KR20220035680A - Method for preparing compound - Google Patents
Method for preparing compound Download PDFInfo
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- KR20220035680A KR20220035680A KR1020200117716A KR20200117716A KR20220035680A KR 20220035680 A KR20220035680 A KR 20220035680A KR 1020200117716 A KR1020200117716 A KR 1020200117716A KR 20200117716 A KR20200117716 A KR 20200117716A KR 20220035680 A KR20220035680 A KR 20220035680A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 124
- 238000000034 method Methods 0.000 title claims description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 66
- 238000005406 washing Methods 0.000 claims abstract description 35
- 239000003637 basic solution Substances 0.000 claims abstract description 24
- 239000000243 solution Substances 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 238000004519 manufacturing process Methods 0.000 claims description 19
- 239000012044 organic layer Substances 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 239000012153 distilled water Substances 0.000 claims description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 150000003512 tertiary amines Chemical class 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000004817 gas chromatography Methods 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 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
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- XEUQMYXHUMKCJY-BYPYZUCNSA-N methyl (2s)-2-methylsulfonyloxypropanoate Chemical compound COC(=O)[C@H](C)OS(C)(=O)=O XEUQMYXHUMKCJY-BYPYZUCNSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000003929 acidic solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- JJKWHOSQTYYFAE-UHFFFAOYSA-N 2-methoxyacetyl chloride Chemical compound COCC(Cl)=O JJKWHOSQTYYFAE-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000005808 Metalaxyl-M Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000769 gas chromatography-flame ionisation detection Methods 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- CIEXPHRYOLIQQD-CYBMUJFWSA-N (R)-furalaxyl Chemical compound CC=1C=CC=C(C)C=1N([C@H](C)C(=O)OC)C(=O)C1=CC=CO1 CIEXPHRYOLIQQD-CYBMUJFWSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 239000005735 Benalaxyl-M Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 230000006181 N-acylation Effects 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-M alaninate Chemical compound CC(N)C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-M 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- CJPQIRJHIZUAQP-MRXNPFEDSA-N benalaxyl-M Chemical compound CC=1C=CC=C(C)C=1N([C@H](C)C(=O)OC)C(=O)CC1=CC=CC=C1 CJPQIRJHIZUAQP-MRXNPFEDSA-N 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- -1 methyl N-(2,6-dimethylphenyl)-D-alaninate ( Methyl N-(2,6-dimethylphenyl)-D-alaninate) Chemical compound 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011814 protection agent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 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
-
- 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
- C07C231/24—Separation; Purification
-
- 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
본 명세서는 화학식 1의 화합물 및 화학식 2의 화합물을 반응시켜 화학식 3의 화합물을 제조하는 제1 반응 단계; 상기 제조된 화학식 3의 화합물 및 화학식 4의 화합물을 반응시켜 화학식 5의 화합물을 제조하는 제2 반응 단계; 상기 제2 반응 단계 이후에 염기성 용액으로 수세하여 미반응한 화합물을 제거하는 수세 단계; 및 수세된 용액으로부터 화학식 5의 화합물을 수득하는 단계를 포함하는 화합물의 제조 방법에 관한 것이다.The present specification includes a first reaction step of preparing a compound of Formula 3 by reacting a compound of Formula 1 and a compound of Formula 2; A second reaction step of preparing a compound of Formula 5 by reacting the prepared compound of Formula 3 with the compound of Formula 4; A washing step of removing unreacted compounds by washing with a basic solution after the second reaction step; and obtaining a compound of formula (5) from the washed solution.
Description
본 발명은 화합물의 제조 방법에 관한 것이다. The present invention relates to methods for preparing compounds.
메탈락실-엠(Metalaxyl-M), 베날락실-엠(Benalaxyl-M) 및 퓨랄락실-엠(Furalaxyl-M)과 같이 살균제로 사용되는 메틸-N-(2,6-디메틸페닐)-D-알라니네이트(Methyl N-(2,6-dimethylphenyl)-D-alaninate)를 기반으로 하는 N-아실(N-acyl) 유도체들은 작물보호제로 사용되며, 상업적으로 중요하다.Methyl-N-(2,6-dimethylphenyl)-D- used as a disinfectant such as Metalaxyl-M, Benalaxyl-M and Furalaxyl-M. N-acyl derivatives based on alaninate (Methyl N-(2,6-dimethylphenyl)-D-alaninate) are used as crop protection agents and are of commercial importance.
종래에는, 전술한 N-아실(N-acyl) 유도체들을 합성하는 일반적인 방법(general scheme)으로 메틸(s)-2-(알킬 또는 아릴 술포닐옥시)프로파노에이트(Methyl (s)-2-(alkyl or aryl sulfonyloxy)propanoate)를 2,6-디메틸아닐린(2,6-Dimethylaniline)에 N-알킬레이션(N-Alkylation)하여 메틸-N-(2,6-디메틸페닐)-D-알라니네이트(Methyl N-(2,6-dimethylphenyl)-D-alaninate)를 만든 후, 다양한 산 염화물(Acid chloride)로 N-아실레이션(N-Acylation)을 이용하는 방법이 알려져 있다. Conventionally, methyl (s)-2- (alkyl or aryl sulfonyloxy) propanoate (Methyl (s)-2- (alkyl or aryl sulfonyloxy)propanoate) is N-alkylated with 2,6-dimethylaniline to produce methyl-N-(2,6-dimethylphenyl)-D-alaniline. There is a known method of making methyl N-(2,6-dimethylphenyl)-D-alaninate and then using N-acylation with various acid chlorides.
그러나, 상기 제조방법은 중간체(Methyl N-(2,6-dimethylphenyl)-D-alaninate) 및 생산물(예컨대, Metalaxyl-M)이 액체 성상을 띄어 결정화 또는 재결정 방법을 사용할 수 없다는 문제점이 있다. 특히, 상기 제조방법은 중간체가 물에 대한 용해도가 높아, 수성 용매와 혼합되는 물성을 가지고 있어 정제 방법이 매우 제한적이라 양산화 공정에 적합한 후처리(work-up 및 정제) 방법을 개발하는데 어려움이 있다.However, the above manufacturing method has a problem in that the intermediate (Methyl N-(2,6-dimethylphenyl)-D-alaninate) and the product (e.g., Metalaxyl-M) are in a liquid state, so crystallization or recrystallization methods cannot be used. In particular, in the above manufacturing method, the intermediate has high solubility in water and has the property of mixing with aqueous solvents, so the purification method is very limited, making it difficult to develop a post-processing (work-up and purification) method suitable for the mass production process. .
따라서, 대량생산에 적용이 가능한 후처리를 도입한 경제적(고수율 및 고순도)인 제조 방법을 개발하는 것이 필요하다.Therefore, it is necessary to develop an economical (high yield and high purity) manufacturing method incorporating post-processing that can be applied to mass production.
본 명세서는 화합물의 제조 방법을 제공한다.This specification provides methods for preparing compounds.
본 명세서의 일 실시상태는One embodiment of this specification is
하기 화학식 1의 화합물 및 하기 화학식 2의 화합물을 반응시켜 하기 화학식 3의 화합물을 제조하는 제1 반응 단계; A first reaction step of preparing a compound of Formula 3 by reacting a compound of Formula 1 below and a compound of Formula 2 below;
상기 제조된 화학식 3의 화합물 및 하기 화학식 4의 화합물을 반응시켜 하기 화학식 5의 화합물을 제조하는 제2 반응 단계; A second reaction step of preparing a compound of Formula 5 by reacting the compound of Formula 3 prepared above with the compound of Formula 4 below;
상기 제2 반응 단계 이후에 염기성 용액으로 수세하여 미반응한 화합물을 제거하는 수세 단계; 및A washing step of removing unreacted compounds by washing with a basic solution after the second reaction step; and
수세된 용액으로부터 상기 화학식 5의 화합물을 수득하는 단계를 포함하는 화합물의 제조 방법을 제공한다.Provided is a method for producing a compound comprising the step of obtaining the compound of Formula 5 from a water-washed solution.
[화학식 1][Formula 1]
[화학식 2] [Formula 2]
[화학식 3][Formula 3]
[화학식 4] [Formula 4]
[화학식 5] [Formula 5]
상기 화학식 1 내지 5에 있어서,In Formulas 1 to 5,
R1은 메틸기; 또는 p-메틸페닐기이고,R1 is a methyl group; or p-methylphenyl group,
R2 및 R3는 서로 같거나 상이하고, 각각 독립적으로 수소; 또는 메틸기이며, 단 R2 및 R3 중 적어도 하나는 메틸기이고,R2 and R3 are the same or different from each other and are each independently hydrogen; or a methyl group, provided that at least one of R2 and R3 is a methyl group,
R4는 탄소수 1 내지 4의 알킬기이다.R4 is an alkyl group having 1 to 4 carbon atoms.
본 명세서의 일 실시상태에 따른 화합물의 제조 방법은 제조된 화합물(화학식 5의 화합물)의 최종 수율을 증가시킬 수 있다.The method for producing a compound according to an exemplary embodiment of the present specification can increase the final yield of the prepared compound (compound of Formula 5).
본 발명의 일 실시상태에 따른 화합물의 제조 방법은 제조된 화합물을 고순도로 수득할 수 있다.The method for producing a compound according to an exemplary embodiment of the present invention can obtain the prepared compound with high purity.
도 1은 실시예에서 제조된 화학식 3의 화합물의 GC 측정 결과를 나타낸 도이다.
도 2는 실시예에서 제조된 화학식 5의 화합물의 GC 측정 결과를 나타낸 도이다.Figure 1 is a diagram showing the GC measurement results of the compound of Formula 3 prepared in Examples.
Figure 2 is a diagram showing the GC measurement results of the compound of Formula 5 prepared in Examples.
이하, 본 발명에 대하여 더욱 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 명세서에 있어서, 어떤 부분이 어떤 구성요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.In this specification, when a part "includes" a certain component, this means that it may further include other components rather than excluding other components, unless specifically stated to the contrary.
본 명세서의 일 실시상태는 하기 화학식 1의 화합물 및 하기 화학식 2의 화합물을 반응시켜 하기 화학식 3의 화합물을 제조하는 제1 반응 단계; An exemplary embodiment of the present specification includes a first reaction step of preparing a compound of Formula 3 by reacting a compound of Formula 1 below and a compound of Formula 2 below;
상기 제조된 화학식 3의 화합물 및 하기 화학식 4의 화합물을 반응시켜 하기 화학식 5의 화합물을 제조하는 제2 반응 단계; A second reaction step of preparing a compound of Formula 5 by reacting the compound of Formula 3 prepared above with the compound of Formula 4 below;
상기 제2 반응 단계 이후에 염기성 용액으로 수세하여 미반응한 화합물을 제거하는 수세 단계; 및A washing step of removing unreacted compounds by washing with a basic solution after the second reaction step; and
수세된 용액으로부터 상기 화학식 5의 화합물을 수득하는 단계를 포함하는 화합물의 제조 방법을 제공한다.Provided is a method for producing a compound comprising the step of obtaining the compound of Formula 5 from a water-washed solution.
[화학식 1][Formula 1]
[화학식 2] [Formula 2]
[화학식 3][Formula 3]
[화학식 4] [Formula 4]
[화학식 5] [Formula 5]
상기 화학식 1 내지 5에 있어서,In Formulas 1 to 5,
R1은 메틸기; 또는 p-메틸페닐기이고,R1 is a methyl group; or p-methylphenyl group,
R2 및 R3는 서로 같거나 상이하고, 각각 독립적으로 수소; 또는 메틸기이며, 단 R2 및 R3 중 적어도 하나는 메틸기이고,R2 and R3 are the same or different from each other and are each independently hydrogen; or a methyl group, provided that at least one of R2 and R3 is a methyl group,
R4는 탄소수 1 내지 4의 알킬기이다.R4 is an alkyl group having 1 to 4 carbon atoms.
본 명세서의 일 실시상태에 있어서, 상기 미반응한 화합물은 화학식 1의 화합물이다. In one embodiment of the present specification, the unreacted compound is a compound of Formula 1.
본 명세서는 화학식 5의 화합물의 제조방법에 관한 것으로, 본 명세서에 있어서, 제조된 화합물은 화학식 5의 화합물이다.This specification relates to a method for producing a compound of Formula 5. In this specification, the prepared compound is a compound of Formula 5.
본 명세서의 일 실시상태는 제2 반응 단계 후에 수세 단계를 진행하기 때문에, 제조된 화합물의 수율이 높은 장점이 있다. One embodiment of the present specification has the advantage of high yield of the prepared compound because the water washing step is performed after the second reaction step.
구체적으로, 상기 화학식 1의 화합물 및 화학식 3의 화합물은 염기성 용액에 잘 용해된다. 따라서, 제1 반응 단계 이후 염기성 용액으로 수세 단계를 진행하게 되면 미반응한 화학식 1의 화합물뿐만 아니라 제조된 화학식 3의 화합물이 폐기되는 수층에 용해되는 양이 많아지므로, 제조된 화학식 3의 화합물의 손실량이 증가되어, 전체 수율이 감소하는 결과를 나타내게 된다.Specifically, the compound of Formula 1 and the compound of Formula 3 are well soluble in basic solutions. Therefore, when the washing step with a basic solution is performed after the first reaction step, the amount of not only the unreacted compound of Chemical Formula 1 but also the prepared compound of Chemical Formula 3 dissolved in the discarded water layer increases, so that the amount of the prepared compound of Chemical Formula 3 increases. The amount of loss increases, resulting in a decrease in overall yield.
반면에, 화학식 5의 화합물은 염기성 용액에 대한 용해도가 낮다. 따라서, 본 명세서의 일 실시상태는 화학식 5가 제조된 후에 염기성 용액으로 수세하는 단계를 진행하기 때문에, 수층으로 손실되는 화학식 3 및 화학식 5의 화합물이 적고, 이에 따라, 제조된 화합물의 수율이 향상되는 효과를 나타낸다. On the other hand, the compound of Formula 5 has low solubility in basic solutions. Therefore, in one embodiment of the present specification, since the step of washing with a basic solution is performed after Formula 5 is prepared, less compounds of Formula 3 and Formula 5 are lost to the water layer, and thus, the yield of the prepared compound is improved. It shows the effect.
본 명세서의 일 실시상태에 있어서, 염기성 용액의 농도는 0.1N 내지 5.0N, 구체적으로 0.1N 내지 3.0N이다.In one embodiment of the present specification, the concentration of the basic solution is 0.1N to 5.0N, specifically 0.1N to 3.0N.
본 명세서의 일 실시상태에 있어서, 염기성 용액은 수산화 나트륨, 수산화 칼륨, 수산화 칼슘 및 암모니아 중 1종 이상을 포함하는 용액이다.In one embodiment of the present specification, the basic solution is a solution containing one or more of sodium hydroxide, potassium hydroxide, calcium hydroxide, and ammonia.
본 명세서의 일 실시상태에 있어서, 상기 염기성 용액은 투입된 화학식 1의 화합물의 질량 대비 1배 내지 10배 첨가된다. 염기성 용액이 화학식 1의 질량 대비 1배 미만으로 사용될 경우 수세가 잘되지 않아 미반응 잔류 화학식 1이 과량으로 남아있는 문제점이 있다. 또한 염기성 용액이 화학식 1의 질량 대비 10배 초과로 사용될 경우, 최종 생성물(화학식 5의 화합물)의 손실이 발생되어 최종 수율이 저하되는 문제점이 있다.In one embodiment of the present specification, the basic solution is added in an amount of 1 to 10 times the mass of the compound of Formula 1 added. If the basic solution is used in an amount less than 1 times the mass of Chemical Formula 1, there is a problem in that the unreacted residual Chemical Formula 1 remains in excess because it is not washed well. Additionally, when the basic solution is used in an amount exceeding 10 times the mass of Formula 1, there is a problem in that the final product (compound of Formula 5) is lost and the final yield is lowered.
본 명세서의 일 실시상태에 있어서, 상기 제1 반응 단계에서 화학식 2의 화합물은 자체적으로 염기 역할을 하므로 추가의 염기 없이도 제1 반응 단계의 진행이 가능하다. 구체적으로, 1차 아민, 2차 아민 또는 무기 염기가 사용되지 않더라도 제1 반응 단계의 진행이 가능하다.In one embodiment of the present specification, in the first reaction step, the compound of Formula 2 itself acts as a base, so the first reaction step can proceed without an additional base. Specifically, the first reaction step can proceed even if no primary amine, secondary amine, or inorganic base is used.
본 명세서의 일 실시상태에 있어서, 상기 제1 반응 단계는 3차 아민을 더 포함하여 반응된다. In one embodiment of the present specification, the first reaction step further includes a tertiary amine.
본 명세서의 일 실시상태에 있어서, 상기 3차 아민은 N-아실 유도체의 제조방법에 사용 가능한 3차 아민이라면 제한 없이 사용 가능하다. 구체적으로, 상기 3차 아민은 트리에틸아민, 디이소프로필에틸아민 또는 피리딘이다.In one embodiment of the present specification, the tertiary amine can be used without limitation as long as it is a tertiary amine that can be used in the method for producing N-acyl derivatives. Specifically, the tertiary amine is triethylamine, diisopropylethylamine, or pyridine.
본 명세서의 일 실시상태는 상기 3차 아민을 사용함으로써 화학식 1이 화학식 2로 N-알킬레이션(N-alkylation)되어 화학식 3이 생성되는 반응 속도를 증가시키는 효과를 나타낼 수 있다.One embodiment of the present specification may have the effect of increasing the reaction rate at which Chemical Formula 1 is N-alkylated to Chemical Formula 2 by using the tertiary amine to produce Chemical Formula 3.
본 명세서의 일 실시상태에 있어서, 상기 제1 반응 단계에 투입된 화학식 1의 화합물 및 화학식 2의 화합물의 몰비는 1:2 내지 1:10이다. 구체적으로 1:4 내지 1:10이다.In one embodiment of the present specification, the molar ratio of the compound of Formula 1 and the compound of Formula 2 added to the first reaction step is 1:2 to 1:10. Specifically, it is 1:4 to 1:10.
본 명세서의 일 실시상태에 있어서, 상기 제1 반응 단계에 투입된 화학식 1의 화합물 및 3차 아민의 몰비는 1:0.5 내지 1:1.5이다. In one embodiment of the present specification, the molar ratio of the compound of Formula 1 and the tertiary amine added to the first reaction step is 1:0.5 to 1:1.5.
본 명세서의 일 실시상태에 있어서, 상기 제1 반응 단계 및 제2 반응 단계는 용매 하에서 수행된다.In one embodiment of the present specification, the first reaction step and the second reaction step are performed under a solvent.
본 명세서의 일 실시상태에 있어서, 상기 제1 반응 단계는 방향족 탄화수소계 용매 하에서 진행된다.In one embodiment of the present specification, the first reaction step is carried out under an aromatic hydrocarbon-based solvent.
본 명세서에 있어서, 방향족 탄화수소계 용매는 당업계에서 사용되는 용매라면 제한 없이 사용 가능하다. 예컨대, 상기 방향족 탄화수소계 용매는 톨루엔, 자일렌 및 클로로벤젠 중 1종 이상이다. In this specification, the aromatic hydrocarbon-based solvent can be used without limitation as long as it is a solvent used in the art. For example, the aromatic hydrocarbon solvent is one or more of toluene, xylene, and chlorobenzene.
본 명세서의 일 실시상태에 있어서, 상기 제1 반응 단계는 100℃ 내지 150℃의 온도범위에서 2시간 내지 24시간 수행된다.In one embodiment of the present specification, the first reaction step is performed at a temperature range of 100°C to 150°C for 2 to 24 hours.
본 명세서의 일 실시상태에 있어서, 상기 제1 반응 단계는 화학식 1의 화합물 및 화학식 2의 화합물이 투입된 후 교반하는 단계를 포함한다. 상기 교반은 100℃ 내지 150℃의 온도 범위에서 이루어진다. 이때 교반은 2시간 내지 24시간 수행된다. In one embodiment of the present specification, the first reaction step includes adding the compound of Formula 1 and the compound of Formula 2 and then stirring. The stirring is performed in a temperature range of 100°C to 150°C. At this time, stirring is performed for 2 to 24 hours.
본 명세서의 일 실시상태에 있어서, 상기 제1 반응 단계와 제2 반응 단계 사이에 기체크로마토그래피(GC)를 통하여 미반응한 화학식 1의 화합물의 양을 확인하는 단계를 더 포함한다. 구체적으로, 상기 제1 반응 단계와 제2 반응 단계 사이에 기체크로마토그래피(GC)를 통하여 미반응한 화학식 1의 화합물의 양을 확인하고, 미반응한 화학식 1의 화합물의 양이 투입한 화학식 1의 화합물 양의 10% 이하일 때, 제2 반응 단계를 수행한다. In one embodiment of the present specification, the step of confirming the amount of unreacted compound of Formula 1 through gas chromatography (GC) between the first reaction step and the second reaction step is further included. Specifically, the amount of the unreacted compound of Formula 1 was confirmed through gas chromatography (GC) between the first reaction step and the second reaction step, and the amount of the unreacted compound of Formula 1 was added to the amount of the compound of Formula 1 added. When the amount of the compound is 10% or less, the second reaction step is performed.
본 명세서의 일 실시상태에 있어서, 상기 제1 반응 단계와 제2 반응 단계 사이에 염기성이 아닌 용액으로 수세하는 단계를 더 포함한다. In one embodiment of the present specification, the step of washing with a non-basic solution is further included between the first reaction step and the second reaction step.
본 명세서에 있어서, 상기 염기성이 아닌 용액은 증류수 및 산성 용액 중 1종 이상이다. 예컨대, 상기 제1 반응 단계와 제2 반응 단계 사이에 제1 반응 후 잔류된 염기성의 화학식 2의 화합물 및 3차 아민을 산성 용액으로 수세하여 제거한 후, 중성 pH 를 맞추기 위하여 증류수로 수세하여 산성 성분을 씻어내는 단계를 더 포함한다.In the present specification, the non-basic solution is one or more of distilled water and an acidic solution. For example, between the first reaction step and the second reaction step, the basic compound of Formula 2 and the tertiary amine remaining after the first reaction are removed by washing with an acidic solution, and then washed with distilled water to adjust neutral pH to remove the acidic component. It further includes the step of washing.
본 명세서의 일 실시상태에 있어서, 산성 용액은 염산, 아세트산 및 메탄설폰산 중 1종 이상이다.In an exemplary embodiment of the present specification, the acidic solution is one or more of hydrochloric acid, acetic acid, and methanesulfonic acid.
본 명세서의 일 실시상태에 있어서, 상기 화합물의 제조 방법은 제1 반응 단계와 제2 반응 단계 사이에 제조된 화학식 3의 화합물을 수득하는 단계; 및 수득된 화학식 3의 화합물을 새로운 용매에 용해하는 단계를 더 포함한다.In one embodiment of the present specification, the method for producing the compound includes obtaining a compound of Formula 3 prepared between the first reaction step and the second reaction step; and dissolving the obtained compound of Formula 3 in a new solvent.
구체적으로, 본 명세서의 일 실시상태는 제1 용매 하에서 상기 화학식 1의 화합물 및 상기 화학식 2의 화합물을 반응시켜 상기 화학식 3의 화합물을 제조하는 제1 반응 단계; 기체크로마토그래피(GC)를 통하여 미반응한 화학식 1의 화합물의 양을 확인하는 단계; 미반응한 화학식 1의 화합물의 양이 투입한 화학식 1의 화합물 양의 10% 이하일 경우, 염기성이 아닌 용액으로 수세하여 유기층을 분리하는 단계; 분리된 유기층을 증류수로 수세한 후 감압농축하여 화학식 3의 화합물을 수득하는 단계; 수득된 화학식 3의 화합물을 제2 용매에 용해하는 단계; 화학식 3이 용해된 용액에 상기 화학식 4의 화합물을 투입하여, 상기 화학식 5의 화합물을 제조하는 제2 반응 단계; 상기 제2 반응 단계 이후에 염기성 용액으로 수세하여 미반응한 화합물을 제거하는 수세 단계; 및 수세된 용액으로부터 화학식 5의 화합물을 수득하는 단계를 포함한다.Specifically, an exemplary embodiment of the present specification includes a first reaction step of preparing a compound of Formula 3 by reacting the compound of Formula 1 and the compound of Formula 2 in a first solvent; Confirming the amount of unreacted compound of Formula 1 through gas chromatography (GC); If the amount of unreacted compound of Formula 1 is less than 10% of the amount of compound of Formula 1 added, separating the organic layer by washing with a non-basic solution; Washing the separated organic layer with distilled water and then concentrating it under reduced pressure to obtain the compound of Formula 3; Dissolving the obtained compound of Formula 3 in a second solvent; A second reaction step of preparing a compound of Formula 5 by adding a compound of Formula 4 to a solution in which Formula 3 is dissolved; A washing step of removing unreacted compounds by washing with a basic solution after the second reaction step; and obtaining the compound of formula 5 from the washed solution.
본 명세서의 일 실시상태에 있어서, 상기 제1 반응 단계와 제2 반응 단계 사이에 염기성이 아닌 용액으로 수세하는 단계를 포함하지 않는다.In one embodiment of the present specification, the step of washing with a non-basic solution is not included between the first reaction step and the second reaction step.
본 명세서의 일 실시상태에 있어서, 상기 제2 반응 단계는 염기를 더 포함하여 반응된다. In one embodiment of the present specification, the second reaction step further includes a base.
본 명세서의 일 실시상태에 있어서, 상기 염기는 탄산수소나트륨(NaHCO3), 탄산나트륨(Na2CO3), 탄산수소칼륨(KHCO3) 및 탄산칼륨(K2CO3) 중 1종 이상이다.In an exemplary embodiment of the present specification, the base is one or more of sodium hydrogen carbonate (NaHCO 3 ), sodium carbonate (Na 2 CO 3 ), potassium hydrogen carbonate (KHCO 3 ), and potassium carbonate (K 2 CO 3 ).
본 명세서의 일 실시상태에 있어서, 상기 염기는 탄산수소나트륨(NaHCO3), 탄산나트륨(Na2CO3), 탄산수소칼륨(KHCO3) 또는 탄산칼륨(K2CO3) 이다. In one embodiment of the present specification, the base is sodium hydrogen carbonate (NaHCO 3 ), sodium carbonate (Na 2 CO 3 ), potassium hydrogen carbonate (KHCO 3 ), or potassium carbonate (K 2 CO 3 ).
본 명세서의 일 실시상태에 있어서, 상기 제2 반응 단계에 투입된 화학식 3의 화합물 및 화학식 4의 화합물의 몰비는 1:1 내지 1:2이다. In one embodiment of the present specification, the molar ratio of the compound of Formula 3 and the compound of Formula 4 added to the second reaction step is 1:1 to 1:2.
본 명세서의 일 실시상태에 있어서, 상기 제2 반응 단계에 투입된 화학식 3의 화합물 및 염기의 몰비는 1:1 내지 1:2이다. In one embodiment of the present specification, the molar ratio of the compound of Formula 3 and the base added to the second reaction step is 1:1 to 1:2.
본 명세서의 일 실시상태에 있어서, 상기 제2 반응 단계는 방향족 탄화수소계 용매 또는 염소계 용매 하에서 진행된다.In one embodiment of the present specification, the second reaction step is carried out under an aromatic hydrocarbon-based solvent or a chlorine-based solvent.
본 명세서에 있어서, 염소계 용매는 당업계에서 사용되는 용매라면 제한 없이 사용 가능하다. 구체적으로, 상기 염소계 용매는 클로로포름, 메틸렌 클로라이드 또는 1,2-디클로로에탄이다. In this specification, the chlorine-based solvent can be used without limitation as long as it is a solvent used in the art. Specifically, the chlorine-based solvent is chloroform, methylene chloride, or 1,2-dichloroethane.
본 명세서에 있어서, 용매의 함량은 각 단계에서 그 함량을 구체적으로 명시한 경우를 제외하고는, 반응물들을 용해시킬 수 있는 충분한 함량을 사용하고, 특별히 한정하지 않는다.In this specification, the content of the solvent is used in an amount sufficient to dissolve the reactants, and is not particularly limited, except when the content is specifically specified in each step.
본 명세서의 일 실시상태에 있어서, 상기 제2 반응 단계는 -20℃ 내지 20℃의 온도범위에서 1시간 내지 6시간 수행된다. In one embodiment of the present specification, the second reaction step is performed for 1 hour to 6 hours at a temperature range of -20°C to 20°C.
본 명세서의 일 실시상태에 있어서, 상기 제2 반응 단계는 화학식 3의 화합물 및 화학식 4의 화합물이 투입된 후 교반하는 단계를 포함한다. 상기 교반은 -20℃ 내지 20℃의 온도 범위에서 이루어진다. 이때 교반은 1시간 내지 6시간 수행된다. In one embodiment of the present specification, the second reaction step includes adding the compound of Formula 3 and the compound of Formula 4 and then stirring. The stirring is carried out in a temperature range of -20°C to 20°C. At this time, stirring is performed for 1 to 6 hours.
본 명세서의 일 실시상태에 있어서, 상기 화학식 5의 화합물을 수득하는 단계는 수세된 용액으로부터 유기층을 분리하는 단계; 및 분리된 유기층을 증류수로 수세한 후 감압농축하는 단계를 포함한다.In one embodiment of the present specification, the step of obtaining the compound of Formula 5 includes separating an organic layer from the washed solution; and washing the separated organic layer with distilled water and then concentrating it under reduced pressure.
구체적으로, 본 명세서의 일 실시상태는 상기 화학식 1의 화합물 및 상기 화학식 2의 화합물을 반응시켜 상기 화학식 3의 화합물을 제조하는 제1 반응 단계; 상기 제조된 화학식 3의 화합물 및 상기 화학식 4의 화합물을 반응시켜 상기 화학식 5의 화합물을 제조하는 제2 반응 단계; 상기 제2 반응 단계 이후에 염기성 용액으로 수세하여 미반응한 화합물을 제거하는 수세 단계; 수세된 용액으로부터 유기층을 분리하는 단계; 및 분리된 유기층을 증류수로 수세한 후 감압농축하여 화학식 5의 화합물을 수득하는 단계를 포함한다.Specifically, an exemplary embodiment of the present specification includes a first reaction step of preparing a compound of Formula 3 by reacting the compound of Formula 1 and the compound of Formula 2; A second reaction step of preparing a compound of Formula 5 by reacting the prepared compound of Formula 3 with the compound of Formula 4; A washing step of removing unreacted compounds by washing with a basic solution after the second reaction step; Separating the organic layer from the washed solution; And washing the separated organic layer with distilled water and then concentrating it under reduced pressure to obtain the compound of Formula 5.
보다 구체적으로, 본 명세서의 일 실시상태는 제1 용매 하에서 상기 화학식 1의 화합물 및 상기 화학식 2의 화합물을 반응시켜 상기 화학식 3의 화합물을 제조하는 제1 반응 단계; 기체크로마토그래피(GC)를 통하여 미반응한 화학식 1의 화합물의 양을 확인하는 단계; 미반응한 화학식 1이 10% 미만일 경우, 산성 용액으로 수세하여 유기층을 분리하는 단계; 분리된 유기층을 증류수로 수세한 후 감압농축하여 상기 화학식 3의 화합물을 수득하는 단계; 수득된 화학식 3의 화합물을 제2 용매에 용해하는 단계; 화학식 3이 용해된 용액에 상기 화학식 4의 화합물을 투입하여, 상기 화학식 5의 화합물을 제조하는 제2 반응 단계; 상기 제2 반응 단계 이후에 염기성 용액으로 수세하여 미반응한 화합물을 제거하는 수세 단계; 수세된 용액으로부터 유기층을 분리하는 단계; 및 분리된 유기층을 증류수로 수세한 후 감압농축하여 화학식 5의 화합물을 수득하는 단계를 포함한다.More specifically, an exemplary embodiment of the present specification includes a first reaction step of preparing a compound of Formula 3 by reacting the compound of Formula 1 and the compound of Formula 2 in a first solvent; Confirming the amount of unreacted compound of Formula 1 through gas chromatography (GC); When the unreacted amount of Chemical Formula 1 is less than 10%, separating the organic layer by washing with an acidic solution; Washing the separated organic layer with distilled water and then concentrating it under reduced pressure to obtain the compound of Formula 3; Dissolving the obtained compound of Formula 3 in a second solvent; A second reaction step of preparing a compound of Formula 5 by adding a compound of Formula 4 to a solution in which Formula 3 is dissolved; A washing step of removing unreacted compounds by washing with a basic solution after the second reaction step; Separating the organic layer from the washed solution; And washing the separated organic layer with distilled water and then concentrating it under reduced pressure to obtain the compound of Formula 5.
본 명세서의 일 실시상태에 있어서, 상기 유기층이 분리되고 남은 용액층은 폐기된다.In one embodiment of the present specification, the organic layer is separated and the remaining solution layer is discarded.
본 명세서의 일 실시상태에 있어서, 상기 미반응한 화학식 1의 화합물이 10% 이상일 경우, 제1 반응 단계를 더 진행한다.In an exemplary embodiment of the present specification, when the unreacted compound of Formula 1 is 10% or more, the first reaction step is further performed.
본 명세서의 일 실시상태에 있어서, 상기 제1 용매는 제1 반응 단계에 사용되는 용매이다. 구체적으로, 상기 제1 용매는 방향족 탄화수소계 용매이다.In one embodiment of the present specification, the first solvent is a solvent used in the first reaction step. Specifically, the first solvent is an aromatic hydrocarbon-based solvent.
본 명세서의 일 실시상태에 있어서, 상기 제2 용매는 제2 반응 단계에 사용되는 용매이다. 구체적으로, 상기 제2 용매는 방향족 탄화수소계 용매 또는 염소계 용매이다.In one embodiment of the present specification, the second solvent is a solvent used in the second reaction step. Specifically, the second solvent is an aromatic hydrocarbon-based solvent or a chlorine-based solvent.
본 명세서의 일 실시상태에 있어서, 상기 제조방법에 의하여 제조된 화합물의 수득률은 70% 이상이다. In one embodiment of the present specification, the yield of the compound prepared by the above production method is 70% or more.
본 명세서의 일 실시상태에 있어서, 상기 제조방법에 의하여 제조된 화합물의 순도는 99% 이상이다.In one embodiment of the present specification, the purity of the compound prepared by the above production method is 99% or more.
본 명세서에 있어서, 순도는 GC/FID(Gas chromatography/Flame ionization detector)측정을 통하여 확인 가능하다.In this specification, purity can be confirmed through GC/FID (Gas chromatography/Flame ionization detector) measurement.
본 명세서의 일 실시상태에 있어서, 상기 GC/FID 측정은 HP-5(0.25mm ID x 30mL, 0.25μm d.f. capillary) 컬럼(Column)을 이용하여 초기 값(initial value)은 50℃ 최종 값(final value)은 320℃, 프로그램 레이트(program rate)는 10℃/min으로 설정하여 측정된다. 이때 인젝터(injector)와 디텍터(detector)의 온도는 340℃이고, 가스 유속(gas flow rate)는 1mL/min이다.In one embodiment of the present specification, the GC/FID measurement uses an HP-5 (0.25mm ID x 30mL, 0.25μm d.f. capillary) column, and the initial value is 50°C and the final value is value) is measured at 320℃, and the program rate is set at 10℃/min. At this time, the temperature of the injector and detector is 340°C, and the gas flow rate is 1mL/min.
본 명세서에 있어서, 알킬기는 직쇄 또는 분지쇄일 수 있고, 탄소수는 특별히 한정되지 않으나 1 내지 60인 것이 바람직하다. 일 실시상태에 따르면, 상기 알킬기의 탄소수는 1 내지 30이다. 상기 알킬기의 구체적인 예로는 메틸기, 에틸기, 프로필기, 이소프로필기, 부틸기, 이소부틸기, tert-부틸기, 펜틸기, 헥실기, 헵틸기, 옥틸기 등이 있으나, 이들에 한정되지 않는다.In the present specification, the alkyl group may be straight chain or branched, and the number of carbon atoms is not particularly limited, but is preferably 1 to 60. According to one embodiment, the carbon number of the alkyl group is 1 to 30. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, and octyl groups.
본 명세서의 일 실시상태에 있어서, 상기 R4는 메틸기; 에틸기; 프로필기; 또는 부틸기이다.In one embodiment of the present specification, R4 is a methyl group; ethyl group; profiler; Or it is a butyl group.
이하, 본 발명을 구체적으로 설명하기 위해 실시예 및 비교예 등을 들어 상세하게 설명하기로 한다. 그러나, 본 발명에 따른 실시예 및 비교예는 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 아래에서 상술하는 실시예 및 비교예에 한정되는 것으로 해석되지 않는다. 본 발명의 실시예 및 비교예는 당 업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, in order to specifically explain the present invention, examples and comparative examples will be described in detail. However, the Examples and Comparative Examples according to the present invention may be modified into various other forms, and the scope of the present invention should not be construed as being limited to the Examples and Comparative Examples described in detail below. Examples and comparative examples of the present invention are provided to more completely explain the present invention to those with average knowledge in the art.
실시예Example . .
상온에서 톨루엔(Toluene) 20 mL가 들어있는 반응기에 메틸(s)-2-(메탄술포닐옥시)프로파노에이트(Methyl (s)-2-(methanesulfonyloxy)propanoate) (20.00 g, 109.78 mmol), 트리에틸아민(Triethylamine) (12.22 g, 120.75 mmol) 및 2,6-디메틸아닐린(2,6-Dimethylaniline)(106.43 g, 878.24 mmol)을 첨가하고, 내부 온도를 120℃ 내지 130℃로 승온한 후에 교반하였다. Methyl (s)-2-(methanesulfonyloxy)propanoate (20.00 g, 109.78 mmol) in a reactor containing 20 mL of toluene at room temperature. Triethylamine (12.22 g, 120.75 mmol) and 2,6-Dimethylaniline (106.43 g, 878.24 mmol) were added, and the internal temperature was raised to 120°C to 130°C. It was stirred.
GC 분석을 통하여 반응 혼합물 내에 잔류한 미반응 메틸(s)-2-(메탄술포닐옥시)프로파노에이트(Methyl (s)-2-(methanesulfonyloxy)propanoate)가 2.0% 이하인 것을 확인 후, 반응 혼합물을 상온으로 냉각하였다. 냉각된 반응 혼합물에 증류수(H2O)(40 mL)를 첨가하여 생성된 고체들을 용해시키고, 톨루엔(Toluene)(100 mL)를 첨가하였다. 그 후, 1N HCl 수용액(40 mL)으로 2회 수세하여 얻어진 유기층을 증류수(100 mL)로 3회 수세하고, 감압농축하여 메틸 N―(2,6-디메틸페닐)-D-알라니네이트(Methyl N-(2,6-dimethylphenyl)-D-alaninate)를 수득하였다. After confirming through GC analysis that the unreacted methyl (s)-2-(methanesulfonyloxy)propanoate remaining in the reaction mixture was 2.0% or less, the reaction mixture was cooled to room temperature. Distilled water (H 2 O) (40 mL) was added to the cooled reaction mixture to dissolve the resulting solids, and toluene (100 mL) was added. Afterwards, the organic layer obtained by washing twice with 1N HCl aqueous solution (40 mL) was washed three times with distilled water (100 mL) and concentrated under reduced pressure to obtain methyl N-(2,6-dimethylphenyl)-D-alaninate ( Methyl N-(2,6-dimethylphenyl)-D-alaninate) was obtained.
수득한 크루드(crude) 메틸 N―(2,6-디메틸페닐)-D-알라니네이트(Methyl N-(2,6-dimethylphenyl)-D-alaninate를 톨루엔(Toluene)(60 mL)에 희석하였다. 여기에 탄산수소나트륨(NaHCO3)(803 g, 95.96 mmol)을 첨가하고 내부 온도를 -5℃ 내지 0℃로 냉각한 후, 메톡시아세틸 클로라이드(Methoxyacetyl chloride)(10.37 g, 95.96 mmol)을 천천히 적가하면서 0℃ 내지 10℃를 유지하며 교반하였다. The obtained crude methyl N-(2,6-dimethylphenyl)-D-alaninate was diluted in toluene (60 mL). Sodium hydrogen carbonate (NaHCO 3 ) (803 g, 95.96 mmol) was added thereto, and the internal temperature was cooled to -5°C to 0°C, followed by methoxyacetyl chloride (10.37 g, 95.96 mmol). was slowly added dropwise and stirred while maintaining 0°C to 10°C.
GC 분석을 통하여 반응 혼합물 내에 잔류한 미반응 메틸 N-(2,6-디메틸페닐)-D-알라니네이트(Methyl N-(2,6-dimethylphenyl)-D-alaninate)가 1.0% 이하인 것을 확인한 후, 반응 혼합물에 0.5N NaOH 용액(20 mL)를 첨가하여 반응 혼합물의 pH를 10으로 조정하고, 유기층을 분리하였다. 분리된 유기층을 증류수(20 mL)로 2회 수세하여 pH 7 내지 8로 만들었다. 그 후, pH가 조절된 유기층을 감압농축하여 순도 99.0%(Methyl (s)-2-(methanesulfonyloxy)propanoate = Not Detected)의 메틸 N-(2,6-디메틸페닐)-N-(메톡시아세틸)-D-알라니네이트(Methyl N-(2,6-Dimethylphenyl)-N-(methoxyacetyl)-D-alaninate)를 72% 수율로 수득하였다. Through GC analysis, it was confirmed that unreacted methyl N-(2,6-dimethylphenyl)-D-alaninate remaining in the reaction mixture was less than 1.0%. Then, 0.5N NaOH solution (20 mL) was added to the reaction mixture to adjust the pH of the reaction mixture to 10, and the organic layer was separated. The separated organic layer was washed twice with distilled water (20 mL) to adjust pH to 7 to 8. Afterwards, the pH-adjusted organic layer was concentrated under reduced pressure to produce methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl) with a purity of 99.0% (Methyl (s)-2-(methanesulfonyloxy)propanoate = Not Detected). )-D-alaninate (Methyl N-(2,6-Dimethylphenyl)-N-(methoxyacetyl)-D-alaninate) was obtained in 72% yield.
도 1에는 제조된 화학식 3의 화합물(Methyl N-(2,6-dimethylphenyl)-D-alaninate)의 GC 측정 결과를 나타내었다.Figure 1 shows the GC measurement results of the prepared compound of Chemical Formula 3 (Methyl N-(2,6-dimethylphenyl)-D-alaninate).
도 2에는 제조된 화학식 5의 화합물(Methyl N-(2,6-Dimethylphenyl)-N-(methoxyacetyl)-D-alaninate)의 GC 측정 결과를 나타내었다.Figure 2 shows the GC measurement results of the prepared compound of Chemical Formula 5 (Methyl N-(2,6-Dimethylphenyl)-N-(methoxyacetyl)-D-alaninate).
비교예Comparative example ..
상온에서 톨루엔(Toluene) 20 mL가 들어있는 반응기에 메틸(s)-2-(메탄술포닐옥시)프로파노에이트(Methyl (s)-2-(methanesulfonyloxy)propanoate) (20.00 g, 109.78 mmol), 트리에틸아민(Triethylamine) (12.22 g, 120.75 mmol) 및 2,6-디메틸아닐린(2,6-Dimethylaniline)(106.43 g, 878.24 mmol)을 첨가하고, 내부 온도를 120℃ 내지 130℃로 승온한 후에 교반하였다. Methyl (s)-2-(methanesulfonyloxy)propanoate (20.00 g, 109.78 mmol) in a reactor containing 20 mL of toluene at room temperature. Triethylamine (12.22 g, 120.75 mmol) and 2,6-Dimethylaniline (106.43 g, 878.24 mmol) were added, and the internal temperature was raised to 120°C to 130°C. It was stirred.
GC 분석을 통하여 반응 혼합물 내에 잔류한 미반응 메틸(s)-2-(메탄술포닐옥시)프로파노에이트(Methyl (s)-2-(methanesulfonyloxy)propanoate)가 2.0% 이하인 것을 확인 후, 반응 혼합물을 상온으로 냉각하였다. 냉각된 반응 혼합물에 증류수(H2O)(40 mL)를 첨가하여 생성된 고체들을 용해시키고, 톨루엔(Toluene)(100 mL)를 첨가하였다. 그 후, 1N HCl 수용액(40 mL)으로 2회 수세하여 얻어진 유기층을 1N NaOH 용액(40 mL)로 2회 수세하였다. 그 후, 증류수(30 mL)로 1회 더 수세하고, 감압농축하여 메틸 N―(2,6-디메틸페닐)-D-알라니네이트(Methyl N-(2,6-dimethylphenyl)-D-alaninate)를 수득하였다. After confirming through GC analysis that the unreacted methyl (s)-2-(methanesulfonyloxy)propanoate remaining in the reaction mixture was 2.0% or less, the reaction mixture was cooled to room temperature. Distilled water (H 2 O) (40 mL) was added to the cooled reaction mixture to dissolve the resulting solids, and toluene (100 mL) was added. After that, the organic layer obtained by washing twice with 1N HCl aqueous solution (40 mL) was washed twice with 1N NaOH solution (40 mL). Afterwards, it was washed once more with distilled water (30 mL) and concentrated under reduced pressure to produce methyl N-(2,6-dimethylphenyl)-D-alaninate. ) was obtained.
수득한 크루드(crude) 메틸 N―(2,6-디메틸페닐)-D-알라니네이트(Methyl N-(2,6-dimethylphenyl)-D-alaninate)를 톨루엔(Toluene)(60 mL)에 희석하였다. 여기에 탄산수소나트륨(NaHCO3)(803 g, 95.96 mmol)을 첨가하고 내부 온도를 -5℃ 내지 0℃로 냉각한 후, 메톡시아세틸 클로라이드(Methoxyacetyl chloride)(10.37 g, 95.96 mmol)을 천천히 적가하면서 0℃ 내지 10℃를 유지하며 교반하였다. The obtained crude methyl N-(2,6-dimethylphenyl)-D-alaninate was dissolved in toluene (60 mL). Diluted. Sodium hydrogen carbonate (NaHCO 3 ) (803 g, 95.96 mmol) was added here, the internal temperature was cooled to -5°C to 0°C, and then methoxyacetyl chloride (10.37 g, 95.96 mmol) was slowly added. While adding dropwise, the temperature was maintained at 0°C to 10°C and stirred.
GC 분석을 통하여 반응 혼합물 내에 잔류한 미반응 메틸 N-(2,6-디메틸페닐)-D-알라니네이트(Methyl N-(2,6-dimethylphenyl)-D-alaninate)가 1.0% 이하인 것을 확인한 후, 반응 혼합물을 증류수(60 mL)로 2회 수세하여 pH 7 내지 8로 만들었다. 그 후, pH가 조절된 유기층을 감압농축하여 순도 99.0%(Methyl (s)-2-(methanesulfonyloxy)propanoate = Not Detected)의 메틸 N-(2,6-디메틸페닐)-N-(메톡시아세틸)-D-알라니네이트(Methyl N-(2,6-Dimethylphenyl)-N-(methoxyacetyl)-D-alaninate)를 58% 수율로 수득하였다. Through GC analysis, it was confirmed that unreacted methyl N-(2,6-dimethylphenyl)-D-alaninate remaining in the reaction mixture was less than 1.0%. Afterwards, the reaction mixture was washed twice with distilled water (60 mL) to adjust pH to 7 to 8. Afterwards, the pH-adjusted organic layer was concentrated under reduced pressure to produce methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl) with a purity of 99.0% (Methyl (s)-2-(methanesulfonyloxy)propanoate = Not Detected). )-D-alaninate (Methyl N-(2,6-Dimethylphenyl)-N-(methoxyacetyl)-D-alaninate) was obtained in 58% yield.
상기 실시예 및 비교예에 있어서, 수율은 하기 식(1)로 계산하였다.In the above examples and comparative examples, the yield was calculated using the following formula (1).
식(1): 수율 = [제조된 화학식 5의 화합물의 몰수/투입된 화학식 1의 화합물의 몰수] x 100 Formula (1): Yield = [Number of moles of the compound of Formula 5 prepared/Number of moles of compound of Formula 1 introduced] x 100
상기 실시예 및 비교예의 실험 과정과 수율을 정리하여 하기 표 1에 나타내었다.The experimental procedures and yields of the examples and comparative examples are summarized and shown in Table 1 below.
상기 실시예 및 비교예에 있어서, 염기성 수세는 미반응한 화학식 1의 화합물을 제거하기 위한 목적으로 시행된 것이다. 상기 표 1을 통하여 염기성 수세 위치를 변경함으로써 실시예의 수율이 비교예에 비하여 향상된 것을 확인할 수 있다.In the above examples and comparative examples, basic water washing was performed for the purpose of removing unreacted compounds of Formula 1. Through Table 1, it can be seen that the yield of the example was improved compared to the comparative example by changing the basic water washing location.
Claims (10)
상기 제조된 화학식 3의 화합물 및 하기 화학식 4의 화합물을 반응시켜 하기 화학식 5의 화합물을 제조하는 제2 반응 단계;
상기 제2 반응 단계 이후에 염기성 용액으로 수세하여 미반응한 화합물을 제거하는 수세 단계; 및
수세된 용액으로부터 상기 화학식 5의 화합물을 수득하는 단계를 포함하는 화합물의 제조 방법:
[화학식 1]
[화학식 2]
[화학식 3]
[화학식 4]
[화학식 5]
상기 화학식 1 내지 5에 있어서,
R1은 메틸기; 또는 p-메틸페닐기이고,
R2 및 R3는 서로 같거나 상이하고, 각각 독립적으로 수소; 또는 메틸기이며, 단 R2 및 R3 중 적어도 하나는 메틸기이고,
R4는 탄소수 1 내지 4의 알킬기이다.A first reaction step of preparing a compound of Formula 3 by reacting a compound of Formula 1 below and a compound of Formula 2 below;
A second reaction step of preparing a compound of Formula 5 by reacting the compound of Formula 3 prepared above with the compound of Formula 4 below;
A washing step of removing unreacted compounds by washing with a basic solution after the second reaction step; and
Method for producing a compound comprising the step of obtaining the compound of formula 5 from a washed solution:
[Formula 1]
[Formula 2]
[Formula 3]
[Formula 4]
[Formula 5]
In Formulas 1 to 5,
R1 is a methyl group; or p-methylphenyl group,
R2 and R3 are the same or different from each other and are each independently hydrogen; or a methyl group, provided that at least one of R2 and R3 is a methyl group,
R4 is an alkyl group having 1 to 4 carbon atoms.
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