JP2018080149A - Manufacturing method of 2-amino-6-methyl nicotinic acid ester and protonic acid salt thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method capable of manufacturing 2-amino-6-methyl nicotinic acid ester, which is a manufacturing intermediate compound of a compound useful as an active ingredient for pharmaceuticals or agricultural chemicals, at high yield and at low cost.SOLUTION: There is provided a synthetic method of 2-amino-6-methyl nicotinic acid ester by reacting alkoxycarbonylmethyl carboamidine protonic acid salt represented by the formula (2) and at least one of 3-oxobutyl aldehyde or acetals thereof in a polar organic solvent in practically absent of basic materials. R is a substituted/unsubstituted aryl group or a substituted/unsubstituted C1 to 8 alkyl group, HX is protonic acid and n is an integer of 1 to 3.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing 2-amino-6-methylnicotinic acid ester or a protonic acid salt thereof. Specifically, the present invention provides 2-amino-6-methylnicotinic acid ester, which is an intermediate compound for producing a compound useful as an active ingredient of a pharmaceutical or agricultural chemical, in a high yield, easy to implement and inexpensive. It relates to a method of manufacturing.

A pharmaceutical or agrochemical produced using 2-amino-6-methylnicotinic acid ester or 2-amino-6-methylnicotinic acid hydrolyzed from it as an intermediate is, for example, WO 2005/33079, It describes in Unexamined-Japanese-Patent No. 2010-083861 and international publication 2014/6945.
As a method for producing 2-amino-6-methylnicotinic acid ester, a method of reacting amidinoacetic acid ester hydrochloride with formylacetone sodium salt (Patent Document 1), or malonic acid-ethyl ester-iminoethyl ether Method of reacting hydrochloride with 3-oxobutyraldehyde (Non-patent document 1), Method of reacting ethyl 3,3-diaminoacrylate with 1-amino-1-buten-3-one (Non-patent document 2) ) Etc. are known.

Japanese Patent Publication No. 45-40288

Chemische Berichte, 73, 544, 545 (1940) Journal of Heterocyclic Chemistry, 33 (6), 1817 (1996)

However, in the production method of Patent Document 1, since formylacetone sodium salt is used, the reaction proceeds under basic conditions, and the yield of 2-amino-6-methylnicotinic acid ester is 56%, sufficient. The yield is not high.
In the method disclosed in Non-Patent Document 1, the yield is as low as 10%.
Furthermore, the method disclosed in Non-Patent Document 2 does not particularly describe the yield, but it is difficult to obtain the raw material 1-amino-1-buten-3-one, and the production method tends to be expensive.
Therefore, a method for producing 2-amino-6-methylnicotinic acid ester or a protonic acid salt thereof having a high yield and easy implementation has been strongly desired.

As a result of intensive studies to solve the above problems, the present inventors have found that the above problems can be solved by the following method, and have reached the present invention.
That is, the present invention provides the following formula (1),

（式（１）中、Ｒは、アリール基または炭素数１〜８のアルキル基を示し、該アリール基またはアルキル基は、置換基を有していてもよい）で表される２−アミノ−６−メチルニコチン酸エステル又はそのプロトン酸塩の製造方法であって、
極性有機溶媒中、下式（２）、

(In formula (1), R represents an aryl group or an alkyl group having 1 to 8 carbon atoms, and the aryl group or alkyl group may have a substituent) A process for producing 6-methylnicotinic acid ester or a protonic acid salt thereof,
In the polar organic solvent, the following formula (2),

（式（２）中、Ｒは、上記定義の通りであり、ＨＸは、プロトン酸を示し、ｎは、１〜３の整数を示す。）で表されるアルコキシカルボニルメチルカルボアミジン・プロトン酸塩と、３−オキソブチルアルデヒドまたはそのアセタール類の少なくともいずれかを、実質的に塩基性物質の非存在下で反応させることを特徴とする２−アミノ−６−メチルニコチン酸エステル又はそのプロトン酸塩の製造方法に関するものである。
本発明においては、上記反応後、反応液から極性有機溶媒および低沸点成分を蒸留で除去する濃縮工程と、上記濃縮工程によって得られた濃縮液から上記式（１）の化合物のプロトン酸塩を水層に抽出する抽出工程と、上記抽出工程によって得られた抽出水層にアルカリ化合物を加えて結晶を析出させる晶析工程と、を含むことが好ましい。

(In formula (2), R is as defined above, HX represents a protonic acid, and n represents an integer of 1 to 3.) And 2-oxo-6-methylnicotinic acid ester or a protonic acid salt thereof, characterized in that 3-oxobutyraldehyde or at least one of its acetals is reacted in the substantial absence of a basic substance It is related with the manufacturing method.
In the present invention, after the reaction, a concentration step of removing the polar organic solvent and the low boiling point component from the reaction solution by distillation, and a protonate of the compound of the formula (1) from the concentrate obtained by the concentration step. It is preferable to include an extraction step for extracting into the aqueous layer and a crystallization step for adding crystals to the extracted aqueous layer obtained by the extraction step to precipitate crystals.

  According to the present invention, 2-amino-6-methylnicotinic acid ester or a protonic acid salt thereof, which is a production intermediate compound of a compound useful as an active ingredient of a pharmaceutical or agricultural chemical, can be easily implemented in a high yield. And can be manufactured at low cost.

Hereinafter, the present invention will be described in more detail.
The present invention provides the following formula (1),

（式（１）中、Ｒは、アリール基または炭素数１〜８のアルキル基を示し、該アリール基またはアルキル基は置換基を有していてもよい。）で表される２−アミノ−６−メチルニコチン酸エステル又はそのプロトン酸塩の製造方法であって、
極性有機溶媒中、下式（２）、

(In formula (1), R represents an aryl group or an alkyl group having 1 to 8 carbon atoms, and the aryl group or alkyl group may have a substituent). A process for producing 6-methylnicotinic acid ester or a protonic acid salt thereof,
In the polar organic solvent, the following formula (2),

（式（２）中、Ｒは、上記定義の通りであり、ＨＸは、プロトン酸を示し、ｎは、１〜３の整数を示す。）で表されるアルコキシカルボニルメチルカルボアミジン・プロトン酸塩と、３−オキソブチルアルデヒドまたはそのアセタール類の少なくともいずれかを、実質的に塩基性物質の非存在下で反応させる方法に関するものである。

(In formula (2), R is as defined above, HX represents a protonic acid, and n represents an integer of 1 to 3.) And at least one of 3-oxobutyraldehyde or acetals thereof in a method substantially in the absence of a basic substance.

In the above formulas (1) and (2), the aryl group represented by R is not particularly limited, and examples thereof include a phenyl group and a tolyl group. Although it does not specifically limit as an alkyl group of 8, For example, a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group Pentyl group, hexyl group, heptyl group, octyl group and the like.
The substituent in the aryl group or alkyl group is not particularly limited, and examples thereof include an alkoxy group and a cyano group.
The protonic acid salt of the above formula (1) is not particularly limited. For example, hydrogen chloride, hydrogen bromide, sulfate, phosphate, methanesulfonate, benzenesulfonate, Examples include formate, acetate, and oxalate. The protonic acid as HX in the formula (2) means a protonic acid involved in the formation of the protonic acid salt of the above formula (1).

The alkoxycarbonylmethylcarbomidine / protonic acid salt represented by the above formula (2) used in the production method of the present invention is, for example, from a known compound according to the method described in International Publication No. 2008/33745. It can be synthesized immediately.
The 3-oxobutyraldehyde or acetals thereof used in the production method of the present invention can be immediately synthesized from a known compound according to, for example, the method described in JP-A-6-16591.

[Reaction process]
In one embodiment of the production method of the present invention, the alkoxycarbonylmethylcarbomidine / protonate salt represented by the above formula (2) is added to a polar organic solvent, and 3-oxobutyraldehyde or an acetal thereof is further added. , Heat and stir.
Hereinafter, each compound in the reaction step will be described in more detail.
(Alkoxycarbonylmethylcarbomidine / protonate)
In the above formula (2), the alkoxycarbonylmethylcarboamidine / protonic acid salt is not particularly limited as the aryl group represented by R, and examples thereof include a phenyl group and a tolyl group. Although it does not specifically limit as a C1-C8 alkyl group shown by these, For example, a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec- Examples thereof include a butyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, and an octyl group, and the protonic acid represented by HX is not particularly limited, but examples thereof include hydrogen chloride and bromide. Examples thereof include hydrogen, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, formic acid, acetic acid, and oxalic acid.

(3-oxobutyraldehyde or acetals thereof)
Although 3-oxobutyraldehyde or its acetals are not particularly limited, for example, 3-oxobutyraldehyde, 1-methoxy-1-butanol-3-one, 1-ethoxy-1-butanol-3 -One, 1,1-dimethoxy-3-butanone, 1,1-diethoxy-3-butanone, 2,4,4-trimethoxy-2-butanol, 2,4,4-triethoxy-2-butanol, 1,1 , 3,3-tetramethoxybutane, 1,1,3,3-tetraethoxybutane, 1,1,3-trimethoxy-2-butene, 1,1,3-triethoxy-2-butene, and the like. The acetals include hemiacetals located between aldehydes and acetals. Examples of the hemiacetal include 1-methoxy-1-butanol-3-one and 1-ethoxy-1-butanol-3-one.

(Polar organic solvent)
The polar organic solvent is not particularly limited. For example, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolide Non-, dimethyl sulfoxide, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, alcohols such as tert-butanol and the like can be mentioned.

(Reaction conditions)
The compound of the above formula (2) is preferably in the range of 5 to 50% by mass in the polar organic solvent. The amount of 3-oxobutyraldehyde or acetals thereof used is preferably in the range of 0.8-fold to 3.0-fold moles relative to the compound of the above formula (2). It is more preferable to make it the range of -2.0 times mole. Thereby, it can be made to react efficiently.
The reaction step may be performed under an inert gas atmosphere such as nitrogen or argon, or a polar organic solvent dehydrated with molecular sieves may be used.
The temperature in the reactor in the reaction step is preferably in the range of 30 to 200 ° C., and more preferably in the range of 50 to 150 ° C. from the efficiency of the reaction.

  The reaction step is preferably performed in the substantial absence of a basic substance. “Substantially in the absence of a basic substance” may be in the presence of a basic substance in a range that does not significantly reduce the reaction yield. Preferably, no basic substance is present at all. When the reaction is carried out by adding a base such as potassium carbonate or sodium methoxide, the reaction rate decreases and the selectivity of the target product also decreases. The reaction substrate is also preferably non-basic. When the reaction is carried out using a free form of ethoxycarbonylmethylcarbomidine, the reaction rate is lowered and the selectivity of the target product is also lowered, which is outside the scope of the present invention. When the reaction is performed in the absence of a basic substance using a non-basic reaction substrate, the target product can be obtained in high yield.

[Processing after reaction]
In one embodiment of the production method of the present invention, after the reaction, a concentration step of removing the polar organic solvent and the low boiling point component from the reaction solution by distillation, and the compound of the formula (1) from the concentrated solution obtained by the concentration step It is preferable to include an extraction step of extracting the protonic acid salt into an aqueous layer and a crystallization step of adding crystals to the extracted aqueous layer obtained by the extraction step to precipitate crystals.
According to the said structure, 2-amino-6-methylnicotinic acid ester can be taken out easily with a high yield.
Further, following the crystallization step, a solid-liquid separation step for separating the slurry obtained by the crystallization step into a solid and a liquid, and a drying step for drying the wet crystal obtained by the solid-liquid separation step. More preferably.

(Concentration process)
In the concentration step, the polar organic solvent and the low boiling point component are removed from the reaction solution by distillation. Distillation may be performed under normal pressure or under reduced pressure. The degree of vacuum and the distillation temperature are appropriately set depending on the type of polar organic solvent. It is preferable to remove the polar organic solvent and the low boiling point component as much as possible.

(Extraction process)
In the extraction step, water and an organic solvent are added to the concentrate obtained in the concentration step, the protonic acid salt of the compound of the formula (1) is extracted into the aqueous layer, and the aqueous layer and the organic layer are separated by liquid separation. To do. In the extraction step, it is preferable to add a mineral acid in order to improve extraction efficiency.
Water or a mineral acid aqueous solution may be added to the separated organic layer, and the extraction process may be performed again.
For example, the amount of water used in the extraction step is preferably 0.1 to 10 times the volume of the concentrated solution, and more preferably 0.5 to 5 times the volume.
The amount of the organic solvent used in the extraction step is, for example, preferably 0.1 to 10 times the volume, more preferably 0.5 to 5 times the volume of the concentrate.
The amount of mineral acid used in the extraction step is preferably 2 mols or less, more preferably 1 mol or less, relative to the compound of the above formula (2) used in the reaction.

  The organic solvent used in the extraction step is not particularly limited, and examples thereof include ester solvents, ether solvents, and halogenated hydrocarbon solvents. Examples of the ester solvent include n-butyl formate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and tert-butyl acetate. Examples of the ether solvent include ethyl ether, isopropyl ether, n-butyl ether, methyl tert-butyl ether, and the like. Examples of the halogenated hydrocarbon solvent include methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chlorobenzene, and the like.

The mineral acid used in the extraction step is not limited to these, and examples include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, and benzenesulfonic acid.
In another aspect of the extraction step, water is added to the concentrated liquid obtained by the concentration step, the protonic acid salt of the compound of the formula (1) is extracted into the aqueous layer, and separated into an aqueous layer and precipitated crystals by filtration. . In the extraction step, it is preferable to add a mineral acid in order to improve extraction efficiency.
The amount of water used in another aspect of the extraction step is preferably, for example, 0.1 to 10 times the volume, more preferably 0.5 to 5 times the volume of the concentrate.
The amount of the mineral acid used in another aspect of the extraction step is preferably 2 mols or less, more preferably 1 mol or less with respect to the compound of the above formula (2) used in the reaction.
Mineral acids used in another aspect of the extraction step include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, and the like. .

(Crystallization process)
In the crystallization step, an alkali compound is added to the extracted aqueous layer obtained by the extraction step to precipitate crystals. The alkali compound may be added as a solid, or may be added as a 1% by mass or more aqueous solution.
The amount of the alkali compound used in the crystallization step is preferably 5 times mol or less and more preferably 3 times mol or less with respect to the compound of the above formula (2) used in the reaction.
Examples of the alkali compound used in the crystallization step include, but are not limited to, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, and carbonate. Examples include calcium and ammonia.

(Solid-liquid separation process)
In the solid-liquid separation step, the slurry obtained in the crystallization step is separated into a solid and a liquid by a method such as filtration. In order to remove the alkali compound remaining in the solid, the solid may be washed with water.

(Drying process)
In the drying step, the wet crystals obtained in the solid-liquid separation step are dried by a method such as an evaporator, shelf drying, or spray dryer. Drying may be performed under normal pressure or under reduced pressure. The degree of decompression or the drying temperature is appropriately set.
The reaction time between 2-amino-6-methylnicotinic acid ester or its protonic acid salt and alkoxycarbonylmethylcarbomidine / protonic acid salt is, for example, 5 hours or more, preferably 10 hours or more. In particular, a constant yield can be achieved regardless of time.
Examples will be shown below, and the embodiments of the present invention will be described in more detail. Of course, the present invention is not limited to the following examples, and it goes without saying that various aspects are possible in detail. Further, the present invention is not limited to the above-described embodiments, and various modifications are possible within the scope shown in the claims, and the present invention is also applied to the embodiments obtained by appropriately combining the respective technical means disclosed. It is included in the technical scope of the invention. Moreover, all the literatures described in this specification are used as reference.

[Measurement method of purity]
The purity of 2-amino-6-methylnicotinic acid ester was measured by an internal standard method of gas chromatography.

[Example 1]
8.33 g (0.05 mol) of ethoxycarbonylmethylcarboamidine hydrochloride and 7.4 ml (0.05 mol) of 1,1-dimethoxy-3-butanone were heated and stirred under reflux with 100 ml of acetonitrile for 24 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure of 4 kPa. 30 g of water, 30 g of ethyl acetate and 2.5 g (0.025 mol) of 37% hydrochloric acid were added to the residue, and the aqueous layer was separated after stirring. The aqueous layer was slowly poured into 88.8 g (0.10 mol) of a 15.5% aqueous potassium carbonate solution. The precipitated crystals were filtered and washed twice with 50 g of water. The wet crystals were dried at 60 ° C. under a reduced pressure of 4 kPa to obtain 6.35 g of light brown crystals (equivalent to 70.5% yield). The purity of the dried ethyl 2-amino-6-methylnicotinate was 93.4%, and the purity of methyl 2-amino-6-methylnicotinate was 2.5%. The yield of 2-amino-6-methylnicotinic acid ester in consideration of purity was 67.6%.

[Example 2]
4.17 g (0.025 mol) of ethoxycarbonylmethylcarboamidine hydrochloride and 3.7 ml (0.025 mol) of 1,1-dimethoxy-3-butanone were heated and stirred under reflux with 50 ml of acetonitrile. The reaction solution was sampled and the production rate of ethyl 2-amino-6-methylnicotinate was followed over time. The reaction yield reached 63.9% in 17 hours from the start of reflux.

Example 3
The same procedure as in Example 2 was performed except that the amount of 1,1-dimethoxy-3-butanone was changed from 3.7 ml (0.025 mol) to 7.4 ml (0.05 mol). The reaction yield reached 62.4% in 9 hours from the start of reflux.

[Comparative Example 1]
The same operation as in Example 2 was conducted except that ethoxycarbonylmethylcarboamidine hydrochloride (0.025 mol) was changed to ethoxycarbonylmethylcarboamidine (0.025 mol). The reaction yield for 4 hours from the start of reflux was 7%. The reaction yield of Example 2 at 4 hours was 37.1%, which was lower than that of Example 2 and more by-products.

[Comparative Example 2]
Ethoxycarbonylmethylcarboamidine hydrochloride 4.17 g (0.025 mol), 1,1-dimethoxy-3-butanone 3.7 ml (0.025 mol) and potassium carbonate 10.4 g (0.075 mol) were mixed with 50 ml of acetonitrile. And heated and stirred under reflux. The reaction yield for 6 hours from the start of reflux was 16%. The reaction yield at 6 hours of Example 2 was 46.2%, which was lower than that of Example 2 and more by-products.

[Comparative Example 3]
4.17 g (0.025 mol) of ethoxycarbonylmethylcarboamidine hydrochloride, 3.7 ml (0.025 mol) of 1,1-dimethoxy-3-butanone and 2.7 g (0.05 mol) of sodium methoxide in acetonitrile The mixture was heated and stirred under reflux with 50 ml. The reaction yield for 6 hours from the start of reflux was 17%. The reaction yield at 6 hours of Example 2 was 46.2%, which was lower than that of Example 2 and more by-products.

  As described above, the production method of the present invention is a method for producing 2-amino-6-methylnicotinic acid ester, which is a production intermediate compound of a compound useful as an active ingredient of a pharmaceutical or agricultural chemical, at high yield and at low cost. It is.

Claims (2)

The following formula (1),

(In Formula (1), R shows an aryl group or a C1-C8 alkyl group, and this aryl group or alkyl group may have a substituent.)
A process for producing 2-amino-6-methylnicotinic acid ester represented by
In the polar organic solvent, the following formula (2),

(In Formula (2), R is as defined above, HX represents a protonic acid, and n represents an integer of 1 to 3.)
And 2-oxybutyraldehyde or at least one of its acetals is substantially reacted in the absence of a basic substance. A process for producing amino-6-methylnicotinic acid ester.   After the reaction, a concentration step in which the polar organic solvent and the low-boiling components are removed from the reaction solution by distillation, and a protonic acid salt of the compound of the formula (1) is extracted from the concentrate obtained by the concentration step into an aqueous layer. The production method according to claim 1, further comprising an extraction step and a crystallization step of adding an alkali compound to the extracted aqueous layer obtained by the extraction step to precipitate crystals.