JPS63208557A - Quaternary ammonium salt and production thereof - Google Patents
Quaternary ammonium salt and production thereofInfo
- Publication number
- JPS63208557A JPS63208557A JP62042209A JP4220987A JPS63208557A JP S63208557 A JPS63208557 A JP S63208557A JP 62042209 A JP62042209 A JP 62042209A JP 4220987 A JP4220987 A JP 4220987A JP S63208557 A JPS63208557 A JP S63208557A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- dichloro
- reaction
- quaternary ammonium
- expressed
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000003242 quaternary ammonium salts Chemical class 0.000 title claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- UMPSXRYVXUPCOS-UHFFFAOYSA-N 2,3-dichlorophenol Chemical compound OC1=CC=CC(Cl)=C1Cl UMPSXRYVXUPCOS-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
- 150000003863 ammonium salts Chemical class 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 abstract description 10
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 abstract description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 abstract description 5
- DZBZSMAUXPQSLH-UHFFFAOYSA-N 6,7-dichloro-2,3-dihydro-1-benzofuran Chemical compound ClC1=CC=C2CCOC2=C1Cl DZBZSMAUXPQSLH-UHFFFAOYSA-N 0.000 abstract description 3
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 abstract description 3
- 230000001882 diuretic effect Effects 0.000 abstract description 3
- 229940102396 methyl bromide Drugs 0.000 abstract description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- QBKVEAIEIVKHGR-UHFFFAOYSA-M di(ethylidene)azanium;chloride Chemical compound [Cl-].CC=[N+]=CC QBKVEAIEIVKHGR-UHFFFAOYSA-M 0.000 abstract description 2
- 239000002934 diuretic Substances 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- 230000029936 alkylation Effects 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- VVDUZZGYBOWDSQ-UHFFFAOYSA-M eschenmoser's salt Chemical compound [I-].C[N+](C)=C VVDUZZGYBOWDSQ-UHFFFAOYSA-M 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 235000015320 potassium carbonate Nutrition 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 238000006243 chemical reaction Methods 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 150000001733 carboxylic acid esters Chemical class 0.000 description 6
- -1 2,3-dichloro-6-aminomethylphenol Chemical compound 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000003276 anti-hypertensive effect Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 229940116269 uric acid Drugs 0.000 description 2
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- ZOIUTQJATWHPMK-UHFFFAOYSA-N 6,7-dichloro-2,3-dihydro-1-benzofuran-2-carboxylic acid Chemical compound C1=C(Cl)C(Cl)=C2OC(C(=O)O)CC2=C1 ZOIUTQJATWHPMK-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- MPAYEWNVIPXRDP-UHFFFAOYSA-N ethanimine Chemical compound CC=N MPAYEWNVIPXRDP-UHFFFAOYSA-N 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 1
- 150000004967 organic peroxy acids Chemical class 0.000 description 1
- XDAGXZXKTKRFMT-UHFFFAOYSA-N propan-2-imine Chemical compound CC(C)=N XDAGXZXKTKRFMT-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- AISMNBXOJRHCIA-UHFFFAOYSA-N trimethylazanium;bromide Chemical compound Br.CN(C)C AISMNBXOJRHCIA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野コ
本発明はＮ−（３，４−ジクロロ−２−ヒドロキシベン
ジル）−Ｎ、Ｎ、Ｎ−トリアルキル四級アンモニウム塩
およびその新規な製造方法を提供する。該化合物は、濃
酸***性の降圧利尿薬として有用な一連の６，７−ジク
ロロ−２，３−ジヒドロベンゾフラン系化合物の中間体
として極めて有用である。Detailed Description of the Invention [Industrial Field of Application] The present invention relates to N-(3,4-dichloro-2-hydroxybenzyl)-N,N,N-trialkyl quaternary ammonium salt and a novel method for producing the same. I will provide a. This compound is extremely useful as an intermediate for a series of 6,7-dichloro-2,3-dihydrobenzofuran compounds useful as acid-extracting antihypertensive diuretics.
［従来の技術］
式：
で示されるカルボン酸エステル（ＩＩＩ）から、尿酸排
泄性の優れた降圧利尿活性を有する一連の６゜７−ジク
ロロ−２，３−ジヒドロベンゾフラン系化合物が合成さ
れている０例えば、ウィリアム・エフ・ホフマン等によ
ってジャーナル・オブ・メデイシーナルケミストリ−［
Ｗｉｌｌｉａｍ Ｆ、 Ｈｏｆｆｍａｎｅｔ ａｔ；
Ｊ、 Ｍａｄ、 Ｃｈｅｍ、 ２４．８６５−８７３
（１９８１）］に２．３−ジクロロフェノールを出発原
料にしてカルボン酸エステルｌ）に導く方法が開示され
ている。また、特開昭８１−６３６７１では該エステル
（ＩＩＩ）を原料として数多くの６．７−ジクロロ−２
，３−ジヒドロベンゾフラン系化合物を合成し、これら
の化合物が尿酸***性の優れた降圧利尿活性を有してい
る事を確認している。[Prior Art] A series of 6゜7-dichloro-2,3-dihydrobenzofuran compounds having excellent antihypertensive diuretic activity and uric acid excretion properties have been synthesized from carboxylic acid ester (III) represented by the formula: 0 For example, the Journal of Medicinal Chemistry [
William F., Hoffmanet;
J, Mad, Chem, 24.865-873
(1981)] discloses a method for producing carboxylic acid ester l) using 2,3-dichlorophenol as a starting material. In addition, in JP-A-81-63671, a large number of 6,7-dichloro-2
, 3-dihydrobenzofuran-based compounds have been synthesized, and it has been confirmed that these compounds have excellent antihypertensive diuretic activity with uric acid excretion.
［発明が解決しようとする問題点］
前述のホフマン等のカルボン酸エステル（ｍ＞の合成法
は、反応に高温を要し、大量生産時には製造コストがか
さむ事、反応中にクロルが転移した異性体が副生じ収率
が低下するのみならず、異性体の分離が困難である事、
また、反応に有機過酸を使用するので爆発の危険性が高
い事等、工業化には種々の問題があった。[Problems to be solved by the invention] The above-mentioned method for synthesizing carboxylic acid esters (m>) by Hoffman et al. requires high temperatures for the reaction, increases manufacturing costs in mass production, and isomers in which chlor is transferred during the reaction. Not only is the isomer produced as a by-product, reducing the yield, but it is also difficult to separate the isomers.
In addition, there were various problems with industrialization, such as the high risk of explosion because organic peracids were used in the reaction.
本発明者等は以上の点に鑑み、反応工程が短く、経済的
かつ安全性の高い製造方法を鋭意検討し、本発明を完成
した。更に詳しくは、本発明が提供するＮ−（３，４−
ジクロロ−２−ヒドロキシヘンシル） −Ｎ、Ｎ、Ｎ−
トリアルキル四級アンモニウム塩を使用すれば、経済的
かつ安全性の高い方法で前記カルボン酸エステルＣＩ）
を製造できる。In view of the above points, the present inventors have intensively studied a production method that has a short reaction step, is economical, and has high safety, and have completed the present invention. More specifically, N-(3,4-
dichloro-2-hydroxyhensyl) -N, N, N-
If a trialkyl quaternary ammonium salt is used, the carboxylic acid ester CI) can be obtained in an economical and highly safe manner.
can be manufactured.
［問題点を解決する為の手段］
本発明の目的化合物は、２，３−ジクロロフェノールに
塩基の存在下、位置選択的にアミノメチル基を導入して
、式：
［但し、式中Ｒ１は低級アルキルを表わすコで示される
２、３−ジクロロ−６−Ｎ、Ｎ−ジアルキルアミンメチ
ルフェノールを得る工程（第１工程）、次いでアルキル
化反応に付して式＝［但し、式中Ｒ１は低級アルキルを
、Ｘは／）ロゲンまたは硫酸根を表わすコ
で示されるＮ−（３，４−ジクロロ−２−ヒドロキシベ
ンジル）−Ｎ、Ｎ、Ｎ−トリアルキル四級アンモニウム
塩を得る工程（第２工程）により製造される。[Means for Solving the Problems] The object compound of the present invention can be obtained by regioselectively introducing an aminomethyl group into 2,3-dichlorophenol in the presence of a base to form the formula: [However, in the formula, R1 is A step (first step) of obtaining 2,3-dichloro-6-N,N-dialkylamine methylphenol represented by ko representing lower alkyl, followed by an alkylation reaction with the formula = [wherein R1 is Step of obtaining N-(3,4-dichloro-2-hydroxybenzyl)-N,N,N-trialkyl quaternary ammonium salt in which lower alkyl is represented by /) rogene or sulfate group 2 steps).
本発明に於て、低級アルキルとはＣ３〜Ｃ６の直鎖また
は分枝状アルキルを意味し、メチル、エチル、プロピル
、イソプロピル、ブチノ呟 イソブチル等が例示される
。ハロゲンとはＣ１、Ｂｒｓ Ｉを意味し、ＣＩおよ
びＢｒが好ましく使用される。In the present invention, lower alkyl means a C3 to C6 straight chain or branched alkyl, and examples thereof include methyl, ethyl, propyl, isopropyl, and isobutyl. By halogen is meant C1, Brs I, with CI and Br being preferably used.
硫酸根とは１価または２価の基を包含し、具体的には、
Ｈ５Ｏ，−やＳＯ，−が例示きれる。The sulfate group includes monovalent or divalent groups, specifically,
Examples include H5O,- and SO,-.
以下に、各工程毎に反応を説明する。Below, the reaction will be explained for each step.
本工程は２，３−ジクロロフェノールの６位に選択的に
アミノメチル基を導入する反応である。This step is a reaction for selectively introducing an aminomethyl group into the 6-position of 2,3-dichlorophenol.
本反応は基本的にはマンニッヒ反応（Ｍａｎｎｉｅｈ
ｒｅ−ａｃｔｉｏｎ）の方法に従って行なえば良く、塩
基の存在下、マンニッヒ試薬として知られるエツシエン
モーザー塩（Ｅｓｃｈｅｎｍｏｓｅｒ’ｓ ５ａｌｔ
）を使用して、直接アミノメチル基を導入する方法が簡
便である。エツシエンモーザー塩は当量〜小過剰量使用
すれば良く、反応は効率良く進行する０反応はθ℃〜加
熱下、数分〜数十時間で完了するが、無加温下で短時間
に反応が進行するので、経済性を考慮すれば室温下で反
応を行なうのが好ましい。This reaction is basically a Mannich reaction (Mannieh reaction).
In the presence of a base, Eschenmoser's 5alt, known as the Mannich reagent,
) to directly introduce an aminomethyl group is convenient. Etsienmoser salt can be used in an equivalent to a small excess amount, and the reaction proceeds efficiently.The reaction is completed in several minutes to several tens of hours under heating at θ℃, but the reaction can be completed in a short time without heating. takes place, so it is preferable to carry out the reaction at room temperature in view of economic efficiency.
反応溶媒としてはトルエン、塩化メチレン、四塩化炭素
、アセトニトリル、エーテル、テトラヒドロフランなど
の非プロトン系溶媒を用いれば良い、塩基としては、炭
酸カリウム、炭酸ナトリウム等のアルカリ金属の炭酸塩
や、水酸化ナトリウム、水酸化カリウム等の無機塩基が
好ましい、また、エツシエンモーザー塩としては塩化Ｎ
、Ｎ−’、；メチルメチレンアンモニウムやヨウ化Ｎ、
Ｎ−ジメチルメチレンアンモニウム等が好ましく使用き
れる。As a reaction solvent, an aprotic solvent such as toluene, methylene chloride, carbon tetrachloride, acetonitrile, ether, or tetrahydrofuran may be used.As a base, an alkali metal carbonate such as potassium carbonate or sodium carbonate, or sodium hydroxide can be used. , potassium hydroxide and other inorganic bases are preferred;
, N-',; methylmethylene ammonium or N iodide,
N-dimethylmethylene ammonium and the like can be preferably used.
［式中、Ｈａｌはハロゲンを意味するコ本工程は第１工
程で得た２、３−ジクロロ−６−アミノメチルフェノー
ル（Ｉ）の第三アミンをアルキル化して四級アンモニウ
ム塩を得る反応である。本反応は常法に従って行なえば
良く、塩化メチル、塩化エチル、塩化プロピル、臭化メ
チル、臭化エチル、臭化プロピル、臭化ブチルおよびヨ
ウ化メチル等のハロゲン化アルキル、あるいはジメチル
硫酸等のアルキル硫酸をアルキル化剤として使用すれば
良い。[In the formula, Hal means halogen] This step is a reaction to obtain a quaternary ammonium salt by alkylating the tertiary amine of 2,3-dichloro-6-aminomethylphenol (I) obtained in the first step. be. This reaction may be carried out according to a conventional method, and can be carried out using alkyl halides such as methyl chloride, ethyl chloride, propyl chloride, methyl bromide, ethyl bromide, propyl bromide, butyl bromide, and methyl iodide, or alkyl halides such as dimethyl sulfate. Sulfuric acid may be used as the alkylating agent.
反応はＯ℃〜加熱下、数分〜数十時間で完了するが、無
加温下の緩和な条件下でも短時間で反応が進行するので
、経済性を考慮すれば室温下で反応を行なうのが好まし
い。The reaction is completed in a few minutes to several tens of hours under heating at 0°C, but the reaction proceeds in a short time even under mild conditions without heating, so for economic reasons, the reaction should be carried out at room temperature. is preferable.
本発明の目的化合物（Ｉｏ）の用途の一例を以下に示す
、化合物（Ｉｏ）は式：
％式％）
［但し、式中Ｒ２およびＲ３はそれぞれ低級アルキルを
表わす］
で示される硫黄イリド（ＩＩ）と反応させて、式：［式
中、Ｒ３は前記と同義］
で示される６、７−ジクロロ−２，３−ジヒドロベンゾ
フラン−２−カルボン酸エステル（ＩＩＩ ） ヲ製造
する（第３工程）ことができる。この工程を更に詳しく
説明する。An example of the use of the object compound (Io) of the present invention is shown below. Compound (Io) is a sulfur ylide (II ) to produce 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid ester (III) represented by the formula: [wherein R3 has the same meaning as above] (third step) be able to. This process will be explained in more detail.
本工程は、第２工程で得た四級アンモニウム塩（ｌｏ）
に次式：
％式％（）
で示きれる硫黄イリド（Ｉ［）を反応させて環化して目
的の６，７−ジクロロ−２，３−ジヒドロベンゾフラン
−２−カルボン酸エステル（Ｉ［［）１％る反応である
０本反応に使用する硫黄イリドは目的のものを調製して
使用すれば良いが、例えば、ジメチルスルホニオエトキ
シカルボニルメタニドなどが好適である０本反応は溶媒
中、緩和な条件下で行なうのが好ましく、反応は数分〜
数十時間で完結する。In this step, the quaternary ammonium salt (lo) obtained in the second step is
is reacted with a sulfur ylide (I[) represented by the following formula: The sulfur ylide used in the 0-unit reaction, which is a 1% reaction, may be prepared and used, but for example, dimethylsulfonioethoxycarbonyl methanide is suitable. It is preferable to carry out the reaction under suitable conditions, and the reaction takes several minutes to
It will be completed in a few dozen hours.
以下に実施例を示し本発明を更に詳しく説明するが、こ
れらは本発明を同等限定するものではない。The present invention will be explained in more detail with reference to Examples below, but these are not intended to limit the present invention in the same way.
（以下余白）
実施例１
（第１工程）
２．３−ジクロロ−６−Ｎ、Ｎ−ジメチルアミノメチル
フェノール（１）の製造：
２．３−ジクロロフェノール（４）５１ｇ（０，３１３
ｍｏｌ）の塩化メチレン（２７０ｍｌ）溶液に無水炭酸
カリウム６６ｇ（０，４７ｍｏｌ）を加え、室温で２時
間攪拌する。この反応液に、Ｎ、Ｎ−ジメチルメチレン
アンモニウムクロリド３２ｇ（０，ａ４ｍｏｌ）とヨウ
化カリウム８３ｇ（０，５ｍｏｌ）と塩化メチレン（１
８０ｍｌ）の混合物を２時間攪拌した懸濁液を室温で添
加し、その後１８時間室温で攪拌反応する。この反応液
に水１５０ｍ１と１０％塩酸２４０ｍ１とを加え水層、
のｐＨをおよそ５．５〜６．０として塩化メチレンで抽
出する。水層は炭酸カリウムで再びｐＨを５．５〜６．
０として塩化メチレンで抽出、この操作を３回繰り返し
、塩化メチレン層は合して無水硫酸マグネシウムで脱水
乾燥、減圧留去する。残渣は短いシリカゲルカラムクロ
マト（シリカゲル１５０ｇ）に付し、塩化メチレン／ア
セトン（６：１）で溶出すると油状の化合物（１）５６
．６５ｇを得る。収率８２％。(Left below) Example 1 (First step) Production of 2.3-dichloro-6-N,N-dimethylaminomethylphenol (1): 2.3-dichlorophenol (4) 51 g (0,313
mol) in methylene chloride (270 ml) was added 66 g (0.47 mol) of anhydrous potassium carbonate, and the mixture was stirred at room temperature for 2 hours. To this reaction solution, 32 g (0.4 mol) of N,N-dimethylmethylene ammonium chloride, 83 g (0.5 mol) of potassium iodide, and methylene chloride (1 mol) were added.
A suspension obtained by stirring a mixture of 80 ml) for 2 hours is added at room temperature, and the reaction is then stirred at room temperature for 18 hours. Add 150 ml of water and 240 ml of 10% hydrochloric acid to this reaction solution to form an aqueous layer.
to a pH of approximately 5.5-6.0 and extracted with methylene chloride. The aqueous layer was again adjusted to pH 5.5-6 with potassium carbonate.
This procedure was repeated three times, and the methylene chloride layers were combined, dehydrated and dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to short silica gel column chromatography (150 g of silica gel) and eluted with methylene chloride/acetone (6:1) to yield oily compound (1) 56
．． Obtain 65g. Yield 82%.
ＮＭＲε（ＣＤＣ１，）ｐｐｍ： ２．３３（６）１．
ｓ）、 ３．６１（２１゜ｓ）、 ６．５７及び６．
８５（２ｘｌＨ，ＡＢｑ、 Ｊ＝９．０Ｈｚ）、 １１
．３８（ＬＨ，ｓ）。NMRε(CDC1,)ppm: 2.33(6)1.
s), 3.61 (21°s), 6.57 and 6.
85 (2xlH, ABq, J=9.0Hz), 11
．． 38 (LH, s).
水晶はそのまま次の工程に供した。The crystal was directly subjected to the next step.
（第２工程）
Ｎ−Ｃ３，４−’；クロロー２−ヒドロキシベンジル）
−Ｎ、Ｎ、Ｎ−トリメチルアンモニウムプロミド（ｌ゛
）の製造：
第１工程で得た粗製の化合物（１）４７．５７ｇ（０，
２１６ｍｏｌ）のアセトン（５０ｍｌ）溶液に、臭化メ
チル７０．６ｇ（０，７４３ｍｏｌ）のアセトン（２５
０ｍｌ）溶液を加え室温下３日間攪拌する０反応液にエ
ーテルを加え、析出した結晶を濾取しエーテル洗浄する
と粗製の化合物（１’）５６．４ｇを得る。収率８３％
。(Second step) N-C3,4-'; chloro-2-hydroxybenzyl)
-Production of N,N,N-trimethylammonium bromide (l゛): 47.57g (0,
70.6 g (0,743 mol) of methyl bromide in acetone (25 ml) was added to a solution of 216 mol) of acetone (50 ml).
Ether is added to the reaction solution, which is stirred at room temperature for 3 days, and the precipitated crystals are collected by filtration and washed with ether to obtain 56.4 g of crude compound (1'). Yield 83%
.
ＮＭＲｌ； （ｄ、−ＤＭＳＯ）ｐｐｍ： ３．１０（
９Ｈ，ｓ）、 ４．５７（２Ｈ。NMRl; (d,-DMSO) ppm: 3.10 (
9H, s), 4.57 (2H.
ｓ）、 ７．２５及び７．４８（２ｘｌＨ，ＡＢｑ、
Ｊ＝９．０）ｌｚ）、 ７．５〜１０（ＩＨ，ｂ）。s), 7.25 and 7.48 (2xlH, ABq,
J=9.0)lz), 7.5-10(IH,b).
参考例１
（第３工程）
６．７−ジクロロ−２，３−ジヒドロベンゾフラン−２
−カルボン酸エチルエステル（３）の製造：第２工程で
得た粗製の化合物（１”） １４．８ｇ（４１ｍｍｏｌ
） 、ジメチルスルホニオエトキシカルボニルメタニド
１（１９６７） １ １ ２ 、 １ ５ ｇ（ ８
２ ｍｍｏｌ）およびアセトニトリル（１００ｍｌ）の
懸濁液を室温にて゛１８時間攪拌反応する。反応液は減
圧で溶媒を留去し残渣に水および塩化メチレンを加えて
溶解し、塩化メチレン層をとる．水層は更に塩化メチレ
ンで抽出し、塩化メチレン層は合し、無水硫酸マグネシ
ウムで脱水乾燥、減圧留去する．残渣は塩化メチレンに
溶かし、短いシリカゲルカラムクロマトに付し、塩化メ
チレン溶出物を集め減圧留去。残渣はｎ−ヘキサンで処
理し粗結晶７．８５ｇを得る．水晶は脱色炭を用いエー
テルから再結晶すると目的の化合物（ ３ ）７．０ｇ
を得る．収率６５．４％。Reference example 1 (3rd step) 6.7-dichloro-2,3-dihydrobenzofuran-2
-Production of carboxylic acid ethyl ester (3): 14.8 g (41 mmol) of the crude compound (1'') obtained in the second step
), dimethylsulfonioethoxycarbonyl methanide 1 (1967) 1 1 2 , 1 5 g ( 8
A suspension of 2 mmol) and acetonitrile (100 ml) was stirred and reacted at room temperature for 18 hours. Distill the solvent from the reaction solution under reduced pressure, dissolve the residue by adding water and methylene chloride, and take the methylene chloride layer. The aqueous layer is further extracted with methylene chloride, and the methylene chloride layers are combined, dehydrated and dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in methylene chloride and subjected to short silica gel column chromatography, and the methylene chloride eluate was collected and evaporated under reduced pressure. The residue was treated with n-hexane to obtain 7.85 g of crude crystals. When the crystal is recrystallized from ether using decolorizing charcoal, 7.0 g of the target compound (3) is obtained.
obtain. Yield 65.4%.
水晶はホフマン等の得た化合物（３）の物理恒数と一致
した。The physical constants of the crystal matched the physical constants of compound (3) obtained by Hoffman et al.
参考例２
（第３工程：別法）
化合物（ １ ’） ４ ７．８ １ｇ（ ０． １
５ ２ｍｏｌ）のアセトニトリル（４６０ｍｌ）懸濁液
に攪拌下１〜４℃でジメチルスルホニオエトキシカルボ
ニルメタニド２ ９．２ ２ｇ（ ０． １ ９ ７ｍ
ｏｌ）を５分間で滴下する．同温度で５．５時間攪拌を
続けた後粉末状の無水炭酸カリウム４２。Ｏｇ（０．３
０ ４ｍｏｌ）を加え３時間同温度で反応した後、２
０時間かけて徐々に室温迄反応温度を上昇する．不溶物
を濾去し、濾液を減圧濃縮後残渣を塩化メチレンに溶か
し水洗後無水硫酸マグネシウムで脱水乾燥、減圧留去す
る．残渣は１００℃の浴上２〜５ ｍｍＨｇで減圧蒸留
し、蒸留残渣を少量の塩化メチレンに溶かし短いシリカ
ゲルカラムクロマトに付す．塩化メチレン溶出物を集め
減圧濃縮後残渣をエーテル／ｎ−ヘキサンにて処理する
と化合物（３）２８．０ｇを得る．収率７０．７％。Reference example 2 (3rd step: alternative method) Compound (1') 4 7.8 1g (0.1
Add 29.22 g (0.197 ml) of dimethylsulfonioethoxycarbonyl methanide to a suspension of 52 mol) in acetonitrile (460 ml) at 1-4°C with stirring.
ol) dropwise over 5 minutes. After continuing stirring at the same temperature for 5.5 hours, powdered anhydrous potassium carbonate 42 was obtained. Og(0.3
After adding 0.4 mol) and reacting at the same temperature for 3 hours,
Gradually raise the reaction temperature to room temperature over 0 hours. Insoluble materials are removed by filtration, the filtrate is concentrated under reduced pressure, and the residue is dissolved in methylene chloride, washed with water, dehydrated and dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue is distilled under reduced pressure of 2 to 5 mmHg on a 100°C bath, and the distillation residue is dissolved in a small amount of methylene chloride and subjected to short silica gel column chromatography. The methylene chloride eluate was collected and concentrated under reduced pressure, and the residue was treated with ether/n-hexane to obtain 28.0 g of compound (3). Yield 70.7%.
Claims (2)
ンまたは硫酸根を表わす］ で示されるＮ−（３，４−ジクロロ−２−ヒドロキシベ
ンジル）−Ｎ，Ｎ，Ｎ−トリアルキル四級アンモニウム
塩。(1) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [However, in the formula, R^1 represents lower alkyl, and X^- represents a halogen or sulfate group] -2-hydroxybenzyl)-N,N,N-trialkyl quaternary ammonium salt.
置選択的にアミノメチル基を導入して、式：▲数式、化
学式、表等があります▼ ［但し、式中Ｒ＾１は低級アルキルを表わす］で示され
る２，３−ジクロロ−６−Ｎ，Ｎ−ジアルキルアミノメ
チルフェノールを得、次いでアルキル化反応に付すこと
を特徴とする式： ▲数式、化学式、表等があります▼ ［但し、式中Ｒ＾１は低級アルキルを、Ｘ＾−はハロゲ
ンまたは硫酸根を表わす］ で示されるＮ−（３，４−ジクロロ−２−ヒドロキシベ
ンジル）−Ｎ，Ｎ，Ｎ−トリアルキル四級アンモニウム
塩の製造方法。(2) An aminomethyl group is regioselectively introduced into 2,3-dichlorophenol in the presence of a base, resulting in the formula: ▲ Numerical formula, chemical formula, table, etc. ▼ [However, in the formula, R^1 is lower alkyl A formula characterized by obtaining 2,3-dichloro-6-N,N-dialkylaminomethylphenol and then subjecting it to an alkylation reaction: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [However, , where R^1 represents lower alkyl and X^- represents a halogen or sulfate group] Method for producing ammonium salts.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62042209A JP2522931B2 (en) | 1987-02-24 | 1987-02-24 | Quaternary ammonium salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62042209A JP2522931B2 (en) | 1987-02-24 | 1987-02-24 | Quaternary ammonium salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63208557A true JPS63208557A (en) | 1988-08-30 |
| JP2522931B2 JP2522931B2 (en) | 1996-08-07 |
Family
ID=12629629
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62042209A Expired - Fee Related JP2522931B2 (en) | 1987-02-24 | 1987-02-24 | Quaternary ammonium salt |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2522931B2 (en) |
-
1987
- 1987-02-24 JP JP62042209A patent/JP2522931B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP2522931B2 (en) | 1996-08-07 |
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