CN116888094A - Method for preparing D-alanine alkyl ester, derivative thereof, and pharmaceutical or agricultural product comprising same - Google Patents

Method for preparing D-alanine alkyl ester, derivative thereof, and pharmaceutical or agricultural product comprising same Download PDF

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CN116888094A
CN116888094A CN202280014398.7A CN202280014398A CN116888094A CN 116888094 A CN116888094 A CN 116888094A CN 202280014398 A CN202280014398 A CN 202280014398A CN 116888094 A CN116888094 A CN 116888094A
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chemical formula
compound
alkyl ester
methyl
ester derivative
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姜明求
金知源
安昞勋
李炅原
李沅宰
郑大然
赵载夏
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LG Chem Ltd
FarmHannong Co Ltd
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FarmHannong Co Ltd
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Priority claimed from PCT/KR2022/009361 external-priority patent/WO2023277590A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
    • A01N37/46—N-acyl derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives

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  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

The present specification relates to a method of preparing a D-alanine alkyl ester, the D-alanine alkyl ester derivative, and a pharmaceutical or agricultural product comprising the same, the method of preparing the D-alanine alkyl ester comprising: distilling a composition comprising the compound of formula 3 synthesized by reacting formula 1 with formula 2 at a pressure of 1 torr to 60 torr and a temperature of 60 ℃ to 200 ℃.

Description

Method for preparing D-alanine alkyl ester, derivative thereof, and pharmaceutical or agricultural product comprising same
Technical Field
The present application claims priority and rights of korean patent application nos. 10-2021-0084514 and 10-2021-0084117, filed on 29 th year 2021, to the korean intellectual property office, the entire contents of both of which are incorporated herein by reference.
The present specification relates to a method of preparing a D-alanine alkyl ester, a D-alanine alkyl ester derivative, and a pharmaceutical or agricultural product comprising the same.
Background
N- (2, 6-dimethylphenyl) -D-alanine methyl ester is of great commercial value as a synthetic intermediate required for the preparation of crop protection agents such as metalaxyl-M, benalaxyl-M and furalaxyl-M.
As a conventional method for synthesizing methyl N- (2, 6-dimethylphenyl) -D-alaninate, it is known to use methyl(s) -2- (methylsulfonyloxy) propionate or methyl(s) -2- (p-toluenesulfonyloxy) propionate and an organic or inorganic base, as well as 2, 6-dimethylamine. In this case, disubstituted impurities are generated due to the excessive reaction, and the commercial value of the product is deteriorated, making it difficult to remove the impurities by conventional purification methods of crystallization or recrystallization.
Therefore, designing a specific method capable of reducing the content of disubstituted impurities due to excessive reaction is an important problem to be solved.
Disclosure of Invention
Technical problem
The present specification provides a method of preparing a D-alanine alkyl ester, a D-alanine alkyl ester derivative, and a pharmaceutical or agricultural product comprising the same.
Technical proposal
An exemplary embodiment of the present specification provides a method for preparing an alkyl D-alaninate, the method comprising: synthesizing a compound of the following chemical formula 3 by reacting a compound of the following chemical formula 1 with a compound of the following chemical formula 2; and
distilling a composition comprising the compound of formula 3 at a pressure of 1 torr to 60 torr and a temperature of 60 ℃ to 200 ℃.
[ chemical formula 1]
[ chemical formula 2]
[ chemical formula 3]
In the chemical formulas 1 to 3,
r1 is methyl or aryl substituted by methyl,
r2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or a methyl group,
r4 is methyl.
Another exemplary embodiment of the present specification provides a method for preparing a D-alanine alkyl ester derivative, the method comprising: synthesizing a compound of the following chemical formula 3 by reacting a compound of the following chemical formula 1 with a compound of the following chemical formula 2;
distilling a composition comprising the compound of formula 3 at a pressure of 1 torr to 60 torr and a temperature of 60 ℃ to 200 ℃; and
the compound of the following chemical formula 6 is synthesized by adding the compound of the following chemical formula 5 to the distilled composition.
[ chemical formula 1]
[ chemical formula 2]
[ chemical formula 3]
[ chemical formula 5]
[ chemical formula 6]
In chemical formulas 1 to 3, 5 and 6,
r1 is methyl or aryl substituted by methyl,
r2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or a methyl group,
r4 is a methyl group, and the R is a methyl group,
r5 is methylene substituted with methoxy; a methylene group substituted with a phenyl group; or furyl.
Another exemplary embodiment of the present specification provides a composition including a compound of the following chemical formula 3 and a compound of the following chemical formula 4, wherein the content of the compound of the following chemical formula 4 is 0.1 area% or less based on the total GC area of the composition.
[ chemical formula 3]
[ chemical formula 4]
In the chemical formula 3 and the chemical formula 4,
r2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or a methyl group,
r4 is methyl.
Yet another exemplary embodiment of the present specification provides a D-alanine alkyl ester derivative prepared by reacting a compound of chemical formula 3 with a compound of chemical formula 5 below in the above composition.
[ chemical formula 5]
In the chemical formula 5, the chemical formula is shown in the drawing,
r5 is methylene substituted with methoxy; a methylene group substituted with a phenyl group; or furyl.
Still another exemplary embodiment of the present specification provides a pharmaceutical or agricultural product comprising the above-described D-alanine alkyl ester derivative.
Advantageous effects
According to the preparation method of one exemplary embodiment of the present specification, a D-alanine alkyl ester having a low content of disubstituted impurities due to excessive reaction can be prepared.
The preparation method according to one exemplary embodiment of the present specification may prepare high purity D-alanine alkyl ester.
The preparation method according to one exemplary embodiment of the present specification may enable confirmation of high purity D-alanine alkyl ester by visual inspection.
Drawings
FIG. 1 is an ultraviolet-visible (UV/vis) absorption spectrum of methanol (blank solvent).
FIG. 2 is a UV/vis transmission spectrum of methanol (blank solvent).
FIG. 3 is a UV/vis absorption spectrum of a methanol solution of chemical formula 3-1 containing 10mg/mL in example 2.
FIG. 4 is a UV/vis transmission spectrum of a methanol solution of formula 3-1 containing 10mg/mL in example 2.
FIG. 5 is a UV/vis absorption spectrum of a methanol solution of chemical formula 6-1 containing 10mg/mL in example 2.
FIG. 6 is a UV/vis transmission spectrum of a methanol solution of chemical formula 6-1 containing 10mg/mL in example 2.
Detailed Description
Hereinafter, the present specification will be described in detail.
In this specification, when a portion "includes" one constituent element, unless otherwise specifically described, this does not mean to exclude another constituent element, but means that another constituent element may be further included.
An exemplary embodiment of the present specification provides a method for preparing an alkyl D-alaninate, the method comprising: synthesizing a compound of the following chemical formula 3 by reacting a compound of the following chemical formula 1 with a compound of the following chemical formula 2; and distilling the composition comprising the compound of formula 3.
[ chemical formula 1]
[ chemical formula 2]
[ chemical formula 3]
In the chemical formulas 1 to 3,
r1 is methyl or aryl substituted by methyl,
r2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or a methyl group,
r4 is methyl.
In one exemplary embodiment of the present specification, the distillation of the composition is distillation of the composition at a pressure of 1 torr to 60 torr and a temperature of 60 ℃ to 200 ℃.
Both the compound of chemical formula 3 and the compound of chemical formula 4 are viscous liquids. This is because the method such as crystallization or recrystallization after dissolution cannot be adopted like the material having the conventional solid properties, and even if the material is washed with water while being dissolved in an organic solvent, it is difficult to remove chemical formula 4, and the yield is lowered due to the loss of chemical formula 3 in the aqueous layer. Specifically, when an organic layer washing method of separating an organic layer by washing the organic layer with water by phase separation without distillation is used, the content of chemical formula 4, which is an impurity generated from a reaction mixture, is hardly reduced. When this organic layer washing method is used, chemical formula 3 in the composition is instead lost due to washing with water, resulting in low yield.
The present inventors devised a method of removing chemical formula 4 by distilling the compound of chemical formula 3.
When distillation is performed outside the corresponding pressure and temperature ranges, or when a combination thereof is not used, a composition comprising chemical formula 3 cannot be obtained from the reaction mixture by distillation.
In contrast, when distillation is performed using a combination of pressure and temperature ranges in one exemplary embodiment of the present specification, the above-described drawbacks are compensated, and thus, a composition containing chemical formula 3 and having a low content of chemical formula 4 can be obtained in a relatively high yield without loss of water washing.
Since the combination of pressure and temperature ranges in one exemplary embodiment of the present specification is not a high temperature or vacuum pressure condition which is difficult to achieve in a mass production process, there is an advantage in that pressure and temperature can be sufficiently applied to mass production in a factory.
In one exemplary embodiment of the present specification, the distillation of the composition is distillation of the composition at the following pressures: 1 to 50 torr, 1 to 40 torr, 1 to 30 torr, 1 to 20 torr, 5 to 15 torr, 5 to 10 torr, or 5 to 7 torr.
In one exemplary embodiment of the present specification, the distillation of the composition is distillation of the composition at the following pressures: 1 torr or more, 2 torr or more, 3 torr or more, 4 torr or more, or 5 torr or less, and 60 torr or less, 55 torr or less, 50 torr or less, 45 torr or less, 40 torr or less, 35 torr or less, 30 torr or less, 25 torr or less, 20 torr or less, 15 torr or less, 10 torr or less, 9 torr or less, 8 torr or less, or 7 torr or less.
In one exemplary embodiment of the present specification, the distillation of the composition is distillation of the composition at the following temperatures: 70 ℃ to 200 ℃, 80 ℃ to 200 ℃, 90 ℃ to 200 ℃, 100 ℃ to 200 ℃, 110 ℃ to 150 ℃, 110 ℃ to 130 ℃, or 118 ℃ to 130 ℃.
In one exemplary embodiment of the present specification, the distillation of the composition is distillation of the composition at the following temperatures: 60 ℃ or more, 70 ℃ or more, 80 ℃ or more, 90 ℃ or more, 100 ℃ or more, 110 ℃ or more, 115 ℃ or more, or 118 ℃ or more, and 200 ℃ or less, 190 ℃ or less, 180 ℃ or less, 170 ℃ or less, 160 ℃ or less, 150 ℃ or less, 140 ℃ or less, or 130 ℃ or less.
In one exemplary embodiment of the present specification, the distillation is to distill the composition comprising the compound of chemical formula 3 at a pressure of 5 torr to 10 torr and a temperature of 110 ℃ to 150 ℃.
In one exemplary embodiment of the present specification, the distillation is distilling the composition comprising the compound of formula 3 at a pressure of 5 torr to 7 torr and a temperature of 118 ℃ to 130 ℃.
In one exemplary embodiment of the present specification, distillation of the composition is to remove disubstituted impurities generated due to an excessive reaction, in particular, to remove the compound of the following chemical formula 4 as the disubstituted impurities. Thus, the compound of formula 3, i.e., D-alanine alkyl ester, can be prepared in high purity, and the purity of the final products such as metalaxyl-M, benalaxyl-M and furalaxyl-M synthesized using D-alanine alkyl ester as an intermediate can also be improved.
In one exemplary embodiment of the present specification, the distillation of the composition is to prepare a composition in which the content of the compound of the following chemical formula 4 is 0.1 area% or less based on the total GC area of the composition.
[ chemical formula 4]
In the chemical formula 4, the chemical formula is shown in the drawing,
r2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or a methyl group,
r4 is methyl.
In an exemplary embodiment of the present specification, in the distillation of the composition, the distillation may be performed one or more times, particularly several times, such as one or more times, two or more times, or three or more times.
In one exemplary embodiment of the present specification, the content of the compound of chemical formula 4 may be 0.1 area% or less, 0.09 area% or less, or 0.08 area% or less based on the total GC area of the composition by distillation of the composition, and the lower the content of the compound of chemical formula 4 is, the better, and thus, the lower limit thereof is not particularly limited.
In one exemplary embodiment of the present specification, the content of the compound of chemical formula 2 is 2 equivalents to 10 equivalents based on the compound of chemical formula 1. In this case, the equivalent of chemical formula 2 used is suitable, and thus, there is an advantage in that side reactions can be controlled while increasing the reaction rate.
Another exemplary embodiment of the present specification provides a method for preparing a D-alanine alkyl ester derivative, the method comprising: synthesizing a compound of the following chemical formula 3 by reacting a compound of the following chemical formula 1 with a compound of the following chemical formula 2; distilling a composition comprising the compound of formula 3 at a pressure of 1 torr to 60 torr and a temperature of 60 ℃ to 200 ℃; and synthesizing the compound of the following chemical formula 6 by adding the compound of the following chemical formula 5 to the distilled composition.
[ chemical formula 1]
[ chemical formula 2]
[ chemical formula 3]
[ chemical formula 5]
[ chemical formula 6]
In chemical formulas 1 to 3, 5 and 6,
r1 is methyl or aryl substituted by methyl,
r2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or a methyl group,
r4 is a methyl group, and the R is a methyl group,
r5 is methylene substituted with methoxy; a methylene group substituted with a phenyl group; or furyl.
In this specification, when the aryl group is a monocyclic aryl group, the number of carbon atoms thereof is not particularly limited, but is preferably 6 to 25. Specific examples of the monocyclic aryl group include phenyl, biphenyl, terphenyl, and the like, but are not limited thereto.
When the aryl group is a polycyclic aryl group, the number of carbon atoms thereof is not particularly limited, but is preferably 10 to 24. Specific examples of polycyclic aryl groups include naphthyl, anthryl, phenanthryl, pyrenyl, perylenyl,A radical, a fluorenyl radical, etc., but is not limited thereto.
In the present specification, a fluorenyl group may be substituted, and adjacent substituents may be bonded to each other to form a ring.
In one exemplary embodiment of the present description, R1 is methyl; or phenyl substituted with methyl.
In one exemplary embodiment of the present description, R1 is methyl; or (b)And->Is the bonding location.
In one exemplary embodiment of the present specification, R2 and R3 are the same or different from each other and are each independently hydrogen; or methyl.
In one exemplary embodiment of the present description, R2 and R3 are methyl.
In one exemplary embodiment of the present specification, R5 is methylene substituted with methoxy. In other words, R5 is in a state in which any one hydrogen of the methyl group is substituted with a methoxy group. In this case, the compound of chemical formula 6 is metalaxyl-M.
In one exemplary embodiment of the present description, R5 is methylene substituted with phenyl. In other words, R5 is in a state in which any one hydrogen of the methyl group is substituted with a phenyl group. In this case, the compound of chemical formula 6 is benalaxyl-M.
In one exemplary embodiment of the present description, R5 is furyl. In this case, the compound of chemical formula 6 is furalaxyl-M.
Yet another exemplary embodiment of the present specification provides a composition including a compound of the following chemical formula 3 and a compound of the following chemical formula 4, wherein the content of the compound of the following chemical formula 4 is 0.1 area% or less based on the total GC area of the composition.
[ chemical formula 3]
[ chemical formula 4]
In the chemical formula 3 and the chemical formula 4,
r2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or a methyl group,
r4 is methyl.
In this specification, the description of the composition refers to the description of the process for preparing the alkyl D-alaninates and their derivatives as described previously.
Another exemplary embodiment of the present specification provides a D-alanine alkyl ester derivative prepared by reacting a compound of chemical formula 3 with a compound of chemical formula 5 below in the above composition.
[ chemical formula 5]
In the chemical formula 5, the chemical formula is shown in the drawing,
r5 is methylene substituted with methoxy; a methylene group substituted with a phenyl group; or furyl.
In this specification, the description of the D-alanine alkyl ester derivative refers to the description of the method for producing the D-alanine alkyl ester and the derivative thereof as described above.
The first exemplary embodiment of the present specification provides a D-alanine alkyl ester derivative comprising a D-alanine alkyl ester derivative and methanol, wherein in a UV/vis absorption spectrum of a solution having a concentration of 10mg/mL, absorbance at 266nm is 3.00 or less, and absorbance at 274nm is 2.60 or less.
A second exemplary embodiment of the present specification provides a D-alanine alkyl ester derivative comprising a D-alanine alkyl ester derivative and methanol, wherein in a UV/vis absorption spectrum of a solution having a concentration of 10mg/mL, the absorbance at 266nm is 3.00 or less, and the absorbance at 274nm is 2.6 or less; and a D-alanine alkyl ester derivative comprising a D-alanine alkyl ester derivative and methanol, wherein in a UV/vis transmittance spectrum of a solution having a concentration of 10mg/mL, the transmittance at 266nm is 0.10 or more and the transmittance at 274nm is 0.29 or more.
A third exemplary embodiment of the present specification provides a D-alanine alkyl ester derivative comprising a D-alanine alkyl ester derivative and methanol, wherein absorbance at 266nm is 3.00 or less in UV/vis absorption spectrum of a solution having a concentration of 10 mg/mL; and a D-alanine alkyl ester derivative comprising a D-alanine alkyl ester derivative and methanol, wherein the transmittance at 266nm in the UV/vis transmittance spectrum of a solution having a concentration of 10mg/mL is 0.10 or more.
A fourth exemplary embodiment of the present specification provides a D-alanine alkyl ester derivative comprising a D-alanine alkyl ester derivative and methanol, wherein absorbance at 274nm is 2.60 or less in UV/vis absorption spectrum of a solution having a concentration of 10 mg/mL; and a D-alanine alkyl ester derivative comprising a D-alanine alkyl ester derivative and methanol, wherein the transmittance at 274nm in the UV/vis transmittance spectrum of a solution having a concentration of 10mg/mL is 0.29 or more.
In the ultraviolet/visible spectrum, the lower the absorbance and the higher the transmittance, the closer the material is to a clear and transparent water-like state as seen with the naked eye when the material is in the dissolved (solution) state. In general, the more in the above state, the brighter and more nearly white in appearance becomes when the liquid is formulated, and thus, is advantageous in that it is commercially advantageous. For example, in the case of an injectable solution, the state of the contents can be seen because the injectable solution is contained in a transparent vial, and thus, the manufacturing company prefers the active ingredient to appear colorless and transparent in the state of the solution. Thus, when a liquid is formulated, yellow instead of brown, yellow which is more transparent than cloudy yellow, and a state closer to water may become advantageous in appearance.
In one exemplary embodiment of the present specification, the D-alanine alkyl ester derivative is the following chemical formula 6-1, which is prepared by reacting a compound of the following chemical formula 3-1 distilled at a pressure of 1 torr to 60 torr and a temperature of 60 ℃ to 200 ℃ with a compound of the following chemical formula 5-1. In other words, the D-alanine alkyl ester derivative may be N- (methoxyacetyl) -N- (2, 6-dimethylphenyl) -D-alanine methyl ester prepared by reacting distilled N- (2, 6-dimethylphenyl) -D-alanine methyl ester with the compound of the following chemical formula 5-1.
[ chemical formula 3-1]
[ chemical formula 5-1]
[ chemical formula 6-1]
In one exemplary embodiment of the present specification, the impurities of the following chemical formula 4-1 are removed by distilling the chemical formula 3-1.
[ chemical formula 4-1]
The compound of chemical formula 3-1 and the compound of chemical formula 4-1 are both viscous liquids. This is because a method such as crystallization or recrystallization after dissolution cannot be adopted like a material having conventional solid properties, and even if the material is washed with water while being dissolved in an organic solvent, it is difficult to remove chemical formula 4-1, and the yield is lowered due to the loss of chemical formula 3-1 in the aqueous layer. Specifically, when an organic layer washing method of separating an organic layer by washing the organic layer with water by phase separation without distillation is used, the content of chemical formula 4-1 as an impurity generated from the reaction mixture is hardly reduced. When this organic layer washing method is used, chemical formula 3-1 in the composition is instead lost due to washing with water, resulting in low yield.
When distillation is performed using a combination of pressure and temperature ranges in one exemplary embodiment of the present specification, a composition containing chemical formula 3-1 and having a low content of chemical formula 4-1 can be obtained in a relatively high yield without loss of water washing. In this case, considering that the above state is a state in which chemical formula 4-1 is contained as an impurity, the state of chemical formula 3-1 before or after distillation may be expressed as a composition containing chemical formula 3-1 or a composition containing chemical formulas 3-1 and 4-1.
In one exemplary embodiment of the present specification, the distillation of the compound of formula 3-1 is distillation of formula 3-1 at the following pressure: 1 to 50 torr, 1 to 40 torr, 1 to 30 torr, 1 to 20 torr, or 5 to 20 torr.
In one exemplary embodiment of the present description, the distillation of the compound of formula 3-1 is to distill the compound of formula 3-1 at the following temperature: 70 ℃ to 200 ℃, 80 ℃ to 200 ℃, 90 ℃ to 200 ℃, 100 ℃ to 200 ℃, 110 ℃ to 200 ℃,120 ℃ to 200 ℃, or 130 ℃ to 200 ℃.
In one exemplary embodiment of the present specification, when distilling the compound of chemical formula 3-1, the distillation may be performed one or more times, specifically, several times, such as one or more times, two or more times, or three or more times.
In one exemplary embodiment of the present specification, the content of the compound of formula 4-1 may be 0.1 area% or less, 0.09 area% or less, or 0.08 area% or less based on the total GC area of the distilled compound of formula 3-1 by distillation of the compound of formula 3-1, and the lower the content of the compound of formula 4-1 is, the better, and thus, the lower limit thereof is not particularly limited.
In one exemplary embodiment of the present specification, the D-alanine alkyl ester derivative is the following chemical formula 6-1 prepared by reacting the compound of the following chemical formula 3-1 with the compound of the following chemical formula 5-1, and the content of the compound of the following chemical formula 4-1 is 0.1 area% or less based on the total GC area of the compounds of the chemical formula 3-1.
[ chemical formula 3-1]
[ chemical formula 5-1]
[ chemical formula 6-1]
[ chemical formula 4-1]
In one exemplary embodiment of the present specification, in the UV/vis absorption spectrum of a methanol solution containing 10mg/mL of the distilled compound of chemical formula 3-1, the absorbance at 266nm may be 3.60 or less, and the absorbance at 274nm may be 3.40 or less.
In one exemplary embodiment of the present specification, in the UV/vis transmission spectrum of a methanol solution containing 10mg/mL of the distilled compound of chemical formula 3-1, the transmittance at 266nm may be 0.03 or more and the transmittance at 274nm may be 0.04 or more.
Since the absorbance of the compound of chemical formula 3-1 is low and the transmittance thereof is high, the compound prepared by using the compound of chemical formula 3-1, i.e., the compound of chemical formula 6-1, may also have low absorbance and high transmittance. The compound of chemical formula 6-1 synthesized from the compound of chemical formula 3-1 has high transparency, and thus, a D-alanine alkyl ester derivative satisfying the conditions of absorbance or transmittance of the present specification can be prepared.
Yet another exemplary embodiment of the present specification provides a pharmaceutical or agricultural product comprising the above-described D-alanine alkyl ester derivative.
In this case, the medicine or agricultural product includes not only a state containing the D-alanine alkyl ester derivative itself but also a state modified for various uses, that is, a state modified by a necessary chemical reaction.
In the present specification, the agricultural product may be various agricultural chemicals such as herbicides, crop protection agents and fungicides.
Hereinafter, the present specification will be described in more detail by way of examples. However, the following examples are provided only to illustrate the present specification and are not intended to limit the same.
Examples (example)
Example 1
Methyl(s) -2- (methylsulfonyloxy) propionate (20.00 g,109.78 mmol), triethylamine (12.22 g,120.75 mmol) and 2, 6-dimethylaniline (106.43 g,274.45 mmol) were added to a reactor containing toluene (20 mL) at room temperature, the internal temperature was raised to 120℃to 130℃and the mixture was stirred.
After confirming that the unreacted(s) -methyl 2- (methylsulfonyloxy) propionate remaining in the reaction mixture was 1.0 area% or less (GC analysis result), the reaction mixture was cooled to room temperature. Thereafter, the internal pressure was reduced to 60 torr at room temperature. After diluting crude N- (2, 6-dimethylphenyl) -D-alanine methyl ester obtained by distillation in toluene (100 mL) by slowly adjusting the internal temperature from 60℃to 200℃under an internal pressure in the range of 1 Torr to 60 Torr, an organic layer obtained by washing the crude N- (2, 6-dimethylphenyl) -D-alanine methyl ester once with 1N aqueous HCl (20 mL) was washed once with distilled water (30 mL), and then concentrated under reduced pressure, thereby obtaining N- (2, 6-dimethylphenyl) -D-alanine methyl ester having a purity of 98.52GC area% in 80% yield.
Example 2
Methyl(s) -2- (methylsulfonyloxy) propionate (20.00 g,109.78 mmol), triethylamine (12.22 g,120.75 mmol) and 2, 6-dimethylaniline (106.43 g,274.45 mmol) were added to a reactor containing toluene (20 mL) at room temperature, the internal temperature was raised to 120℃to 130℃and the mixture was stirred.
After confirming that the unreacted(s) -methyl 2- (methylsulfonyloxy) propionate remaining in the reaction mixture was 1.0 area% or less (GC analysis result), the reaction mixture was cooled to room temperature. Thereafter, the internal pressure was reduced to 50 torr at room temperature. The crude chemical formula 3-1 (=n- (2, 6-dimethylphenyl) -D-alanine methyl ester) is obtained by distillation by slowly increasing and adjusting the internal temperature from 50 ℃ to 150 ℃ under the condition that the internal pressure is in the range of 1 torr to 50 torr. After diluting the crude chemical formula 3-1 with toluene (100 mL), the organic layer obtained by washing the crude chemical formula 3-1 once with 1N aqueous HCl (20 mL) was washed once with distilled water (30 mL), and then concentrated under reduced pressure. Thus, colorless transparent methyl ester of chemical formula 3-1 (=n- (2, 6-dimethylphenyl) -D-alanine) was obtained in 80% yield, with a purity of 98.5%, an absorbance at 266nm of 3.569 (transmittance of 0.027), and an absorbance at 274nm of 3.353 (transmittance of 0.044).
Chemical formula 3-1 (18.08 g,87.24 mmol) was diluted in toluene (60 mL). To which NaHCO is added 3 (8.03 g,95.96 mol) and cooling the internal temperature to-5 ℃ to 0 ℃, chemical formula 2 (=methoxyacetyl chloride) (10.37 g,95.96 mmol) was slowly added thereto so that the internal temperature was maintained, and then the resulting mixture was stirred while maintaining the temperature at 0 ℃ to 10 ℃. After confirming that the unreacted chemical formula 1 remaining in the reaction mixture was 0.1 area% or less (GC analysis result), the pH was confirmed to be 7 to 8 by washing the reaction mixture twice with distilled water (60 mL), and then the organic layer obtained by layer separation was concentrated under reduced pressure. Thus, methyl ester of chemical formula 6-1 (=n- (2, 6-dimethylphenyl) -N- (methoxyacetyl) -D-alanine) was obtained in a yield of 90% as a bright yellow color with a purity of 98.8%, an absorbance at 266nm of 2.974 (transmittance of 0.106), and an absorbance at 274nm of 2.527 (transmittance of 0.297).
Comparative example 1
Methyl(s) -2- (methylsulfonyloxy) propionate (20.00 g,109.78 mmol), triethylamine (12.22 g,120.75 mmol) and 2, 6-dimethylaniline (106.43 g,274.45 mmol) were added to a reactor containing toluene (20 mL) at room temperature, the internal temperature was raised to 120℃to 130℃and the mixture was stirred.
After confirming that the unreacted(s) -methyl 2- (methylsulfonyloxy) propionate remaining in the reaction mixture was 1.0 area% or less (result of GC analysis), the reaction mixture was cooled to room temperature, and then a catalyst was prepared by adding H thereto 2 The solid produced by O (40 mL) was dissolved, then diluted in toluene (100 mL), then the organic layer obtained by washing the solid three times with 1N aqueous HCl (40 mL) was washed twice with 1N aqueous NaOH solution (40 mL), then the organic layer was washed once with distilled water (30 mL), then concentrated under reduced pressure to give methyl N- (2, 6-dimethylphenyl) -D-alaninate with a purity of 97.24GC area% in 68% yield.
Comparative example 2
Methyl(s) -2- (methylsulfonyloxy) propionate (20.00 g,109.78 mmol), triethylamine (12.22 g,120.75 mmol) and 2, 6-dimethylaniline (106.43 g,274.45 mmol) were added to a reactor containing toluene (20 mL) at room temperature, the internal temperature was raised to 120℃to 130℃and the mixture was stirred.
After confirming that the unreacted(s) -methyl 2- (methylsulfonyloxy) propionate remaining in the reaction mixture was 1.0 area% or less (GC analysis result), the reaction mixture was cooled to room temperature. Thereafter, the internal pressure was lowered to 100 torr at room temperature, and in a state where the internal pressure was in a range of 61 torr to 100 torr, the internal temperature was slowly raised from 60 ℃ and adjusted to 200 ℃, but N- (2, 6-dimethylphenyl) -D-alanine methyl ester could not be obtained.
Comparative example 3
Methyl(s) -2- (methylsulfonyloxy) propionate (20.00 g,109.78 mmol), triethylamine (12.22 g,120.75 mmol) and 2, 6-dimethylaniline (106.43 g,274.45 mmol) were added to a reactor containing toluene (20 mL) at room temperature, the internal temperature was raised to 120℃to 130℃and the mixture was stirred.
After confirming that unreacted(s) -methyl 2- (methylsulfonyloxy) propionate remaining in the reaction mixture was 1.0 area% or less (result of GC analysis), the reaction mixture was cooled to room temperature, and then a catalyst was prepared by adding H thereto 2 O (40 mL) and then diluted in toluene (100 mL). The organic layer obtained by washing the diluted solid three times with 1N aqueous HCl (40 mL) was washed twice with 1N NaOH solution (40 mL), then washed once with distilled water (30 mL), and then concentrated under reduced pressure. As a result, methyl ester of the formula 3-1 (=N- (2, 6-dimethylphenyl) -D-alanine) was obtained in a yield of 68% as yellow with a purity of 97.2%, an absorbance at 266nm of 3.842 (transmittance of 0.014), and an absorbance at 274nm of 3.685 (transmittance of 0.021).
Chemical formula 3-1 (18.08 g,87.24 mmol) was diluted in toluene (60 mL). To which NaHCO is added 3 (8.03 g,95.96 mmol) and cooling the internal temperature to-5℃to 0℃and then slowly adding thereto the compound of formula 5-1 (=methoxy)Acetyl chloride) (10.37 g,95.96 mmol) such that the internal temperature is maintained, and then the resulting mixture is stirred while the temperature is maintained at 0 to 10 ℃. After confirming that the unreacted chemical formula 3-1 remaining in the reaction mixture was 0.1 area% or less (GC analysis result), the reaction mixture was washed twice with distilled water (60 mL). After confirming the pH of 7 to 8, the organic layer obtained by layer separation was concentrated under reduced pressure. As a result, brown methyl chemical formula 6-1 (=N- (2, 6-dimethylphenyl) -N- (methoxyacetyl) -D-alaninate) was obtained in a yield of 90%, which was 97.4% pure, and had an absorbance at 266nm of 3.211 (transmittance of 0.062) and an absorbance at 274nm of 2.841 (transmittance of 0.144).
Test example 1
Samples were taken from the syntheses of example 1 and comparative examples 1 and 2, and were measured by gas chromatography analysis with flame ionization detector (GC/FID) using Shimadzu GC-2030 under the following conditions. The results are summarized in table 1 below. In this case, the respective purities and contents refer to GC area% based on the total GC area measured by GC/FID.
In this case, the GC/FID analysis of the reaction mixture was measured using Shimadzu GC-2030 under the following conditions.
Column: [ HP-5] (0.25 mm ID. Times.30 mL,0.25 μm d.f. Capillary)
Oven temperature
Initial value and hold time: 50 ℃ for 5 minutes
Program rate: 10 ℃/min
Final value and hold time: 320 ℃ for 18 minutes
Injector temperature: 340 DEG C
Detector temperature: 340 DEG C
Gas flow rate: column (N) 2 )：1mL/min
Split ratio: 1/20
Injection amount: 1.0uL
TABLE 1
It was confirmed from table 1 that when distillation was not performed, the yield was significantly reduced due to washing with water, the impurity of chemical formula 4 was not removed well, and in the case of comparative example 2 in which the distillation condition was not suitable, the target compound was not captured even when distillation was performed, and thus the final product could not be obtained. In contrast, when distillation was performed under the conditions of the present specification, it was confirmed that the yield was high, and the impurity of chemical formula 4 was also significantly removed.
Test example 2
To confirm absorbance and transmittance, samples were taken in each step of example 2 and comparative example 3, and absorbance and transmittance were measured using a UV/Vis spectrophotometer, and were measured using Agilent Technologies, cary 8454 UV-Vis under the following conditions. The results are summarized in table 2 below.
Further, absorbance and transmittance spectra of example 2, comparative example 3, and methanol as a blank solvent are shown in fig. 1 to 6.
Analysis concentration: 10mg/mL
Dilution solvent (or blank solvent): meOH (MeOH)
Analysis wavelength: 266nm and 274nm
And (3) an analysis pool: quartz cell with path length of 10mm
TABLE 2
In the ultraviolet/visible spectrum, the lower the absorbance and the higher the transmittance, the closer the material is to a clear, transparent, water-like state that is visible to the naked eye when the material is in a dissolved (solution) state. In Table 2, it was confirmed that, when the absorbance at 266nm of chemical formula 6-1 as a D-alanine alkyl ester derivative was compared, example 2 showed 2.974 satisfying the range of 3.00 or less, but comparative example 3 showed 3.211 exceeding 3.00. It was confirmed that the absorbance at 274nm of chemical formula 6-1 was 2.527 in example 2 and satisfied the range of 2.60 or less, but was 2.841 in comparative example 3 and exceeded 2.60.
In Table 2, it was confirmed that when the transmittance at 266nm of chemical formula 6-1 as a D-alanine alkyl ester derivative was compared, example 2 was 0.106, a range of 0.10 or more was satisfied, and comparative example 3 was 0.062, less than 0.10. Further, it was confirmed that the transmittance at 274nm of chemical formula 6-1 was 0.297 in example 2, which satisfied the range of 0.29 or more, but was 0.144 in comparative example 3, which was less than 0.29.
Thus, example 2 was clearer and more transparent than comparative example 3 by visual observation, and example 2, which was improved in transparency, had a high aesthetic appearance, and thus was commercially highly preferred.

Claims (13)

1. A method of preparing a D-alanine alkyl ester, the method comprising:
synthesizing a compound of the following chemical formula 3 by reacting a compound of the following chemical formula 1 with a compound of the following chemical formula 2; and
distilling a composition comprising the compound of formula 3 at a pressure of 1 torr to 60 torr and a temperature of 60 ℃ to 200 ℃:
[ chemical formula 1]
[ chemical formula 2]
[ chemical formula 3]
Wherein, in chemical formulas 1 to 3,
r1 is methyl or aryl substituted by methyl,
r2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or a methyl group,
r4 is methyl.
2. The method of claim 1, wherein the distillation of the composition is to prepare a composition in which the content of the compound of the following chemical formula 4 is 0.1 area% or less based on the total GC area of the composition:
[ chemical formula 4]
In the chemical formula 4, the chemical formula is shown in the drawing,
r2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or a methyl group,
r4 is methyl.
3. The method of claim 1, wherein the compound of formula 2 is contained in an amount of 2 to 10 equivalents based on the compound of formula 1.
4. A method of preparing a D-alanine alkyl ester derivative, the method comprising:
synthesizing a compound of the following chemical formula 3 by reacting a compound of the following chemical formula 1 with a compound of the following chemical formula 2;
distilling a composition comprising the compound of formula 3 at a pressure of 1 torr to 60 torr and a temperature of 60 ℃ to 200 ℃; and
the compound of the following chemical formula 6 is synthesized by adding the compound of the following chemical formula 5 to the distilled composition:
[ chemical formula 1]
[ chemical formula 2]
[ chemical formula 3]
[ chemical formula 5]
[ chemical formula 6]
In chemical formulas 1 to 3, 5 and 6,
r1 is methyl or aryl substituted by methyl,
r2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or a methyl group,
r4 is a methyl group, and the R is a methyl group,
r5 is methylene substituted with methoxy; a methylene group substituted with a phenyl group; or furyl.
5. The method of claim 1 or 4, wherein the distilling is distilling the composition comprising the compound of formula 3 at a pressure of 5 torr to 10 torr and a temperature of 110 ℃ to 150 ℃.
6. A composition comprising a compound of the following chemical formula 3 and a compound of the following chemical formula 4,
wherein the content of the compound of the following chemical formula 4 is 0.1 area% or less based on the total GC area of the composition:
[ chemical formula 3]
[ chemical formula 4]
In the chemical formula 3 and the chemical formula 4,
r2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or a methyl group,
r4 is methyl.
7. A D-alanine alkyl ester derivative prepared by reacting a compound of formula 3 with a compound of formula 5 below in the composition of claim 5:
[ chemical formula 5]
In the chemical formula 5, the chemical formula is shown in the drawing,
r5 is methylene substituted with methoxy; a methylene group substituted with a phenyl group; or furyl.
8. The D-alanine alkyl ester derivative as claimed in claim 7, wherein in UV/vis absorption spectrum of a solution of methanol containing 10mg/mL of the D-alanine alkyl ester derivative, absorbance at 266nm is 3.00 or less, and absorbance at 274nm is 2.60 or less.
9. The D-alanine alkyl ester derivative as claimed in claim 7, wherein in the UV/vis transmission spectrum of a solution of methanol containing 10mg/mL of the D-alanine alkyl ester derivative, the transmittance at 266nm is 0.10 or more, and the transmittance at 274nm is 0.29 or more.
10. The D-alanine alkyl ester derivative as claimed in claim 7, wherein in UV/vis absorption spectrum of a solution of methanol containing 10mg/mL of the D-alanine alkyl ester derivative, absorbance at 266nm is 3.00 or less, and
in the UV/vis transmission spectrum of a solution of methanol containing 10mg/mL of the D-alanine alkyl ester derivative, the transmittance at 266nm is 0.10 or more.
11. The D-alanine alkyl ester derivative as claimed in claim 7, wherein in UV/vis absorption spectrum of a solution of methanol containing 10mg/mL of the D-alanine alkyl ester derivative, absorbance at 274nm is 2.60 or less, and
in the UV/vis transmission spectrum of a solution containing 10mg/mL of the D-alanine alkyl ester derivative in methanol, the transmittance at 274nm is 0.29 or more.
12. A medicament comprising the D-alanine alkyl ester derivative of claim 7.
13. An agricultural product comprising the D-alanine alkyl ester derivative of claim 7.
CN202280014398.7A 2021-06-29 2022-06-29 Method for preparing D-alanine alkyl ester, derivative thereof, and pharmaceutical or agricultural product comprising same Pending CN116888094A (en)

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PCT/KR2022/009361 WO2023277590A1 (en) 2021-06-29 2022-06-29 Method for preparing alkyl-d-alaninate, alkyl-d-alaninate, alkyl-d-alaninate derivative, and pharmaceutical or agricultural product including same

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