom connected to the 5-, 6-, 7- or 8-position of the quinolinone Monocyclic aromatic heterocyclic group; R attached to the 5-, 6-, 7- or 8-position, hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkane Thio, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, halo, CF ₃ , hydroxyl, hydroxymethyl, or cyano; R ¹ is hydrogen, cyano, (C ₁ -C ₄ alkoxy)carbonyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl, nitro, halo, -NR ³ R ⁴ or CONR ³ R ⁴ , wherein R ³ and R ⁴ are respectively H or C ₁ -C ₄ alkyl, or together with a nitrogen atom to form a saturated 5- or 6-membered heterocyclic group, which may contain one selected from O, S and NR ⁵ (R ⁵ is hydrogen or C ₁ -C ₄ alkyl) heteroatom or group; R ² is hydrogen, C ₁ -C ₄ alkyl, or 2-hydroxyethyl; Y is H or C ₁ -C ₄ alkyl; 3- and 4- A dotted line between them indicates whether it can or cannot be a key. Its characteristics are: the compound of chemical formula (II) is demethylated,

wherein R, R ¹ , Het, Y and the dashed line are as defined above to form a compound of formula (I) in which R ² is H, followed by optionally one or more of the following steps: (a) Convert the -COOH group at the 3-position to -COO(C ₁ -C ₄ alkyl) by esterification; (b) Reductive conversion of the nitroester represented by ^R1 into an amine group; (c) the hydrogen atom represented by ^R1 is converted into Cl, Br or I by halogenation; (d) Oxidize the nitrogen-containing heterocyclic ring represented by "Het" to N-oxide by using a peroxyacid oxidizing agent; (e) With the help of a strong base, it is reacted with C ₁ -C ₄ alkyl halides or bis(C ₁ -C ₄ ) alkyl sulfate, or 2-hydroxyethyl halide, and the hydrogen atom represented by R ² Converted to C ₁ -C ₄ alkyl, or 2-hydroxyethyl; (f) by catalytic hydrogenation, the product of formula (I) having a double bond between the 3- and 4-positions is converted into a 3,4-dihydro derivative; (g) in the presence of AG ₂ SO ₄ and concentrated H ₂ SO ₄ , react with chlorine, bromine or iodine respectively, and will be represented by R at the 8-position of the chemical formula (I) of 3,4-dihydroquinolinone The hydrogen atom is converted into Cl, Br or I; (h) in CH ₃ COOH, make the 3,4-dihydro product of chemical formula (I) react with bromine and sodium sulfonate to convert into the chemical formula (I) having a double bond between the 3- and 4-positions compound; (i) In the presence of a Cu(I) catalyst, react with a salt of C ₁ -C ₄ alkylthio to convert the 8-position halogen atom into a C ₁ -C ₄ alkylthio; (j) Convert the C ₁ -C 4 alkylthio group represented by R into C ₁ -C ₄ alkylsulfinyl or C _{1 -C 4} alkane by means of an appropriate organic oxygen acid or sodium metaperiodate reaction Sulfonyl; (k) demethylating the C ₁ -C ₄ alkoxy group represented by R with an inorganic acid and converting it into a hydroxyl group; (1) first react with C ₁ -C ₄ alkyllithium and then react with formaldehyde, R is Cl, Br or I, and the compound at the 8-position of the chemical formula (I) is converted into R as a hydroxymethyl group; (m) reacting with a suitable acid to convert the product of formula (I) into a pharmaceutically acceptable acid addition salt; and (n) reacting with a suitable base to convert the product of formula (I) into a metal salt. 2. The method as claimed in claim 1, wherein the characteristic is that the demethylation system uses an inorganic acid. 3. The method as claimed in claim 2, characterized in that: demethylation is carried out by using HBr aqueous solution, HCl aqueous solution, or ethanol containing 5-15% volume ratio of HBr aqueous solution. 4. The method according to claims 1 to 3, characterized in that it is carried out at a temperature ranging from room temperature to the reflux temperature of the solution. 5. A process for producing a compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof. Its characteristics are: in the presence of a catalyst of chemical formula Pd(PPh ₃ ) ₄ , the compound of chemical formula (Ⅲ): Wherein R R ¹ R ² Y and the dashed line are as defined in claim 1, and Q is a hetero group; And the chemical formula is the compound of Het-Zn-Cl, wherein "Het" is as defined in claim 1; the method can optionally be one or more steps of steps (a) to (h) as defined in claim 1. 6. The method according to claim 5, characterized in that it is carried out in an organic solvent at a temperature between room temperature and the reflux temperature of the material, and Q is Cl, Br or I. 7. A method for producing the compound of chemical formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, which is characterized in that the compound of chemical formula (IV) is cyclized:

wherein "Het" and R are as defined in claim 1, and Q is a hetero group, thus forming a compound of formula (I), wherein R ¹ , R ² and Y are H, which can optionally be defined in the claims section One or more steps of (a) and (c) to (n). 8. The method according to claim 7, characterized in that Q is methoxy or ethoxy, and the cyclization is carried out with concentrated sulfuric acid. 9. The method according to claims 1 to 6, characterized in that: R is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, C ₁ - C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfinyl, halo, CF ₃ , hydroxy or hydroxymethyl. 10. The method according to claim 9, characterized in that: R is connected to the 7- or 8-position, and is H, C ₁ -C ₄ alkyl, methoxy, methylthio, methylsulfinyl , methylsulfonyl, bromo, hydroxy, or hydroxymethyl; R ¹ is H, cyano, methoxycarbonyl, nitro, bromo or amine; R ² is H or CH ₃ ; "Het" is connected to 5- , 6- or 7-position, is pyridyl, its N-oxide, pyrimidyl, pyridazinyl, pyrazinyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,

Azolyl, thienyl or furyl, all optionally substituted by 1 or 2 substituents selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, cyano, amino and carbamoyl Those; there is a double bond between the 3- and 4-positions; and Y is H or CH ₃ . 11. The method as claimed in claim 10, characterized in that: "Het" is selected from (a) optionally replaced by 1 or 2 methyl groups, or replaced by a single methoxy group, cyano group, amino group or carbamoyl group Substituted pyridyl, (b) pyridyl N-oxide, (c) pyrimidinyl, (d) pyridazinyl, (e) pyridyl

base, (f) triazolyl or N-methyltriazolyl, (g) tetrazolyl or N-(n-butyl)-tetrazolyl, (h) N-methylimidazolyl, (i)

Diazozolyl, (j) imidhienyl, (k) thienyl or (l) furyl. 12. The method as claimed in claim 11, characterized in that it is used to produce the compound of formula (IA):

Wherein "Het" is as defined in claim 11. and R is as defined in claim 10. 13. The method according to claims 1 to 6, which is characterized in that it is used to produce the compound of chemical formula (I), or its pharmaceutically acceptable salts, wherein "Het" is any carbon atom attached to the Quinolinone 5-, 6-, 7- or 8-substituted 5- or 6-membered monocyclic aromatic heterocyclic group; R connected to 5-, 6-, 7- or 8-position, is H, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; R ¹ is hydrogen, cyano, (C ₁ -C ₄ alkoxy) carbonyl, C ₁ -C ₄ alkyl, -NR ³ R ⁴ or -CONR ³ R ⁴ , wherein R ³ and R ⁴ are H or C ₁ -C ₄ alkyl, or connected with a nitrogen atom to form a 5- or 6-membered saturated heterocyclic group, which may contain one selected from O, S and NR ⁵ (R ⁵ is H or C ₁ -C ₄ alkyl) hetero ring atoms or groups; R ² is H, C ₁ -C ₄ alkyl or 2-hydroxyethyl; Y is H or CH ₃ ; and the dotted line between the 3-position and the 4-position may or may not be a bond. 14. A process as claimed in claims 1 to 6, characterized in that it is used for the manufacture of compounds of formula (I), wherein R ¹ , R ² and Y are all H, and R is CH ₃ at the 3-position , there is a double bond between the 3- and 4-positions, and "Het" is connected to the 6-position, which is 2,6-dimethylpyridin-3-yl or 1-methyl-(1H)-1,2, 4-triazol-5-yl. 15. The method as claimed in claim 14, characterized in that: "Het" is 2,6-dimethylpyridin-3-yl, and its product is converted into sodium salt by reacting with NaOH. 16. A method of making a pharmaceutical composition, which is characterized by: mixing the compound of formula (I) as defined in the claim, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable diluent or carrier. 17. The method as claimed in claim 16, characterized in that the compound of formula (I) or its salts are prepared by the method of claims 1-15.