KR810000738B1 - Process for preparing 5-alkoxy picolinic acid ester - Google Patents

Abstract

Title compds.[I; R1 = C1-6 lower alkyl; R2 CH(R3)OCOR4 (R3 = H, Me ; R4 = C1-5 lower alkyl, lower alkoxy, phenyl, substituted phenyl, aralkyl), C6H2R6R7R8(R6,R7,R8 = H, lower alkyl, alkoxy, halogen) were prepd. by reaction of II(M = H, metal atom) and III(R5 = C1-5 lower fatty acid, alloyl, aralloyl) such as acyloxyalkylhalide, alkoxyalkylhalide and 3-bromophthalide, or reaction II and IV. Thus, 975mg II(R1 = Bu, M = H) in 20 ml(CH3)2NCHO was reacted with 1.5 g III (X = Cl; R3 = Me; R5 = C4H5) to give 1.38 g I[R2 = C4H5C(Me) (Cl) .

Description

Preparation of 5-alkoxy-picolinate

The present invention relates to a process for producing novel 5-alkoxy-pincholate esters represented by the following general formula (6).

Compound 5-alkoxy-picolinic acid ester of the present invention

[Formula 1]

To a 5-alkoxy-picolinic acid or a metal salt thereof, wherein R ₁ represents a lower alkyl group having ₁ to 6 carbon atoms, M represents a hydrogen atom or a metal atom

[Formula 2]

(Wherein X represents a halogen atom, R ₃ represents a hydrogen atom or a methyl group, R ₅ represents a lower fatty acid residue having 1 to ₅ carbon atoms (carbon number does not include a carbonyl group), an aroyl group and an ataloyl group) Oxyalkylhalide or alkoxyalkylhalide or 3-bromo phthalide is reacted in the presence of a deoxidizer, or

[Formula 3]

Reacting a phenol or a substituted phenol represented by (R ₆ , R ₇ , R ₈ represents the same or different hydrogen atom, lower alkyl group, lower alkoxy group or halogen) in the presence of a condensing agent, or Obtained by reacting 5-alkoxy-picolinic acid or a metal salt thereof with an acid halogenated reagent

[Formula 4]

Wherein R ₁ represents a lower alkyl group having ₁ to 6 carbon atoms and X represents a halogen atom.

[Formula 5]

Amyloxy alkanoyl represented by (wherein R ₃ is a hydrogen atom or a methyl group, R ₅ is a C1-5 lower fatty acid residue (carbon number does not contain a carbonyl group), an aloyl group, an araloyl group), Alkoxy alkanoyl or general formula

By reacting a phenol and a substituted phenol represented by (wherein R ₆ , R ₇ , R ₈ represent the same or different hydrogen atoms, lower alkyl groups, lower alkoxy groups or halogens) in the presence of a deoxidizer

[Formula 6]

(R3는 수소 또는 메틸기를 표시하고, R₄는 탄소수 1-5에 저급알킬기, 탄소수 1-4의 저급알콕시기, 페닐기, 치환페닐기, 알랄킬기)로 표시되는 아실옥시 알칼기, 알콕시알킬기, 프탈리딜기, 또는 일반식,(R ₁ is the same as above, R2 is the general formula

R 3 represents hydrogen or a methyl group, R ₄ represents a lower alkyl group having 1 to 5 carbon atoms, a lower alkoxy group having 1 to ₄ carbon atoms, a phenyl group, a substituted phenyl group, an allyl group, and the like. Thalidil group, or general formula,

페닐 또는 치환페닐기를 표시한다)를 표시한다)으로 표시되는 5-알콕시-피콜린산에스테르를 얻음으로써 제조된다. 5-알콕시-피콜린산은 본 발명자등에 의해 합성된 신규의 혈압강하제로 의약으로서 유용하다(일본 특원소 51-116641호).(R ₆ , R ₇ , R ₈ have the same meaning as above)

Phenyl or a substituted phenyl group)) to produce a 5-alkoxy-picolinate ester. 5-alkoxy-picolinic acid is a novel blood pressure lowering agent synthesized by the present inventors and the like, and is useful as a medicine (Japanese Patent Application No. 51-116641).

Ester derivatives of the 5-alkoxy-picolinic acid of the present invention are equivalent to or higher than those of the 5-alkoxy-picolinic acid, and the compounds are useful in treating hypertension because the toxicity of the original is reduced.

The production method of the present invention will be described in detail again. Among the 5-alkoxy-picolinate esters, which are the target compounds of the present invention, acetoxymethyl, isobutyloxymethyl, pivaloyloxymethyl, pivaloyloxyethyl and isovaloyl Acyl oxyalkyl esters such as oxyethyl, benzoyloxyethyl, P-methoxybenzoyloxyethyl, 3,4,5-trimethoxybenzoyloxyethyl, ethoxycarbonyloxyethyl, phthalidyl esters, and methoxymethyl esters And methoxyepoxymethyl ester are represented by the general formula (2) in the presence of a base such as pyridinetriethylamine in a solvent such as dimethylformamide or dimethyl sulfoxide in 5-alkoxy-picolinic acid represented by the general formula (1) or a metal salt thereof. It is obtained by acting the acyloxyalkyl halide or 3-bromo phthalide or the alkoxyalkyl halide represented by

The reaction temperature is in the range of -20 ° C to 80 ° C and the reaction time is 4-20 hours.

Acyloxyalkyl esters and alkoxyalkyl esters also react acid-halogen reagents such as phosphorus trichloride, trisulfide, and thionyl chloride with 5-alkoxy-picolinic acid of the general formula (1). Induced by the acid halide of the compound, it is acyloxyalkanoyl represented by the general formula (5) in pyridine or organic solvents such as benzene, chloroform, methylene chloride, dimethylformamide, dioxane in the presence of a base such as triethylamine. Alternatively, it can be obtained by reacting alkanoyl.

The reaction temperature is in the range of -20 ° C-50 ° C and the reaction time is 1-10 hours.

Phenyl and substituted phenyl esters are 5-alkoxy-picolinic acid of formula (1) and phenoyl or substituted phenoyl represented by formula (3) in the presence of a condensing agent such as multicyclohexylcarbodiimide, chloroform, di Chloroform, methylene chloride, dimethylform are reacted in an organic solvent such as oxane, dimethylformamide, pyridine, or an acid halide of 5-alkoxypicolinic acid of the general formula (4) in pyridine or in the presence of a base such as triethylamine. It is obtained by making it react with the phenoyl or substituted phenoyl of General formula (3) in organic solvents, such as an amide and dioxane.

In both cases, the reaction temperature is typically 0 ° C-40 ° C, and the reaction time is 3-10 hours.

Any compound of the present invention exhibits a blood pressure-lowering effect by oral administration and is useful as a medicine.

Three spontaneous hypertensive rats (15-20 weeks of age, 175-190 mmHg pre-administration blood pressure) were used in one group, and either the compound of the present invention was suspended or emulsified in 80% solution of 5% Arabian rubber + 2% Tween. Administered.

Blood pressure was inserted into the tail artery of the anesthesia-free rat by inserting a polyethylene catheter into the polygraph (Japanese ray RM-85) through the blood pressure transjuvener (Japanese photoelectric MP-24T). Recorded in.

the results are as follow.

Oral administration of the compound of the present invention, toxic LD50 is 300-500 mg / kg free acid, acyloxymethyl esters and alkoxyalkyl esters are 600-1000 mg / kg and phthalidyl ester is about 1200 mg / kg. In comparison to all the toxicity is reduced.

In the case of clinical oral administration, the formulations are taken as tablets or capsules with excipients commonly used in the compounds of the present invention, or as dry syrups, but in some cases parenteral administration such as subcutaneous injections is also possible.

It is also possible to take with other physiologically active agents, in particular diuretics.

The example of the manufacturing method is illustrated below.

Example 1

975 mg of 5-n-butyloxy-picolinic acid was dissolved in 20 ml of dimethylformamide, 1.5 g of chloromethyl pivalrayo and 1.4 ml of triethylamine were added thereto, followed by stirring at room temperature for 6 hours.

10 ml of ice water was added to the reaction solution, and the mixture was left for 2 hours and concentrated to dryness. 80 ml of ethyl acetate was added to the residue, and the resultant was washed with 50 ml of acidic water, 5% sodium bicarbonate and 50 ml of water.

The ethyl acetate layer was dehydrated with anhydrous sodium sulfate, concentrated and dried under high vacuum to obtain 1.38 g of pivaloyloxymethyl ester oil of 5-n-butyloxy-picolinic acid.

This compound showed a single spot at Rf 0.73 by silica gel thin layer chromatography (developing solvent: Benze: acetone = 10: 1).

Elemental Analysis Values: C62.18%, H7.38%, N4.53%

Molecular Formula: Theoretical as C ₁₆ H ₂₃ NO ₅ : C62.13, H7.44, N4.53 (%)

Example 2

980 mg of 5-n-butyloxy-picolinic acid was dissolved in 25 ml of dimethylformamide, 1010 mg of 3-bromophthalide was added thereto, and 0.8 ml of triethylamine was added thereto, followed by stirring at room temperature for 5 hours. 5 ml of ice water was added to the reaction solution, and the mixture was left for 2 hours and concentrated to dryness. 100 ml of ethyl acetate was added to the residue, and the resultant was washed with 5 ml of acidic water, 10 sodium bicarbonate water and water.

The ethyl acetate layer was dehydrated with anhydrous sodium sulfate, concentrated to about 15 ml and left at 3 ° C to precipitate crystals.

This was filtered and 1.22g of white needle crystals of the phthalidyl ester of n-butyloxy- picolinic acid were obtained.

This compound showed a single spot at Rf 0.58 by silica gel thin layer chromatography (developing solvent: benzene: acetone = 10: 1).

Melting Point: 137-138 ℃

Elemental Analysis Values: C66.08, H5.17, N4.36 (%)

Molecular Formula: Theoretical as C ₁₈ H ₁₇ NO ₅ : C66.05, H5.20, N4.28 (%)

Example 3

835 mg of 5-n-propyloxy-picolinic acid is dissolved in 25 ml of dimethylformamide, 850 mg of chloromethyl acetate and 1.3 ml of triethylamine are added thereto, followed by stirring at room temperature for 4 hours.

The precipitated triethylamine hydrochloride is filtered off, the filtrate is concentrated to about 5 ml, 100 ml of ethyl acetate and 50 ml of water are added and pH 8.5 as 2N caustic soda is transferred to the aqueous layer with unreacted and remaining dimethylformamide.

The ethyl acetate layer was washed twice with 40 ml of water, and then dehydrated with anhydrous sodium sulfate and concentrated.

Drying under high vacuum yielded 1.14 g of acetoxymethyl ester oil of 5-n-propyloxypicolinic acid.

The present compound was subjected to silica gel thin layer chromatography (developing solvent: benzene: acetone = 10: 1) to show a single spot at Rf 0.43.

Elemental Analysis Values: C57.01, H5.90, N5.51 (%)

Molecular Formula: Theoretical as C ₁₃ H ₁₄ NO ₅ : C56.92, H5.93, N5.53 (%)

Example 4

975 mg of 5-n-butyloxypicolinic acid was dissolved in 20 ml of dimethylformamide, 1.52 g of α-pivaloyloxyethyl chloride and 1.4 ml of triethylamine were added thereto, followed by stirring at 30 ° C for 20 hours.

The same treatment as in Example 3 below was carried out to concentrate the obtained ethyl acetate layer to obtain a crystalline residue.

This was recrystallized with the mixture of hexane, and 1.28 g of white needle crystals of (alpha)-pivaloyl oxyethyl ester of 5-n-butyloxy picolinic acid were obtained.

This compound showed a single spot at Rf 0.77 by silica gel thin layer chromatography (developing solvent: benzene: acetone = 10: 1).

Melting Point: 67-68 ℃

Elemental Analysis Values: C63.12, H7.76, N4.35 (%)

Molecular Formula: Theoretical as C ₁₇ H ₂₅ NO ₅ : C63.16, H7.74, N4.33 (%)

Example 5

835 mg of 5-n-propyloxy-picolinic acid was dissolved in 20 ml of dimethylformamide, and 1.7 g of bromine methyl isobutylate and 1.3 ml of triethylamine were added thereto and allowed to react at room temperature for 10 hours.

The ethyl acetate layer obtained by the same treatment as in Example 1 below was concentrated and dried under high vacuum to obtain 0.92 g of an oily product of isophthyloxyester of 5-n-propyloxypicolinic acid.

This compound showed a single spot at Rf 0.55 by silica gel thin layer chromatography (developing solvent: benzene: acetone = 10: 1).

Elemental Analysis Values: C61.13, H7.18, N4.72 (%)

Molecular Formula: Theoretical value as C ₁₅ H ₂₁ O ₅ N: C61.02, H7.12, N4.76 (%)

Example 6

975 mg of 5-n-butyloxypicolinic acid was dissolved in 30 ml of dimethylformamide, and 1.8 g of α-chloroethylbenzoate and 1.4 ml of triethylamine were added thereto and reacted at 35 ° C for 15 hours.

The ethyl acetate layer obtained by the same treatment as in Example 3 below was concentrated and dried under high vacuum to obtain 1.14 g of an oily substance of α-benzoyloxyethyl ester of 5-n-butyloxypicolinic acid.

This compound showed a single spot at Rf 0.76 by silica gel chromatography (electric solvent: benzene: acetone = 10: 1).

Elemental Analysis Values: C66.51, H6.08, N4.11 (%)

Molecular Formula: Theoretical as C ₁₉ H ₂₁ O ₅ N: C66.47, H6.12, N4.08 (%)

Example 7

975 mg of 5-n-butyloxypicolinic acid was dissolved in 30 ml of dimethylformamide, 1.65 g of α-isovalerooxyethyl chloride and 1.4 ml of triethylamine were added thereto, followed by stirring at 40 ° C for 15 hours.

The ethyl acetate layer obtained by following the same procedure as in Example 1 was concentrated. The residue was dissolved in 5 ml of hexane and left at 30 ° C. to precipitate crystals. This was filtered off and dried under high vacuum to obtain 920 ml of white crystals of α-isovalerooxyethyl ester of 5-n-butyloxypicolinic acid.

This compound showed a single spot at Rf 0.78 by silica gel thin layer chromatography (developing solvent: benzene: acetone = 10: 1).

Melting Point: 54-55 ℃

Elemental Analysis Values: C63.08, H7.79, N4.29 (%)

Molecular Formula: Theoretical as C ₁₇ H ₂₅ O ₅ N: C63.16, H7.74, N4.33 (%)

Example 8

975 mg of 5-n-butyloxy-picolinic acid was dissolved in 20 ml of dimethylformamide, and 2.0 g of α-3,4,5-trimethoxy benzoyloxyethyl chloride and 1.3 ml of triethylamine were added thereto at 50 ° C. Stir for 18 hours. The ethyl acetate layer obtained by the same treatment as in Example 3 below was concentrated. Then, 2.9 g of the concentrate was dissolved in 4 ml of benzene, developed into benzene-acetone (30: 1) by silica gel (100 ml) column filled with benzene, and divided into 10 ml portions.

Fractions 30-62 were collected, concentrated, dissolved in 10 ml of ethyl ether, and left at 30 ° C to precipitate crystals.

This was filtered and dried under high vacuum to obtain 2.1 g of crystals of α-3,4,5-trimethoxybenzoyloxy ethyl ester of 5-n-butyloxypicolinic acid.

This compound showed a single spot at Rf 0.61 by silica gel thin layer chromatography (developing solvent: benzene: acetone = 10: 1).

Melting Point: 80-80.5 ℃

Elemental Analysis Values: C61.02, H6.21, N3.18 (%)

Molecular Formula: Theoretical as C ₂₂ H ₂₇ O ₆ N: C60.97, H6.24, N3.23 (%)

Example 9

3 g of 5-n-butyloxy-picolinic acid was suspended in 30 ml of benzene, 8 ml of thionyl chloride was added, and the mixture was reacted at 70 ° C for 3 hours.

The reaction solution was concentrated to dryness as it was, and 10 ml of benzene was added to the residue, which was dried again.

This operation was repeated twice to remove byproduct hydrogen chloride and sulfurous acid gas to form an acid chloride (hydrochloride) of 5-n-butyloxy-picolinic acid.

1.2 g of this acid chloride was dissolved in 5 ml of benzene and added dropwise over 10 minutes with stirring to a solution of 0.58 g of phenol and 2.5 ml of triethylamine in 100 ml of benzene under ice cooling.

After reacting for 2 hours at 5-10 ° C. and again for 2 hours at room temperature, the reaction mixture was dried.

The residue was taken up in 100 ml of ethyl acetate and washed with cooled hydrochloric acid at pH 2, alkaline water at pH 9 and 50 ml of water.

The ethyl acetate layer is dehydrated with anhydrous sodium sulfate and concentrated to dryness to obtain a crystalline residue.

Recrystallization was performed by mixing a mixture of ethyl ether and hexane to obtain 0.98 g of white needle crystals of phenyl ester of 5-n-butyloxypicolinic acid.

Melting Point: 71-72 ℃

Elemental Analysis Values: C71.03, H6.14, N5.21 (%)

Molecular Formula: Theoretical as C ₁₆ H ₁₇ NO ₃ : C70.85, H6.27, N5.17 (%)

Example 10

0.55 g of P-ethylphenol and 2.2 ml of triethylamine were dissolved in 30 ml of chloroform solution, and 10 ml of a chloroform solution of 1.1 g of an acid chloride (hydrochloride) of 5-n-butyloxy-picolinic acid of Example 9 was dissolved under ice cooling. Added dropwise.

After reacting again at room temperature for 2 hours at 5-10 ° C. for 3 hours, the reaction solution was washed with cooled hydrochloric acid of pH 2, alkaline water of pH 9 and 20 ml of water.

The chloroform layer was dehydrated with anhydrous sodium sulfate, dried and crystallized by a mixture of ethyl ether hexane to obtain 0.92 g of white crystals of P-ethylphenyl ester of 5-n-butyloxy-picolinic acid.

Melting Point: 67-68 ℃

Elemental Analysis Values: C71.92, H7.13, N4.74 (%)

Molecular Formula: Theoretical as C ₁₈ H ₂₁ NO ₃ : C72.24, N7.02, N4.68 (%)

Example 11

0.69 g of P-hydroxy acetophenone and 2.5 ml of triethylamine were dissolved in 20 ml of dichloromethane, and 5 ml of dichloromethane solution of 1.25 g of acid chloride (hydrochloride) of 5-n-butyloxy-picolinic acid of Example 9 was added thereto. Was added dropwise ice-cooled.

0.75 g of white crystals (crystallized with ethyl acetate) of P-acetylphenyl ester of 5-n-butyloxy-picolinic acid after the same treatment as in Example 10 after reaction at 3-5 ° C. for 3 hours at room temperature. Got.

Melting Point: 94-96 ℃

Elemental Analysis Values: C69.17, H6.01, N4.50 (%)

Molecular Formula: Theoretical as C ₁₈ H ₁₉ NO ₄ : C69.01, H6.07, N4.47 (%)

Example 12

3 g of 5-n-butyloxy-picolinic acid was suspended in 30 ml of benzene, 8 ml of thionyl chloride was added, and the mixture was reacted at 70 ° C for 3 hours.

10 ml of benzene was added to the residue obtained by concentrating and drying the reaction solution as it was, and drying again.

This operation was repeated twice again to remove by-product hydrogen chloride and sulfurous acid gas to prepare an acid chloride (hydrochloride) of 5-n-butyloxy-picolinic acid.

This acid chloride was then dissolved in 20 ml of benzene and added dropwise over 10 minutes with stirring to 30 ml of a benzene solution containing 2.1 g of 5-hydroxyindane and 7.7 ml of triethylamine under ice cooling.

The reaction was continued for 1.5 hours at 5-10 ° C. and 4 hours at room temperature, and then the reaction was dried.

The residue was taken up in 100 ml of ethyl acetate and washed with cooled hydrochloric acid at pH 2, alkaline water at pH 9 and 50 ml of water.

The ethyl acetate layer was dehydrated with anhydrous sodium sulfate, and then concentrated to dryness to obtain a crystalline residue.

4.59 g of crystals of 5-indanyl ester of 5-n-butyloxy-picolinic acid were obtained by recrystallization from a mixture of ethyl ether and hexane.

Melting Point: 58-59 ℃

Elemental Analysis Values: C73.28, H6.86, N4.35 (%)

Molecular Formula: Theoretical as C ₁₉ H ₂₁ NO ₃ : D73.31, H6.75, N4.50 (%)

Claims (1)

The acyloxyalkyl halide or alkoxyalkyl halide or 3-bromophthalide represented by the following general formula (2) is deoxidized to 5-alkoxy-picolinic acid or its metal salt represented by the following general formula (1). 5-alkoxy-picolinic acid of the following general formula (6) characterized by reacting in the presence of a compound or reacting a phenol or a substituted phenol represented by the general formula (3) in the presence of a condensing agent. Preparation of esters.

In the above formula, R ₁ is a lower alkyl group having 1-6 carbon atoms, R ₂ is a general formula

[Wherein R ₃ is hydrogen or methyl group, R ₄ is lower alkyl group of 1-5 carbon atoms, lower alkoxy group of 1-4 carbon atoms, phenyl group, acyloxyaryl group represented by substituted phenyl group, aralkyl group, alkoxyalkyl group, phthalidyl group Or general formula

Phenyl or substituted phenyl group represented by (wherein R ₆ , R ₇ , R 8 may represent the same or different hydrogen atom, lower alkyl group, lower alkoxy group or halogen atom), R 3 is hydrogen atom or methyl group, R ₅ is carbon number 1-5 lower acid residues (carbon number does not include carbonyl group), aroyl group, arloyl group, R ₆ , R ₇ , R ₈ may be the same or different hydrogen atoms, lower alkyl group, lower alkoxy group or halogen The atom M represents a hydrogen atom or a metal atom, and X represents a halogen atom.