CN116829531A - Method for preparing N-acyl derivative, composition and medicine or agricultural product containing the same - Google Patents
Method for preparing N-acyl derivative, composition and medicine or agricultural product containing the same Download PDFInfo
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- CN116829531A CN116829531A CN202280014397.2A CN202280014397A CN116829531A CN 116829531 A CN116829531 A CN 116829531A CN 202280014397 A CN202280014397 A CN 202280014397A CN 116829531 A CN116829531 A CN 116829531A
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- 239000000203 mixture Substances 0.000 title claims abstract description 99
- 238000000034 method Methods 0.000 title claims abstract description 31
- 239000003814 drug Substances 0.000 title claims description 3
- 239000000126 substance Substances 0.000 claims abstract description 217
- 150000001875 compounds Chemical class 0.000 claims abstract description 143
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 51
- 238000004821 distillation Methods 0.000 claims description 27
- 230000002194 synthesizing effect Effects 0.000 claims description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 14
- 229910052805 deuterium Inorganic materials 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 15
- 239000010410 layer Substances 0.000 description 14
- 239000012535 impurity Substances 0.000 description 12
- LPEKGGXMPWTOCB-VKHMYHEASA-N methyl (S)-lactate Chemical compound COC(=O)[C@H](C)O LPEKGGXMPWTOCB-VKHMYHEASA-N 0.000 description 11
- 238000004817 gas chromatography Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 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 9
- 239000011541 reaction mixture Substances 0.000 description 9
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 description 8
- 230000001738 genotoxic effect Effects 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 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 5
- 239000000243 solution Substances 0.000 description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- 231100000025 genetic toxicology Toxicity 0.000 description 4
- 231100000024 genotoxic Toxicity 0.000 description 4
- 229940101629 l- methyl lactate Drugs 0.000 description 4
- JJKWHOSQTYYFAE-UHFFFAOYSA-N 2-methoxyacetyl chloride Chemical compound COCC(Cl)=O JJKWHOSQTYYFAE-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 3
- 239000011369 resultant mixture Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000417 fungicide Substances 0.000 description 2
- 238000000769 gas chromatography-flame ionisation detection Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 239000011814 protection agent Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- 208000031404 Chromosome Aberrations Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 231100000005 chromosome aberration Toxicity 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000002080 perylenyl group Chemical group C1(=CC=C2C=CC=C3C4=CC=CC5=CC=CC(C1=C23)=C45)* 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- 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
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Agronomy & Crop Science (AREA)
- Dentistry (AREA)
- Plant Pathology (AREA)
- Pest Control & Pesticides (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Engineering & Computer Science (AREA)
- Emergency Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present specification relates to a method of preparing an N-acyl derivative, which distills a first composition including a compound of chemical formula 1 and uses the distilled first composition, the N-acyl derivative prepared thereby, and a pharmaceutical or agricultural product including the same.
Description
Technical Field
The present patent application claims priority and rights of korean patent application No. 10-2021-008409, filed on the korean intellectual property office at month 29 of 2021, the entire contents of which are incorporated herein by reference.
The present application relates to a method for preparing an N-acyl derivative, a composition and a pharmaceutical or agricultural product comprising the composition.
Background
N-acyl derivatives of N- (2, 6-dimethylphenyl) -D-alanine methyl ester are commercially important as fungicides in crop protection agents.
Methods for preparing N-acyl derivatives are generally known to be synthesized from D-alanine alkyl esters such as N- (2, 6-dimethylphenyl) -D-alanine methyl ester.
However, this synthetic method inevitably generates impurities inducing genotoxicity in the final N-acyl derivative. However, due to the physical properties of the final product having liquid properties, it is difficult to remove these impurities by conventional purification methods such as crystallization or recrystallization.
Therefore, designing a specific method capable of reducing the content of the corresponding genotoxic impurities is an important problem to be solved urgently.
Disclosure of Invention
Technical problem
The present specification intends to provide a method for preparing an N-acyl derivative, an N-acyl derivative prepared thereby, and a pharmaceutical or agricultural product comprising the same.
Technical proposal
An exemplary embodiment of the present specification provides a method for preparing an N-acyl derivative, the method comprising: distilling a first composition comprising a compound of formula 1 below; synthesizing a compound of the following chemical formula 3 by adding the compound of the following chemical formula 2 to the distilled first composition; synthesizing a compound of the following chemical formula 5 by reacting a compound of the chemical formula 3 with a compound of the following chemical formula 4; and synthesizing a compound of the following chemical formula 7 by reacting the compound of the chemical formula 5 with a compound of the following chemical formula 6.
[ chemical formula 1]
[ chemical formula 2]
[ chemical formula 3]
[ chemical formula 4]
[ chemical formula 5]
[ chemical formula 6]
[ chemical formula 7]
In the chemical formulas 1 to 7,
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 and R5 are methyl.
Another exemplary embodiment of the present specification provides a method for preparing an N-acyl derivative, the method comprising: synthesizing a compound of the following chemical formula 3 by adding a compound of the following chemical formula 2 to a first composition comprising the compound of the following chemical formula 1, wherein the content of the compound of the following chemical formula 8 is 0.05 area% or less based on the total GC area of the first composition; synthesizing a compound of the following chemical formula 5 by reacting a compound of the chemical formula 3 with a compound of the following chemical formula 4; and synthesizing a compound of the following chemical formula 7 by reacting the compound of the chemical formula 5 with a compound of the following chemical formula 6.
[ chemical formula 1]
[ chemical formula 2]
[ chemical formula 3]
[ chemical formula 4]
[ chemical formula 5]
[ chemical formula 6]
[ chemical formula 7]
[ chemical formula 8]
In the chemical formulas 1 to 7,
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 and R5 are methyl.
Yet another exemplary embodiment of the present specification provides a composition including a compound of the following chemical formula 7 and a compound of the following chemical formula 10, wherein the content of the compound of the following chemical formula 10 is 0.05 area% or less based on the total GC area of the composition.
[ chemical formula 7]
[ chemical formula 10]
In the chemical formula 7 and the chemical formula 10,
r2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or a methyl group,
r4 and R5 are methyl.
Still another exemplary embodiment provides a pharmaceutical or agricultural product comprising the above composition.
Advantageous effects
The preparation method according to one exemplary embodiment of the present specification may prepare an N-acyl derivative having a low content of impurities inducing genotoxicity.
The preparation method according to one exemplary embodiment of the present specification can prepare a high-purity N-acyl derivative.
Detailed Description
Hereinafter, the present specification will be described in detail.
In this specification, when a part "includes" one constituent element, unless otherwise specifically described, this does not mean to exclude another constituent element, but means that another constituent element may also be included.
An exemplary embodiment of the present specification provides a method for preparing an N-acyl derivative, the method comprising: distilling a first composition comprising a compound of formula 1 below; synthesizing a compound of the following chemical formula 3 by adding the compound of the following chemical formula 2 to the distilled first composition; synthesizing a compound of the following chemical formula 5 by reacting a compound of the chemical formula 3 with a compound of the following chemical formula 4; and synthesizing a compound of the following chemical formula 7 by reacting the compound of the chemical formula 5 with a compound of the following chemical formula 6.
Another exemplary embodiment of the present specification provides a method for preparing an N-acyl derivative, the method comprising: distilling a first composition comprising a compound of formula 1 below; synthesizing a compound of the following chemical formula 3 by adding the compound of the following chemical formula 2 to the distilled first composition; synthesizing a compound of the following chemical formula 5 by reacting a compound of the chemical formula 3 with a compound of the following chemical formula 4; distilling a second composition comprising a compound of formula 5; and synthesizing the compound of the following chemical formula 7 by adding the compound of the following chemical formula 6 to the distilled second composition.
In chemical formulas 1 to 7, R1 is methyl or aryl substituted with methyl, R2 and R3 are the same or different from each other, and each is independently hydrogen; deuterium; or methyl, R4 and R5 are methyl.
This synthetic method itself inevitably generates impurities such as the following chemical formula 10 inducing genotoxicity in the final N-acyl derivative.
[ chemical formula 10]
Since the material of chemical formula 10 has genotoxicity and chromosomal aberration (classogenicity), thereby causing mutation of DNA constituting a gene, and such mutation may appear as a disaster in the next generation with the expression of a genetic disease, it is necessary to remove the material by a purification process or to control it at a very low level.
However, since the compound of chemical formula 7 and the compound of chemical formula 9 have a height Wen Feidian of 295 ℃ or higher, which makes it difficult to distill the compounds in a mass production process, it is difficult to separate and purify the compounds by distillation in a final composition state.
Therefore, in this specification, by removing the precursor that generates the compound of chemical formula 10 by distillation in the pre-synthesis step of chemical formula 7 to reduce the probability of generation of the compound of chemical formula 10, the compound of chemical formula 7 can be synthesized more easily with high purity. This is possible because the compound of chemical formula 1 of the first composition and the compound of chemical formula 6 of the second composition have boiling points at a level at which distillation can be performed even in a mass production process.
Specifically, as in the following reaction scheme, chemical formula 10 is prepared from chemical formula 8, and chemical formula 8 is an impurity of chemical formula 1.
[ reaction scheme ]
In the reaction scheme, the definitions of R1 to R5 are the same as those in chemical formulas 1 to 7.
In this specification, before chemical formula 1 is caused to participate in the reaction, a portion of chemical formula 8 may be removed by distillation to reduce the possibility of generating impurities, thereby reducing the content of the compound of chemical formula 10, which is difficult to separate in synthesizing the final N-acyl derivative.
In one exemplary embodiment of the present specification, the distillation of the first composition is to prepare a first composition in which the content of the compound of the following chemical formula 8 is 0.05 area% or less based on the total GC area of the first composition. Specifically, the content of the compound of formula 8 in the first composition is reduced by distilling the first composition including both the compound of formula 1 and the compound of formula 8 below to remove the compound of formula 8 below from the first composition.
[ chemical formula 8]
In one exemplary embodiment of the present specification, in the distillation of the first composition, one or more distillations, in particular, several times, such as one or more times, two or more times, or three or more times, may be performed.
In one exemplary embodiment of the present specification, the content of the compound of chemical formula 8 may be 0.05 area% or less, 0.04 area% or less, or 0.03 area% or less based on the total GC area of the first composition by distillation of the first composition, and the lower the content of the compound of chemical formula 8 is, the better, and thus, the lower limit thereof is not particularly limited.
In one exemplary embodiment of the present specification, distillation of the first composition distills the first composition at a pressure of 40 torr to 60 torr and a temperature of 70 ℃ to 100 ℃. In this case, since the generation amount of chemical formula 9 to be removed in the next distillation step is reduced, there is an advantage in that the second composition of chemical formula 5 having a higher content can be obtained. In addition, since the distillation conditions of the first composition are not high temperature or too low vacuum pressure conditions which are not suitable for mass production, there is an advantage in that the distillation conditions can be easily applied to mass production processes.
In this specification, before allowing chemical formula 5 to participate in the reaction, a portion of chemical formula 9 may be removed by distillation to reduce the possibility of generating impurities, thereby reducing the content of the compound of chemical formula 10, which is difficult to separate when synthesizing the final product.
In one exemplary embodiment of the present specification, the distillation of the second composition is to prepare a second composition in which the content of the compound of the following chemical formula 9 is 0.05 area% or less based on the total GC area of the second composition. Specifically, the content of the compound of formula 9 in the second composition is reduced by distilling the second composition including both the compound of formula 5 and the compound of formula 9 below to remove the compound of formula 9 below from the second composition.
[ chemical formula 9]
In chemical formula 9, R2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or methyl, and R4 is methyl.
In an exemplary embodiment of the present specification, in the distillation of the second composition, the distillation may be performed one or more times, particularly several times, for example, 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 9 may be 0.05 area% or less, 0.04 area% or less, or 0.03 area% or less based on the total GC area of the second composition by distillation of the second composition, and the lower the content of the compound of chemical formula 9 is, the better, and thus, the lower limit thereof is not particularly limited.
In one exemplary embodiment of the present specification, the distillation of the second composition distills the second composition at a pressure of 2 torr to 20 torr and a temperature of 130 ℃ to 200 ℃. In this case, since the generation amount of chemical formula 10 to be removed in the next distillation step is reduced, there is an advantage in that the third composition of chemical formula 7 having a higher content can be obtained.
In one exemplary embodiment of the present specification, the content of the compound of chemical formula 2 is 1.0 equivalent to 2.0 equivalents based on the compound of chemical formula 1.
In one exemplary embodiment of the present specification, the content of the compound of chemical formula 4 is 2.0 equivalents to 10.0 equivalents based on the compound of chemical formula 3. In this case, the equivalent of chemical formula 4 used is appropriate, and thus, there is an advantage in that side reactions can be controlled while increasing the reaction rate.
In one exemplary embodiment of the present specification, the content of the compound of chemical formula 6 is 1.0 equivalent to 2.0 equivalents based on the compound of chemical formula 5.
In one exemplary embodiment of the present specification, the content of the compound of the following chemical formula 10 is 0.05 area% or less based on the total GC area of the third composition including the compound of chemical formula 7. In the entire reaction scheme, the compound of chemical formula 1 and the compound of chemical formula 5 are distilled to remove the compounds of chemical formula 8 and chemical formula 9 as impurities before the respective compounds participate in the reaction, and thus, the content of the following compound of chemical formula 10 in the final synthesized final product is reduced. Specifically, the content of the compound of the following chemical formula 10 is 0.05 area% or less, 0.04 area% or less, 0.03 area% or less, 0.02 area% or less, based on the total GC area of the third composition.
[ chemical formula 10]
In the chemical formula 10, 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 and R5 are methyl.
Another exemplary embodiment of the present specification provides a method for preparing an N-acyl derivative, the method comprising: synthesizing a compound of the following chemical formula 3 by adding a compound of the following chemical formula 2 to a first composition comprising the compound of the following chemical formula 1, wherein the content of the compound of the following chemical formula 8 is 0.05 area% or less based on the total GC area of the first composition; synthesizing a compound of the following chemical formula 5 by reacting a compound of the chemical formula 3 with a compound of the following chemical formula 4; and synthesizing a compound of the following chemical formula 7 by reacting the compound of the chemical formula 5 with a compound of the following chemical formula 6.
Yet another exemplary embodiment of the present specification provides a method for preparing an N-acyl derivative, the method comprising: synthesizing a compound of the following chemical formula 3 by adding a compound of the following chemical formula 2 to a first composition comprising the compound of the following chemical formula 1, wherein the content of the compound of the following chemical formula 8 is 0.05 area% or less based on the total GC area of the first composition; synthesizing a compound of the following chemical formula 5 by reacting a compound of the chemical formula 3 with a compound of the following chemical formula 4; and synthesizing the compound of the following chemical formula 7 by adding the compound of the following chemical formula 6 to the second composition including the compound of the chemical formula 5, wherein the content of the compound of the following chemical formula 9 is 0.05 area% or less based on the total GC area of the second composition.
[ chemical formula 1]
[ chemical formula 2]
[ chemical formula 3]
[ chemical formula 4]
[ chemical formula 5]
[ chemical formula 6]
[ chemical formula 7]
[ chemical formula 8]
[ chemical formula 9]
In chemical formulas 1 to 7 and 9, R1 is methyl or aryl substituted with methyl, R2 and R3 are the same or different from each other, and each is independently hydrogen; deuterium; or methyl, R4 and R5 are methyl.
Yet another exemplary embodiment of the present specification provides a composition including a compound of the following chemical formula 7 and a compound of the following chemical formula 10, wherein the content of the compound of the following chemical formula 10 is 0.05 area% or less based on the total GC area of the composition.
[ chemical formula 7]
[ chemical formula 10]
In the chemical formula 7 and the chemical formula 10,
r2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or a methyl group,
r4 and R5 are methyl.
Here, the description of the N-acyl derivative may refer to the aforementioned description of the method for producing the N-acyl derivative.
In this specification, when the aryl group is a monocyclic aryl group, there is no particular limitation on the number of carbon atoms thereof, but it 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, there is no particular limitation on the number of carbon atoms thereof, but it 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.
The present specification provides a pharmaceutical or agricultural product comprising the above composition. In this case, the pharmaceutical or agricultural product includes not only the state containing the N-acyl derivative as in the composition, but also the derivative modified for each purpose, that is, the derivative modified by the necessary chemical reaction.
In the present specification, the agricultural product may be various agricultural chemicals such as herbicides, crop protection agents and fungicides.
Detailed Description
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
A solution containing 100g (manufactured by TCI, purity 98% or more (GC), 0.96 mol) of methyl L-lactate was injected into the flask, the internal pressure was adjusted to 60 Torr, and the temperature was raised to 70 DEG C
Methyl L-lactate was distilled by raising the temperature from 70 ℃ and adjusting to 100 ℃ while reducing the internal pressure again from 60 torr to 40 torr. As a result, by performing distillation so that the content of L-lactic acid was 0.05 area% based on the total GC area of the distilled solution, methyl L-lactate was obtained in a yield of 95%.
Distilled L-methyl lactate (104.11 g,1.0 mol) and triethylamine (154.60 mL,111.31g,1.1 mol) were added to the bag at room temperatureIn a reactor containing 400mL of dichloromethane and the internal temperature was cooled to 0 ℃. P-toluenesulfonyl chloride (209.70 g,1.1 mol) was slowly added while maintaining the internal temperature at 0℃to 5℃and, after the addition was completed, the resulting mixture was stirred for 4 hours while maintaining the internal temperature at 0℃to 5 ℃. After confirming that unreacted L-methyl lactate remaining in the reaction mixture was 1.0 area% or less (result of GC analysis), 400mL of 1N aqueous hydrochloric acid (HCl) was added, and the resulting mixture was stirred while maintaining the internal temperature at 15℃to 20℃and then 400mL of 1% sodium bicarbonate (NaHCO) 3 ) The aqueous solution was added to the organic layer obtained by delamination, and the resulting mixture was stirred. After that, the organic layer was separated and concentrated under reduced pressure to give methyl(s) -2- (p-toluenesulfonyloxy) propionate with a purity of 98.40GC area% and a yield of 79% (204.05 g,0.79 mol).
2, 6-dimethylaniline (56.30 g,464.58 mmol) was added to the prepared methyl(s) -2- (p-toluenesulfonyloxy) propionate (20.00 g,77.43 mmol), and the resulting mixture was stirred by raising the internal temperature to 120℃to 130 ℃. After confirming that the remaining unreacted(s) -methyl 2- (p-toluenesulfonyloxy) propionate in the reaction mixture was 1.0 area% or less (GC analysis result), the remaining 2, 6-dimethylaniline was separated by distillation while slowly lowering the internal pressure to 20 torr and discarded. Thereafter, the impurity was separated by distillation by raising the temperature from 130℃to 200℃while lowering the internal pressure from 20 Torr to 2 Torr, thereby obtaining crude N- (2, 6-dimethylphenyl) -D-alanine methyl ester (13.64 g,65.82 mmol) having a purity of 95.22GC area% and a yield of 85%.
N- (2, 6-dimethylphenyl) -D-alanine methyl ester obtained by distillation was directly diluted in toluene (100 mL) and washed once with 1N aqueous HCl (20 mL), and the obtained organic layer was washed once with distilled water (30 mL) and then concentrated under reduced pressure to obtain N- (2, 6-dimethylphenyl) -D-alanine methyl ester having a purity of 98.52GC area% and a yield of 81% (13.00 g,62.72 mmol).
To which NaHCO is added 3 (6.85 g,81.54 mmol) and toluene (52 mL)The resulting mixture was cooled to-5℃to 0℃and then methoxy acetyl chloride (8.85 g,81.54 mmol) was added dropwise thereto. After the completion of the dropwise addition, the resultant mixture was stirred for 3 hours so as to maintain the internal temperature at 10 to 15 ℃. After confirming that unreacted N- (2, 6-dimethylphenyl) -D-alanine methyl ester remaining in the reaction mixture was 1.0 area% or less (result of GC analysis), H was added thereto 2 O (52 mL), then pH 7 to 8 was confirmed by dropwise addition of 1N NaOH thereto, and then the aqueous layer was discarded by layer separation. Adding H to the separated organic layer 2 O (26 mL), after stirring, the aqueous layer was discarded again by layer separation. After removing foreign matter by filtration of the separated organic layer, the residue was concentrated under reduced pressure to give methyl N- (2, 6-dimethylphenyl) -N- (methoxyacetyl) -D-alaninate with a purity of 98.82GC area% and a yield of 84% (14.72 g,52.68 mmol). In this case, the genotoxic substance was 0.02 area% based on the total GC area of the obtained N- (2, 6-dimethylphenyl) -N- (methoxyacetyl) -D-alanine methyl ester.
Example 2
A solution containing 100g (manufactured by TCI, purity 98% or more (GC), 0.96 mol) of methyl L-lactate was injected into the flask, the internal pressure was adjusted to 60 Torr, and the temperature was raised to 70 ℃.
Methyl L-lactate was distilled by raising the temperature from 70 ℃ and adjusting to 100 ℃ while reducing the internal pressure again from 60 torr to 40 torr. As a result, methyl L-lactate (104.11 g,1.0 mol) obtained by distillation was introduced into a reactor containing 400mL of methylene chloride at room temperature so that the content of L-lactic acid was 0.05 area% based on the total GC area of the distilled solution. Triethylamine (154.60 mL,111.31g,1.1 mol) was further added thereto, and the internal temperature was cooled to 0 ℃. Para-toluenesulfonyl chloride (209.70 g,1.1 mol) was slowly added while maintaining the internal temperature at 0℃to 5℃and, after completion of the addition, the resulting mixture was stirred for 4 hours while maintaining the internal temperature at 0℃to 5 ℃. After confirming that the unreacted L-methyl lactate remaining in the reaction mixture was 1.0 area% or less (as a result of GC analysis), 400mL of a 1N aqueous hydrochloric acid (HCl) solution was added and keptThe resulting mixture was stirred while maintaining the internal temperature at 15℃to 20℃and 400mL of 1% sodium bicarbonate (NaHCO 3 ) The aqueous solution was added to the organic layer obtained by layer separation, and the resulting mixture was stirred. After that, the organic layer was separated and concentrated under reduced pressure to give methyl(s) -2- (p-toluenesulfonyloxy) propionate with a purity of 98.36GC area% and a yield of 79% (204.44 g,0.79 mol).
2, 6-dimethylaniline (56.30 g,464.58 mmol) was added to the prepared methyl(s) -2- (p-toluenesulfonyloxy) propionate (20.00 g,77.43 mmol), and the resulting mixture was stirred by raising the internal temperature to 120℃to 130 ℃.
After confirming that the remaining unreacted(s) -methyl 2- (p-toluenesulfonyloxy) propionate in the reaction mixture was 1.0 area% or less (GC analysis result), the internal temperature was cooled to Room Temperature (RT), toluene (100 mL) was added thereto, and then the resulting mixture was cooled again to 0 ℃, stirred for 1 hour, and then filtered. The organic layer obtained by washing the filtrate twice with 1N aqueous HCl (20 mL) was washed once with distilled water (30 mL) and then concentrated under reduced pressure to give methyl N- (2, 6-dimethylphenyl) -D-alaninate (10.11 g,48.78 mmol) having a purity of 97.42GC area% and a yield of 63%.
To which NaHCO is added 3 After (5.33 g,63.41 mmol) and toluene (40 mL), the resulting mixture was cooled to-5℃to 0℃and then methoxy acetyl chloride (6.88 g,63.41 mmol) was added dropwise thereto. After the completion of the dropwise addition, the resultant mixture was stirred for 3 hours so as to maintain the internal temperature at 10 to 15 ℃. After confirming that unreacted N- (2, 6-dimethylphenyl) -D-alanine methyl ester remaining in the reaction mixture was 1.0 area% or less (result of GC analysis), H was added thereto 2 O (40 mL), then pH 7 to 8 was confirmed by dropwise addition of 1N NaOH thereto, and then the aqueous layer was discarded by layer separation. Adding H to the separated organic layer 2 O (20 mL), after stirring, the waste aqueous layer was separated by layer. After removing foreign matters by filtering the separated organic layer, the residue was concentrated under reduced pressure to give N- (2, 6) having a purity of 97.62GC area% and a yield of 84% (11.45 g,40.98 mmol)-dimethylphenyl) -N- (methoxyacetyl) -D-alanine methyl ester. In this case, the genotoxic substance was 0.11 area% based on the total GC area of the obtained N- (2, 6-dimethylphenyl) -N- (methoxyacetyl) -D-alanine methyl ester.
Comparative example 1
Methyl L-lactate (104.11 g,1.0 mol) which was not distilled and thus contained 0.20 area% of L-lactic acid in the total GC area was placed in a reactor containing 400mL of methylene chloride at room temperature, triethylamine (154 mL,111.31g,1.1 mol) was added thereto, and the internal temperature was cooled to 0 ℃. Para-toluenesulfonyl chloride (209.70 g,1.1 mol) was slowly added while maintaining the internal temperature at 0℃to 5℃and, after the addition was completed, the resulting mixture was stirred for 4 hours while maintaining the internal temperature at 0℃to 5 ℃. After confirming that unreacted L-methyl lactate remaining in the reaction mixture was 1.0 area% or less (result of GC analysis), 400mL of 1N aqueous hydrochloric acid (HCl) was added, and the resulting mixture was stirred while maintaining the internal temperature at 15℃to 20℃and then 400mL of 1% sodium bicarbonate (NaHCO) 3 ) The aqueous solution was added to the organic layer obtained by layer separation, and the resulting mixture was stirred. Thereafter, the organic layer was separated and concentrated under reduced pressure to give methyl(s) -2- (p-toluenesulfonyloxy) propionate with a purity of 98.23GC area% and a yield of 79% (204.38 g,0.79 mol).
2, 6-dimethylaniline (56.30 g,464.58 mmol) was added to the prepared methyl(s) -2- (p-toluenesulfonyloxy) propionate (20.00 g,77.43 mmol), and the resulting mixture was stirred by raising the internal temperature to 120℃to 130 ℃.
After confirming that unreacted(s) -methyl 2- (p-toluenesulfonyloxy) propionate remaining in the reaction mixture was 1.0 area% or less (GC analysis result), the internal temperature was cooled to Room Temperature (RT), toluene (100 mL) was added thereto, and then the resulting mixture was cooled again to 0 ℃, stirred for 1 hour, and then filtered. The organic layer obtained by washing the filtrate twice with 1N aqueous HCl (20 mL) was washed once with distilled water (30 mL) and then concentrated under reduced pressure to give methyl N- (2, 6-dimethylphenyl) -D-alaninate with a purity of 97.40GC area% and a yield of 64% (10.27 g,49.56 mmol).
To which NaHCO is added 3 After (5.41 g,64.43 mmol) and toluene (40 mL), the resulting mixture was cooled to-5℃to 0℃and then methoxy acetyl chloride (6.99 g,64.43 mmol) was added dropwise thereto. After the completion of the dropwise addition, the resultant mixture was stirred for 3 hours so as to maintain the internal temperature at 10℃to 15 ℃. After confirming that unreacted N- (2, 6-dimethylphenyl) -D-alanine methyl ester remaining in the reaction mixture was 1.0 area% or less (result of GC analysis), H was added thereto 2 O (40 mL), then pH 7 to 8 was confirmed by dropwise addition of 1N NaOH thereto, and then the aqueous layer was discarded by layer separation. Adding H to the separated organic layer 2 O (20 mL), after stirring, the waste aqueous layer was separated by layer. After removing foreign matter by filtration of the separated organic layer, the residue was concentrated under reduced pressure to give methyl N- (2, 6-dimethylphenyl) -N- (methoxyacetyl) -D-alaninate with a purity of 97.57GC area% and a yield of 83% (11.49 g,41.13 mmol). In this case, the genotoxic substance was 0.19 area% based on the total GC area of the obtained N- (2, 6-dimethylphenyl) -N- (methoxyacetyl) -D-alanine methyl ester.
Test example 1
Samples were taken from the respective steps of the syntheses of examples 1 and 2 and comparative example 1, and were measured by gas chromatography 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 of GC/FID.
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
As can be seen from table 1, in comparative example 1 in which distillation was not performed, the purity of the final compound was low, and the impurity content of chemical formula 10 was high. It was confirmed that example 1 in which all the compounds of chemical formula 1 and chemical formula 5 were distilled had higher purity and lower content of the impurity of chemical formula 10, even compared with example 2 in which only the compound of chemical formula 1 was distilled.
Claims (12)
1. A method of preparing an N-acyl derivative, the method comprising:
distilling a first composition comprising a compound of formula 1 below;
synthesizing a compound of the following chemical formula 3 by adding the compound of the following chemical formula 2 to the distilled first composition;
synthesizing a compound of the following chemical formula 5 by reacting the compound of the chemical formula 3 with a compound of the following chemical formula 4; and
synthesizing a compound of the following chemical formula 7 by reacting the compound of the chemical formula 5 with a compound of the following chemical formula 6:
[ chemical formula 1]
[ chemical formula 2]
[ chemical formula 3]
[ chemical formula 4]
[ chemical formula 5]
[ chemical formula 6]
[ chemical formula 7]
Wherein, in chemical formulas 1 to 7,
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 and R5 are methyl.
2. The method of claim 1, further comprising:
distilling a second composition comprising the compound of formula 5,
wherein the synthesis of the compound of chemical formula 7 is to synthesize the compound of chemical formula 7 by adding the compound of chemical formula 6 to the distilled second composition.
3. A method of preparing an N-acyl derivative, the method comprising:
synthesizing a compound of the following chemical formula 3 by adding a compound of the following chemical formula 2 to a first composition comprising the compound of the following chemical formula 1, wherein the content of the compound of the following chemical formula 8 is 0.05 area% or less based on the total GC area of the first composition;
synthesizing a compound of the following chemical formula 5 by reacting the compound of the chemical formula 3 with a compound of the following chemical formula 4; and
synthesizing a compound of the following chemical formula 7 by reacting the compound of the chemical formula 5 with a compound of the following chemical formula 6:
[ chemical formula 1]
[ chemical formula 2]
[ chemical formula 3]
[ chemical formula 4]
[ chemical formula 5]
[ chemical formula 6]
[ chemical formula 7]
[ chemical formula 8]
Wherein, in chemical formulas 1 to 7,
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 and R5 are methyl.
4. A method according to claim 3, wherein the synthesis of the compound of formula 7 synthesizes the compound of formula 7 by adding the compound of formula 6 to a second composition comprising the compound of formula 5, wherein the content of the following compound of formula 9 is 0.05 area% or less based on the total GC area of the second composition:
[ chemical formula 9]
In the chemical formula 9, the chemical formula (II),
r2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or a methyl group,
r4 is methyl.
5. The method of claim 1, wherein the distilling of the first composition distills the first composition at a pressure of 40 torr to 60 torr and a temperature of 70 ℃ to 100 ℃.
6. The method of claim 2, wherein the distilling of the second composition distills the second composition at a pressure of 2 torr to 20 torr and a temperature of 130 ℃ to 200 ℃.
7. The method of claim 1, wherein the distillation of the first composition is a preparation, wherein the content of the compound of the following chemical formula 8 is 0.05 area% or less of the first composition based on the total GC area of the first composition:
[ chemical formula 8]
8. The method according to claim 2, wherein the distillation of the second composition is a preparation in which the content of the compound of the following chemical formula 9 is 0.05 area% or less of the second composition based on the total GC area of the composition:
[ chemical formula 9]
In the chemical formula 9, the chemical formula (II),
r2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or a methyl group,
r4 is methyl.
9. The method according to claim 1 or 3, further comprising purifying the synthesized compound of formula 7,
wherein the content of the compound of the following chemical formula 10 is 0.05 area% or less based on the total GC area of the third composition including the purified compound of chemical formula 7:
[ chemical formula 10]
In the chemical formula 10, 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 and R5 are methyl.
10. A composition comprising a compound of the following chemical formula 7 and a compound of the following chemical formula 10,
wherein the content of the compound of the following chemical formula 10 is 0.05 area% or less based on the total GC area of the composition:
[ chemical formula 7]
[ chemical formula 10]
In the chemical formula 7 and the chemical formula 10,
r2 and R3 are the same or different from each other and are each independently hydrogen; deuterium; or methyl, R4 and R5 are methyl.
11. A medicament comprising the composition of claim 10.
12. An agricultural product comprising the composition of claim 10.
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