CN118043307A - Process for preparing high purity N-acyl derivatives - Google Patents
Process for preparing high purity N-acyl derivatives Download PDFInfo
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- CN118043307A CN118043307A CN202280063521.4A CN202280063521A CN118043307A CN 118043307 A CN118043307 A CN 118043307A CN 202280063521 A CN202280063521 A CN 202280063521A CN 118043307 A CN118043307 A CN 118043307A
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 239000000203 mixture Substances 0.000 claims abstract description 29
- -1 metal hydroxide compound Chemical class 0.000 claims abstract description 23
- 229910000000 metal hydroxide Inorganic materials 0.000 claims abstract description 18
- 239000003021 water soluble solvent Substances 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 229910052805 deuterium Inorganic materials 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 abstract 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 239000010410 layer Substances 0.000 description 30
- ZQEIXNIJLIKNTD-GFCCVEGCSA-N metalaxyl-M Chemical compound COCC(=O)N([C@H](C)C(=O)OC)C1=C(C)C=CC=C1C ZQEIXNIJLIKNTD-GFCCVEGCSA-N 0.000 description 18
- 239000005808 Metalaxyl-M Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 231100000025 genetic toxicology Toxicity 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 238000004817 gas chromatography Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000007674 genetic toxicity Effects 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000004821 distillation Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 230000001738 genotoxic effect Effects 0.000 description 3
- NEOYGRJJOGVQPO-SNVBAGLBSA-N methyl (2r)-2-(2,6-dimethylanilino)propanoate Chemical compound COC(=O)[C@@H](C)NC1=C(C)C=CC=C1C NEOYGRJJOGVQPO-SNVBAGLBSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 description 2
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 239000005807 Metalaxyl Substances 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000000417 fungicide Substances 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- LPEKGGXMPWTOCB-VKHMYHEASA-N methyl (S)-lactate Chemical compound COC(=O)[C@H](C)O LPEKGGXMPWTOCB-VKHMYHEASA-N 0.000 description 2
- ZQEIXNIJLIKNTD-UHFFFAOYSA-N methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)alaninate Chemical compound COCC(=O)N(C(C)C(=O)OC)C1=C(C)C=CC=C1C ZQEIXNIJLIKNTD-UHFFFAOYSA-N 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000011814 protection agent Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- LFMBKSRGQHUJKP-VKHMYHEASA-N (2s)-2-methylsulfonyloxypropanoic acid Chemical compound OC(=O)[C@H](C)OS(C)(=O)=O LFMBKSRGQHUJKP-VKHMYHEASA-N 0.000 description 1
- JJKWHOSQTYYFAE-UHFFFAOYSA-N 2-methoxyacetyl chloride Chemical compound COCC(Cl)=O JJKWHOSQTYYFAE-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 208000031404 Chromosome Aberrations Diseases 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 231100000005 chromosome aberration Toxicity 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000000769 gas chromatography-flame ionisation detection Methods 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940101629 l- methyl lactate Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of 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
-
- 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
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a method for removing a compound of chemical formula 1, comprising the step of adding a metal hydroxide compound to a composition containing the compound of chemical formula 1 and a water-soluble solvent; and a method for producing an N-acyl derivative using the removal method.
Description
[ Technical field ]
The present application claims the benefit of priority based on korean patent application No. 10-2021-0129121 filed on 9/29 of 2021, the entire contents of which are incorporated by reference as part of the present specification.
The present invention relates to a process for preparing high purity N-acyl derivatives.
[ Background Art ]
N-acyl derivatives of N- (2, 6-dimethylphenyl) -D-alanine methyl ester are of great commercial value as fungicides in crop protection agents.
The preparation of N-acyl derivatives is generally known to be synthesized by alkyl D-alaninates (e.g., methyl N- (2, 6-dimethylphenyl) -D-alaninate).
However, this synthetic method leads to unavoidable production of impurities of the final N-acyl derivative that induce genotoxicity. However, due to the physical nature of the final product as a liquid, it is difficult to remove these impurities by conventional purification methods such as crystallization or recrystallization.
Therefore, it is necessary to study specific methods that can reduce the content of impurities that cause genetic toxicity.
[ Prior Art literature ]
[ Patent literature ]
Korean patent No. 10-1502592
[ Summary of the invention ]
[ Technical problem ]
Recently, the specification standard of one micro component [ 1-methoxy-1-oxopropan-2-yl N- (2, 6-dimethylphenyl) -N- (2-methoxyacetyl) alanine ester (CGA 226048) ] in metalaxyl-M (Metalaxyl-M) has been enhanced due to the problem of genetic toxicity, but it is difficult to remove the micro component using conventional methods such as raw material purification, intermediate distillation, crystallization and recrystallization.
Accordingly, the present inventors have studied a method for easily removing a micro-component, and as a result, have found that a production method for removing a micro-component with high purity can be developed by decomposing a micro-component with an alkali and washing with water after the reaction, wherein with this method, it is possible to apply to mass production without additional steps of raw material purification, distillation, etc., and thus completed the present invention.
It is therefore an object of the present invention to provide a method for removing trace components in metalaxyl-M which may cause problems of genotoxicity, and a method for preparing an N-acyl derivative using the same.
Technical scheme
An exemplary embodiment of the present specification provides a method for removing a compound of the following formula 1, which includes the steps of: a metal hydroxide compound is added to a composition containing a compound of formula 1 and a water-soluble solvent, and stirred:
[ 1]
Wherein,
R2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or methyl, and
R4 and R5 are the same or different from each other and are each independently methyl.
Another exemplary embodiment of the present specification provides a method for preparing an N-acyl derivative, comprising the steps of: a) Adding a metal hydroxide compound to a composition containing a compound of the following formula 1, a compound of the following formula 2, and a water-soluble solvent, and stirring the same; b) Adding an organic solvent and a strong acid to the stirred composition to adjust pH, then stirring to separate layers, and then removing the aqueous layer; c) Adding water again to the composition from which the water layer has been removed, stirring, layering, and then removing the water layer; and d) removing the organic solvent by distilling the composition from which the aqueous layer has been removed under reduced pressure:
[ 1]
[ 2]
Wherein,
R2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or methyl, and
R4 and R5 are the same or different from each other and are each independently methyl.
[ Advantageous effects ]
The preparation method of one exemplary embodiment of the present specification can prepare an N-acyl derivative having a low content of impurities causing genetic toxicity.
The preparation method of one exemplary embodiment of the present specification can prepare an N-acyl derivative with high purity.
Detailed description of the preferred embodiments
Hereinafter, the present invention will be described in detail.
In this specification, when a portion "comprises" a certain component, unless explicitly stated to the contrary, this means that other components may also be included, not excluded.
An exemplary embodiment of the present specification provides a method for removing a compound of the following formula 1, which includes the steps of: adding a metal hydroxide compound to a composition comprising a compound of formula 1 and a water-soluble solvent:
[ 1]
Wherein,
R2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or methyl, and
R4 and R5 are the same or different from each other and are each independently methyl.
The compound of formula 1 is a minor component (impurity) which causes genetic toxicity generated during the preparation of the N-acyl derivative, has genetic toxicity and chromosomal aberration, and causes mutation of DNA constituting genes, wherein since mutation is a manifestation form of genetic disease and thus may bring about disastrous to offspring, the compound must be removed or controlled at an extremely low level through a purification process. Thus, in the present invention, the trace component represented by formula 1 is removed, thereby minimizing the content of the compound of formula 1 generated when synthesizing an N-acyl derivative (e.g., metalaxyl).
For this reason, in an exemplary embodiment of the present invention, the water-soluble solvent may contain 20% by weight or more of water. By using a water-soluble solvent containing 20% by weight or more of water, the present invention can have an effect of removing the minor components by dissolving and reacting the metal hydroxide salt with the minor components. The water content in the aqueous solution may be 20 wt% or more, 30 wt% or more, 40 wt% or more, 50 wt% or more, 60 wt% or more, 70 wt% or more, 80 wt% or more, 90 wt% or more, or 100 wt% or more.
Further, in an exemplary embodiment of the present invention, the solvent may further include one or more solvents selected from the group consisting of Tetrahydrofuran (THF), methanol and acetone.
Furthermore, in one exemplary embodiment of the present invention, the metal hydroxide compound may be M (OH) n (n is an integer of 1 to 2). By using the metal hydroxide compound, the effect of removing the trace component and the R/S ratio is good can be obtained. In this case, M may be any one of group 1 or group 2 metals selected from the group consisting of Li, K, ca, and Ba.
Furthermore, in one exemplary embodiment of the present invention, the weight ratio of the water-soluble solvent to the metal hydroxide compound may be 30:0.4 to 30:2.0. If the weight ratio of the water-soluble solvent and the metal hydroxide compound satisfies the above range, good effects can be achieved.
Furthermore, in one exemplary embodiment of the present invention, the reaction in this step may be performed at a pH of 10 to pH 12 and a temperature of 0to 10 ℃. If the above pH and reaction temperature ranges are satisfied, there are advantages in that the trace components are removed and the R/S ratio is good.
An exemplary embodiment of the present invention provides a method for preparing an N-acyl derivative, comprising the steps of: a) Adding a metal hydroxide compound to a composition containing a compound of the following formula 1, a compound of the following formula 2, and a water-soluble solvent, and stirring the same; b) Adding an organic solvent and a strong acid to the stirred composition to adjust pH, then stirring to separate layers, and then removing the aqueous layer; c) Adding water again to the composition from which the water layer has been removed, stirring, layering, and then removing the water layer; and d) removing the organic solvent by distilling the composition from which the aqueous layer has been removed under reduced pressure:
[ 1]
[ 2]
Wherein,
R2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or methyl, and
R4 and R5 are the same or different from each other and are each independently methyl.
In step a) of the method for preparing an N-acyl derivative according to one embodiment of the present specification, information of the water-soluble solvent and the metal hydroxide compound is the same as the above-described method for removing the compound of formula 1.
In step b) of the method for preparing an N-acyl derivative according to one embodiment of the present specification, the pH is adjusted by adding an organic solvent and a strong acid to the stirred composition, and then it is stirred to be layered, and the aqueous layer is removed. The organic solvent is not particularly limited as long as it is an organic solvent usable for layer separation, but preferably the organic solvent may be toluene, THF, benzene, n-heptane, octane, hexamethylene, isoprene, or the like. The strong acid is not particularly limited as long as it can adjust the pH by reaction with the metal hydroxide compound, but preferably the strong acid may be hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, perchloric acid, or the like. In step b), layer separation is performed as described above, and then the aqueous layer is removed, thereby removing impurities in the aqueous layer.
In step c) of the method for producing an N-acyl derivative according to one embodiment of the present specification, water is added again to the composition from which the aqueous layer has been removed, and then stirred, layered, and the aqueous layer is removed. In step c), water is added again and layered again to further remove impurities present in the aqueous layer.
In step d) of the method for producing an N-acyl derivative according to one embodiment of the present specification, the composition from which the aqueous layer has been removed is distilled under reduced pressure to remove the organic solvent. By removing the organic solvent as described above, an N-acyl derivative can be finally obtained.
The N-acyl derivative prepared by the method for preparing an N-acyl derivative according to one embodiment of the present specification may contain the compound of formula 1 removed as much as possible so as to be trace, wherein the content of the compound of formula 1 may be 0.0018 (GC area) or less, preferably 0.015 (GC area) or less, more preferably 0.010 (GC area) or less, most preferably 0.006 (GC area) or less of the total composition (i.e., the total amount of the compounds of formulae 1 and 2), and thus the content of impurities causing genotoxicity may be minimized.
Furthermore, the R form: S form of the N-acyl derivative of formula 2 prepared by the method for preparing an N-acyl derivative of one embodiment of the present specification may be 96:4 to 99.9:0.1, preferably 97:3 to 99:1.
The present invention provides a medical or agricultural article comprising a compound produced by the above production method. In this case, they include not only the state in which the N-acyl derivative is contained in the composition, but also medical or agricultural products containing the derivative modified for various purposes (i.e., modified by the necessary chemical reaction).
In the present specification, the agricultural product may be various agricultural products 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 present specification.
Examples
[ Synthetic example of metalaxyl-M ]
Methyl L-lactate (104.11 g,1.0 mol) was added to a reactor containing 433.5g of toluene at room temperature, followed by triethylamine (131.5 g,1.3 mol) and the internal temperature was cooled to-10℃to-5 ℃. Methanesulfonyl chloride (118.0 g,1.03 mol) was slowly added while maintaining the internal temperature at 0 to 10 ℃, and after the addition was completed, the mixture was stirred for 3 hours while maintaining the internal temperature at 10 to 15 ℃. After confirming that the unreacted L-methyl lactate remaining in the reaction mixture was 0.5 area% or less (obtained by GC analysis), the internal temperature of the reaction mixture was cooled to-10℃to-5℃and the precipitated solid was filtered and the solid was washed with 149.9g of toluene. While the organic layer was kept at 10 to 15 ℃, 93.7g of an aqueous solution of 2n hydrochloric acid (HCl) was added, the resulting mixture was stirred, layers were separated, 104.1g of water was added to the resulting organic layer, and the resulting mixture was stirred. Then, the organic layer was separated and concentrated under reduced pressure to give methyl(s) -2- ((methylsulfonyl) oxy) propanoate having a purity of 98.4GC area% and a yield of 91.0% (165.8 g,0.91 mol).
To the prepared methyl(s) -2- ((methylsulfonyl) oxy) propionate (20.00 g,0.11 mol) was added 2, 6-dimethylaniline (66.5 g,0.549 mol), the internal temperature was raised to 120℃to 135℃and the resulting mixture was stirred. After confirming that the unreacted(s) -2- ((methylsulfonyl) oxy) propanoic acid methyl ester remained in the reaction mixture was 0.1 area% or less (GC analysis result), the internal temperature was cooled to 0 ℃, the reaction mixture was stirred for 1 hour, and then filtered. The resulting solid was washed with 20g of toluene. The filtrate was washed twice with 1N aqueous HCl (20 mL), and the resulting organic layer was washed once with distilled water (20 mL) and then concentrated under reduced pressure to give methyl N- (2, 6-dimethylphenyl) -D-alaninate (16.4 g,0.081 mol) in 99.4GC area% purity and 74% yield.
NaHCO 3 (7.3 g,0.087 mol) and toluene (42.7 g) were added thereto, then cooled to-5℃to 0℃and then methoxyacetyl chloride (9.4 g,0.087 mol) was added dropwise. After the completion of the dropwise addition, the mixture was stirred for 2 hours while keeping the internal temperature between 10℃and 15 ℃. After confirming that the unreacted N- (2, 6-dimethylphenyl) -D-alanine methyl ester remaining in the reaction mixture was 0.06 area% or less (obtained by GC analysis), H 2 O (65.6 mL) was added, then 1N NaOH was added dropwise, pH7 to pH8 was detected, and then the layers were separated and the aqueous layer was discarded. H 2 O (20 mL) was added to the separated organic layer, stirred, then the layers were separated, and the aqueous layer was discarded. After removing foreign matters by filtration of the separated organic layer, it was then concentrated under reduced pressure to obtain methyl N- (2, 6-dimethylphenyl) -N- (methoxyacetyl) -D-alaninate with a purity of 99.4GC area% and a yield of 93% (20.6 g,0.074 mol). In this case, the minor component (CGA 226048) was 0.12 area% based on the total GC area of the resulting N- (2, 6-dimethylphenyl) -N- (methoxyacetyl) -D-alanine methyl ester.
Example 1
25G of metalaxyl-M (prepared internally, purity 98% (GC), 0.089 mol) and 40g of water were added to the flask, and the internal temperature was cooled to 5℃to 7 ℃. While maintaining the temperature, 0.5g of LiOH was added. It was stirred at the same temperature for 2 hours.
Two drops of the stirred reaction mixture were dissolved in 1.5ml of acetonitrile and then analyzed. The minor components (CGA 226048) were removed by gas chromatography according to the GC method described later, and after confirming the R/S type ratio by HPLC chromatography according to the HPLC method described later, 20g of toluene was added to the reactor, and the pH was adjusted to 6.5 with hydrochloric acid at 10℃or less. The resulting mixture was stirred for 30 minutes, layered, and then the aqueous layer was discarded. To the organic layer was added 20g of water and stirred for 30 minutes, the layers were separated and the aqueous layer was discarded.
Toluene was removed from the organic layer by distillation under reduced pressure at 70 ℃. 24.3g (purity 99.8% or more) of metalaxyl-M was obtained, which had a trace component (CGA 226048) of 0.006% (GC area) or less and R form: S form=97:3 ratio.
Example 2
25G of metalaxyl-M (prepared internally, purity 98% (GC), 0.089 mol) and 40g of water were added to the flask, and the internal temperature was cooled to 5℃to 7 ℃. While maintaining the temperature, 0.5g of Ca (OH) 2 was added. It was stirred at the same temperature for 2 hours.
Two drops of the reaction mixture were dissolved in 1.5ml of acetonitrile and then analyzed. After removing the minor component (CGA 226048) and confirming the R/S type ratio, 20g of toluene was added to the reactor, and the pH was adjusted to 6.5 with hydrochloric acid at 10℃or lower. The resulting mixture was stirred for 30 minutes, layered, and then the aqueous layer was discarded. To the organic layer was added 20g of water and stirred for 30 minutes, the layers were separated and the aqueous layer was discarded.
Toluene was removed from the organic layer by distillation under reduced pressure at 70 ℃. 24.3g (purity 99.8% or more) of metalaxyl-M was obtained, which had a trace component (CGA 226048) of 0.006% (GC area) or less and R form: S form=97:3 ratio.
Example 3
15G of metalaxyl-M (prepared internally, purity 98% (GC), 0.054 mol) and 20g of toluene/water were each added to the flask, and the internal temperature was cooled to 5℃to 7 ℃. While maintaining the temperature, 0.03g of KOH was added. It was stirred at the same temperature for 2 hours.
Two drops of the reaction mixture were dissolved in 1.5ml of acetonitrile and then analyzed. The minor component (CGA 226048) was 0.012% (GC area), and the ratio of R form to S form was 96.4:3.6.
Example 4
15G of metalaxyl-M (prepared internally, purity 98% (GC), 0.054 mol) and 20g of THF/water were each added to the flask, and the internal temperature was cooled to 5℃to 7 ℃. While maintaining the temperature, 0.03g of KOH was added. It was stirred at the same temperature for 2 hours.
Two drops of the reaction mixture were dissolved in 1.5ml of acetonitrile and then analyzed. The minor component (CGA 226048) was 0.016% (GC area), the ratio of R form to S form was 96.4:3.6.
Comparative example 1
15G of metalaxyl-M (prepared internally, purity 98% (GC), 0.054 mol) and 20g of methanol/water were each added to the flask, and the internal temperature was cooled to 5℃to 7 ℃. 0.03g NaOH was added at room temperature. It was stirred at the same temperature for 2 hours.
Two drops of the reaction mixture were dissolved in 1.5ml of acetonitrile and then analyzed. The micro component (CGA 226048) (trace) was removed, but since a new micro component was generated, it was not in compliance with the specification, and thus, the subsequent process was not performed.
Comparative example 2
15G of metalaxyl-M (prepared internally, purity 98% (GC), 0.054 mol) and 40g of methanol were added to the flask, and the internal temperature was cooled to 5℃to 7 ℃. While maintaining the temperature, 0.03g NaOMe was added. It was stirred at the same temperature for 2 hours.
Two drops of the reaction mixture were dissolved in 1.5ml of acetonitrile and then analyzed. Minor amounts of the component (CGA 226048) (trace amounts) were removed, but since the R form to S form was changed to a 57:43 ratio, it was not satisfactory, and thus no subsequent process was carried out.
Comparative example 3
15G of metalaxyl-M (prepared internally, purity 98% (GC), 0.054 mol) and 40g of methanol were added to the flask, and the internal temperature was cooled to 5℃to 7 ℃. While maintaining the temperature, 6.0g K 2CO3 a was added. Stirred at the same temperature for 1 hour.
Two drops of the reaction mixture were dissolved in 1.5ml of acetonitrile and then analyzed. Minor amounts of the component (CGA 226048) (trace amounts) were removed, but since the R form to S form was changed to a 52:48 ratio, it was not satisfactory and therefore no subsequent procedure was carried out.
Comparative example 4
15G of mefenoxam (prepared internally, 98% pure (GC), 0.054 mol) and 20g of methanol/toluene are added to the flask and the internal temperature is cooled to 5℃to 7 ℃. While maintaining the temperature, 6.0g K 2CO3 a was added. Stirred at the same temperature for 1 hour.
Two drops of the reaction mixture were dissolved in 1.5ml of acetonitrile and then analyzed. It was confirmed that the minor component (CGA 226048) was not removed, and thus, the subsequent process was not performed.
Comparative example 5
15G of metalaxyl-M (prepared internally, purity 98% (GC), 0.054 mol) and 40g of methanol were added to the flask, and the internal temperature was cooled to 5℃to 7 ℃. While maintaining the temperature, 6.0g of TEA was added. Stirred at the same temperature for 1 hour.
Two drops of the reaction mixture were dissolved in 1.5ml of acetonitrile and then analyzed. It was confirmed that the minor component (CGA 226048) was not removed, and thus, the subsequent process was not performed.
Comparative example 6
15G of metalaxyl-M (prepared internally, purity 98% (GC), 0.054 mol) and 10g of acetone/water/methanol were added separately to the flask, and the internal temperature was cooled to 5℃to 7 ℃. While maintaining the temperature, 6.0g of Ba (OH) 2 was added. Stirred at the same temperature for 1 hour.
Two drops of the reaction mixture were dissolved in 1.5ml of acetonitrile and then analyzed. It was confirmed that the minor component (CGA 226048) was not removed, and thus, the subsequent process was not performed.
Measurement method
GC method (Process control)
Instrument Agilent 7890A system, 7693 autosampler, G4513 injector
Column: HP-5,30m 0.320mm,0.25 μm (Agilent, U.S.A.)
Oven temperature
TABLE 1
| Rate of DEG C per minute | Value of DEG C | Hold time min | Run time minutes | |
| Initial initiation | 55 | 5 | 5 | |
| Slope 1 | 15 | 150 | 0 | 11.3 |
| Slope 2 | 5 | 180 | 0 | 17.3 |
| Slope 3 | 1 | 200 | 0 | 37.3 |
| Slope 4 | 50 | 320 | 15 | 54.7 |
Injector temperature: 180 DEG C
Detector temperature: 340 DEG C
Injector temperature: 180 DEG C
Detector temperature: 340 DEG C
Gas flow rate: column (N2): 1 mL/min
Split ratio: 10:1
Injection amount: 1.0uL
HPLC method (R/S ratio analysis)
Instrument Agilent 1260HPLC system
Column: CHIRALCEL OD-H,25cm 4.6mm, particle size=5 μm, DAICEL Corp., japan
Pump flow rate: 1.0 mL/min
Mobile phase: n-hexane: isopropanol=50:50 (isocratic)
Run time: 30 minutes
Column temperature: 40 DEG C
UV detector: 230nm (b.w. =4, ref=off)
Experimental example 1:
Samples were collected at each stage of the synthesis of examples 1 to 4 and comparative examples 1 to 6, and the removal of micro-components (CGA 226048) was measured using GC/FID (gas chromatography with flame ionization detector) analysis as described in the measurement methods above. The ratio of R/S-form was confirmed by HPLC analysis. The results are summarized in table 1 below. At this time, the ratio of the minor component and the R/S-form means the average area% based on the entire GC/HPLC area.
TABLE 2
From the above table 2, it can be seen that when the solvent is prepared by adding water and an OH-containing metal salt, the micro component (CGA 226048) can be removed well, particularly in the case of examples 1 and 2, the removal effect of the micro component (CGA 226048) is optimal, and metalaxyl having an R/S-form ratio satisfying the specification can be obtained.
Claims (13)
1. A method for removing a compound of formula 1 below, comprising the steps of: a metal hydroxide compound is added to a composition containing a compound of formula 1 and a water-soluble solvent, and stirred:
[ 1]
Wherein,
R2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or methyl, and
R4 and R5 are the same or different from each other and are each independently methyl.
2. The method for removing the compound of formula 1 according to claim 1, wherein the water-soluble solvent comprises at least 20% by weight of water.
3. The method for removing the compound of formula 1 according to claim 1, wherein the solvent further comprises at least one solvent selected from the group consisting of Tetrahydrofuran (THF), methanol and acetone.
4. The method for removing a compound of formula 1 according to claim 1, wherein the metal hydroxide compound is M (OH) n (where n is an integer of 1 to 2), where M is any one group 1 or group 2 metal selected from the group consisting of Li, K, ca, and Ba.
5. The method for removing the compound of formula 1 according to claim 1, wherein the weight ratio of the water-soluble solvent to the metal hydroxide compound is 30:0.4 to 30:2.0.
6. The method for removing the compound of formula 1 according to claim 1, wherein the step is performed at a temperature of pH 10 to pH 12 and 0 to 10 ℃.
7. A process for preparing an N-acyl derivative comprising the steps of:
a) Adding a metal hydroxide compound to a composition containing a compound of the following formula 1, a compound of the following formula 2, and a water-soluble solvent, and stirring the same;
b) Adding an organic solvent and a strong acid to the stirred composition to adjust pH, then stirring to separate layers, and then removing the aqueous layer;
c) Adding water again to the composition from which the water layer has been removed, stirring it, layering, and then removing the water layer; and
D) The organic solvent is removed by distilling the composition from which the aqueous layer has been removed under reduced pressure:
[ 1]
[ 2]
Wherein,
R2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or methyl, and
R4 and R5 are the same or different from each other and are each independently methyl.
8. The method for producing an N-acyl derivative according to claim 7, wherein the water-soluble solvent contains at least 20% by weight of water.
9. The method for preparing an N-acyl derivative according to claim 7, wherein the solvent further comprises at least one solvent selected from the group consisting of Tetrahydrofuran (THF), methanol and acetone.
10. The method for producing an N-acyl derivative according to claim 7, wherein the metal hydroxide compound is M (OH) n (where N is an integer of 1 to 2), wherein M is any one group 1 or group 2 metal selected from the group consisting of Li, K, ca and Ba.
11. The process for producing an N-acyl derivative according to claim 7, wherein the weight ratio of the water-soluble solvent to the metal hydroxide compound is from 30:0.4 to 30:2.0.
12. The process for producing an N-acyl derivative according to claim 7, wherein the content of the compound of formula 1 is 0.0018 (GC area)% or less based on the total composition.
13. The process for preparing an N-acyl derivative according to claim 7, wherein the compound of formula 2 has a form R/form S of 96:4 to 99.9:0.1.
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| KR1020210129221A KR20230046122A (en) | 2021-09-29 | 2021-09-29 | Methods for manufacturing a n-acyl derivative with high purity |
| KR10-2021-0129221 | 2021-09-29 | ||
| PCT/KR2022/014515 WO2023055050A1 (en) | 2021-09-29 | 2022-09-28 | Method for preparing highly pure n-acyl derivative |
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| CN100388886C (en) * | 2006-04-05 | 2008-05-21 | 湖南化工研究院 | Carbamate sterilization compound containing vinyl oxime ether |
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