JPH02235865A - Production of cyclic imide derivative - Google Patents
Production of cyclic imide derivativeInfo
- Publication number
- JPH02235865A JPH02235865A JP1056583A JP5658389A JPH02235865A JP H02235865 A JPH02235865 A JP H02235865A JP 1056583 A JP1056583 A JP 1056583A JP 5658389 A JP5658389 A JP 5658389A JP H02235865 A JPH02235865 A JP H02235865A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- formulas
- tables
- group
- chemical formulas
- 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
- -1 cyclic imide Chemical class 0.000 title claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 3
- 150000004885 piperazines Chemical class 0.000 claims abstract 3
- 239000000126 substance Substances 0.000 claims description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000004437 phosphorous atom Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 abstract description 30
- 238000006243 chemical reaction Methods 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 9
- NIDSRGCVYOEDFW-UHFFFAOYSA-N 1-bromo-4-chlorobutane Chemical compound ClCCCCBr NIDSRGCVYOEDFW-UHFFFAOYSA-N 0.000 abstract description 6
- 239000003960 organic solvent Substances 0.000 abstract description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 abstract description 5
- 239000000047 product Substances 0.000 abstract description 5
- 239000003444 phase transfer catalyst Substances 0.000 abstract description 4
- 230000000561 anti-psychotic effect Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 230000000049 anti-anxiety effect Effects 0.000 abstract 1
- 239000002249 anxiolytic agent Substances 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 235000015320 potassium carbonate Nutrition 0.000 abstract 1
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 description 1
- WLDMPODMCFGWAA-UHFFFAOYSA-N 3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione Chemical compound C1CCCC2C(=O)NC(=O)C21 WLDMPODMCFGWAA-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 150000004714 phosphonium salts Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 1
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- RYVBINGWVJJDPU-UHFFFAOYSA-M tributyl(hexadecyl)phosphanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC RYVBINGWVJJDPU-UHFFFAOYSA-M 0.000 description 1
- 238000005406 washing Methods 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
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
で示される基を表わし、Ｒは、置換又は無置換のフェニ
ル基、置換又は無置換の２−ビリジル基、置換又は無置
換の２−ピリミジル基、置換又は無置換の１，２−ベン
ゾー３−イソチアゾリル基を表わし、前記の置換基は、
ハロゲン原子、炭素数１から４のアルコキシ基またはシ
アノ基を表わす。〕
で表わされる本発明目的化合物は抗精神病作用あるいは
抗不安作用を有し、医薬として有用であることが知られ
ている。Detailed Description of the Invention [Industrial Application Field] Represents a group represented by the following, R is a substituted or unsubstituted phenyl group, a substituted or unsubstituted 2-pyridyl group, a substituted or unsubstituted 2-pyrimidyl group. represents a substituted or unsubstituted 1,2-benzo-3-isothiazolyl group, and the substituent is
Represents a halogen atom, an alkoxy group having 1 to 4 carbon atoms, or a cyano group. ] The compound of the present invention represented by the following is known to have antipsychotic or anxiolytic effects and to be useful as a medicine.
例えば、これら化合物群は特開昭５８−１２６８６５号
、特開昭５８−３８２７７号、特開昭５８−１１０５７
６号、特開昭５ ９−１ ４ ８７８０号、特開昭６２
−１２３１７９号及びＪ．Ｍｅｄ，Ｃｈｅｍ．，２６．
１９４ （１９８３）などに記載されており、その製造
方法も各種の合成経路が知られていた。For example, these compound groups include JP-A-58-126865, JP-A-58-38277, and JP-A-58-11057.
No. 6, JP-A-5 9-1-4-8780, JP-A-Sho 62
-123179 and J. Med, Chem. , 26.
194 (1983), etc., and various synthetic routes for its production were known.
特に、一般式〔■〕で表わされる化合物を用いた本発明
目的化合物〔Ｉ〕の製造については、以下に示す反応経
路による製造方法がより簡便なものであるとされていた
（特開昭６０−８７２６２号）。In particular, for the production of the compound [I] of the present invention using the compound represented by the general formula [■], the production method according to the reaction route shown below was considered to be simpler (Japanese Patent Application Laid-Open No. 1983-1993). -87262).
［Ｉｒ〕
ＣＩ［＋］
（１’Ｖ］
〔Ｉ〕
〔式中、ＡおよびＲは前述と同じ意味を表す。〕即ち、
一般式ＣＩＩ）で表わされるイミド化合物と１、４ジブ
ロムブタン（Ｉ〕とを縮合させ、一般式〔■〕で表わさ
れる化合物へ導き、これを単離後、一般式ＣｒＶ］で表
わされるアミン誘導体と縮合させることにより、目的と
する化合物〔■〕を得る方法である。[Ir] CI[+] (1'V] [I] [In the formula, A and R represent the same meanings as above.] That is,
The imide compound represented by the general formula CII) and 1,4 dibromobutane (I) are condensed to form a compound represented by the general formula [■], which is isolated and then converted into an amine derivative represented by the general formula CrV]. This is a method of obtaining the target compound [■] by condensation.
従来の製法においては、例えば前述の化合物（ＩＩ１と
１、４−ジブロムプタン［ＩＩＩ］との反応において、
化合物ＣＩＯ）に対して化合物〔■〕を等モル使用した
場合は副成物である２量体［ＶＩ］
〔式中、Ａは前述と同じ意味を表わす。〕が、大量に副
成した（収率３０％以上）。In the conventional production method, for example, in the reaction of the above-mentioned compound (II1 and 1,4-dibromptan [III],
When the compound [■] is used in equimolar amounts with respect to the compound CIO), the dimer [VI] which is a by-product [wherein A represents the same meaning as above]. ] was produced as a by-product in large quantities (yield of 30% or more).
この副底物の生成を避ける為に、１、４−ジブロムブタ
ン［ＩＩ［］を化合物〔■〕に対して大過剰（５倍モル
量以上）用いる必要があった。In order to avoid the formation of this secondary product, it was necessary to use 1,4-dibromobutane [II[] in large excess (more than 5 times the molar amount) relative to compound [■].
しかしながら、１、４−ジブロムブタンＣＩ［Ｉ］のｋ
ｉＭ剰量の使用は、生成物〔■コの単離を難しくして
いた。即ち、１、４−ジブロムブタン［ＩＩＩ］は、高
沸点（ｂｐ６３−６５℃／ ［ｉ ｎｏ ｝Ｉｇ）であ
る為、大過剰に使用すると、化合物［ＩＩ［］の留去に
は高温での減圧蒸留が必要であり、生成物〔■〕の単離
精製が問題となっていた。However, the k of 1,4-dibromobutane CI[I]
The use of iM surplus made isolation of the product [■] difficult. That is, since 1,4-dibromobutane [III] has a high boiling point (bp63-65°C/[i no }Ig), if it is used in large excess, compound [II[] must be distilled off under reduced pressure at a high temperature. Distillation was required, and isolation and purification of the product [■] was a problem.
上記の課題を解決すべく鋭意検討を重ねた結果、相聞移
動触媒存在下に水一有機溶媒の二相系で反応を行い、化
合物［ＩＩＩ］の代わりに、１ーブロモ−４−クロロブ
タンを用いることにより、収率よく、効率的に目的物を
製造する新規な合成法を見出し、本発明を完成するに至
った。As a result of intensive studies to solve the above problems, we found that the reaction was carried out in a two-phase system of water and organic solvent in the presence of a phase transfer catalyst, and 1-bromo-4-chlorobutane was used instead of compound [III]. As a result, a new synthetic method for efficiently producing the desired product with good yield was discovered, and the present invention was completed.
さらに詳しく説明すると、本発明は一般式［■）
■
〔式中、Ａは前述と同じ意味を表す。〕で表わされる化
合物を、相関移動触媒として一般式〔■〕
Ｑ” Ｘ− Ｃ■〕〔式中、
Ｘ一はハロゲンイオン、ヒドロキシイオンまたは硫酸水
素イオンを表わし、Ｑ４は一般式〔■〕
ＲＩ Ｒ２ Ｒｓ Ｒ．Ｗ” （■
〕（式中、Ｒ＋ ．Ｒ２ ．Ｒ３およびＲ４はそれぞれ
、炭素数が１から２０よりなる直鎮又は分枝状のアルキ
ル基を表わし、Ｗは窒素原子またはリン原子を表す。）
で示される基を表わす。〕で表わされる４級オニウム塩
および塩基の存在下に、２相系の反応溶媒中で１−ブロ
ムー４ークロロブタンと反応させ、生成物を単離するこ
となし、同じ反応系内に、一般式（Ｖ）〔式中、Ｒは前
述と同じ意味を表わす。〕で表わされる化合物を加えて
、反応させることを特徴とする
一般式〔■〕
〔式中、ＡおよびＲは前述と同じ意味を表わす。To explain in more detail, the present invention is based on the general formula [■) (1) [wherein A represents the same meaning as described above]. ] A compound represented by the general formula [■] Q"X-C■] [wherein,
X1 represents a halogen ion, hydroxy ion or hydrogen sulfate ion, and Q4 represents the general formula [■] RI R2 Rs R. W” (■
] (In the formula, R+ .R2 .R3 and R4 each represent a straight or branched alkyl group having 1 to 20 carbon atoms, and W represents a nitrogen atom or a phosphorus atom.)
represents a group represented by ] in the presence of a quaternary onium salt and a base represented by the general formula ( V) [wherein R represents the same meaning as above. General formula [■] characterized by adding a compound represented by the formula [■] [In the formula, A and R have the same meanings as above.
で表わされる環状イミド誘導体またはそれらの酸付加塩
の製造方法に関するものである。The present invention relates to a method for producing a cyclic imide derivative or an acid addition salt thereof.
本発明の方法によれば、化合物〔■〕に対して、等モル
量あるいは、やや過剰量の１−ブロムー４−クロロブタ
ンを使用するだけで、問題となる二量体［Ｖ１）の副生
を５％以下に抑制でき、目的物である環状イミド誘導体
ＣＩ’ｌを９５％以上の高収率で得ることができる。According to the method of the present invention, the problematic by-product of dimer [V1] can be avoided by simply using an equimolar amount or a slightly excessive amount of 1-bromo-4-chlorobutane with respect to compound [■]. 5% or less, and the target cyclic imide derivative CI'l can be obtained with a high yield of 95% or more.
すなわち、前記一般式（１’Ｖ）の単離精Ｍ揉作は、全
く不要となり、引き続き同一反応系内に、単に一般式〔
■〕の化合物を加えて加熱するだけで反応が進行し、目
的とする一般式〔Ｉ〕の環状イミド誘導体が高収率で生
成する。このように本発明方法は、実質的に一段階で一
般式ＣＩ［］の化合物から最終目的化合物である〔Ｉ〕
の環状イミド誘導体を合成できる、新規かつ有用な製造
方法である。That is, the isolation and purification process of the general formula (1'V) becomes completely unnecessary, and subsequently, in the same reaction system, simply the general formula [
The reaction proceeds simply by adding the compound (2) and heating, and the desired cyclic imide derivative of the general formula [I] is produced in high yield. Thus, the process of the present invention can be carried out substantially in one step from the compound of the general formula CI[] to the final target compound [I]
This is a new and useful manufacturing method that allows the synthesis of cyclic imide derivatives.
本発明方法において、用いられる反応溶媒としては、水
と共に、疎水性有機溶媒が用いられる。疎水性有機溶媒
としては、例えば、ベンゼン、トルエン、キシレン等の
芳香族炭化水素系溶媒、例えば、ｎ−ヘキサン，ｎ−ベ
ンタン等の脂肪族炭化水素系溶媒等が挙げられ、これら
の混合溶媒を用いることもできる。好ましくは、ベンゼ
ン、トルエン、キシレン等の芳香族炭化水素系溶媒を挙
げることができる。In the method of the present invention, a hydrophobic organic solvent is used together with water as the reaction solvent. Examples of hydrophobic organic solvents include aromatic hydrocarbon solvents such as benzene, toluene, and xylene, and aliphatic hydrocarbon solvents such as n-hexane and n-bentane. It can also be used. Preferred examples include aromatic hydrocarbon solvents such as benzene, toluene, and xylene.
相関移動触媒としては、例えば、フッ化テトラ−ｎ−プ
チルアンモニウム、塩化テトラ−ｎ一プチルアンモニウ
ム、臭化テトラ−ｎ−プチルアンモニウム、ヨウ化テト
ラ−ｎ−プチルアンモニウム、硫酸水素テトラ−ｎ−プ
チルアンモニウム、水酸化テトラ−ｎ−プチルアンモニ
ウム等の４級アンモニウム塩、臭化ヘキサデシルトリブ
チルホスホニウム等の４級ホスホニウム塩が挙げられる
が、特に好ましいものとしては硫酸水素テトラ−ｎ−プ
チルアンモニウム等が挙げられる。Examples of phase transfer catalysts include tetra-n-butylammonium fluoride, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, and tetra-n-butylammonium hydrogen sulfate. Examples include ammonium salts, quaternary ammonium salts such as tetra-n-butylammonium hydroxide, and quaternary phosphonium salts such as hexadecyltributylphosphonium bromide, and particularly preferred ones include tetra-n-butylammonium hydrogen sulfate. It will be done.
塩基としては、例えば、水酸化ナ｝ ＩＪウム、炭酸ナ
トリウム、炭酸カリウム、重炭酸ナトリウム等のアルカ
リ金属塩、例えば水酸化カルシウム、等のアルカリ土類
金属塩を挙げることができる。好ましいものとしては、
例えば、炭酸ナトリウム、重炭酸ナトリウム等のアルカ
リ金属の炭酸塩、重炭酸塩を挙げることができる。Examples of the base include alkali metal salts such as sodium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate, and alkaline earth metal salts such as calcium hydroxide. Preferably,
Examples include alkali metal carbonates and bicarbonates such as sodium carbonate and sodium bicarbonate.
反応は、一般的には反応温度を上昇又は降下させること
により、反応を促進又は抑制させることができるが、反
応温度としては、室温ないしは、溶媒の沸点で実施する
ことが好ましい。The reaction can generally be promoted or suppressed by increasing or decreasing the reaction temperature, but the reaction temperature is preferably room temperature or the boiling point of the solvent.
さらに、本発明方法においては、塩基に加えて、反応助
剤として例えば、ヨウ化カリウム、ヨウ化ナトリウ・ム
等のアルカリ金属のヨウ素酸塩を用いてもよい。Furthermore, in the method of the present invention, in addition to the base, an alkali metal iodate such as potassium iodide or sodium iodide may be used as a reaction aid.
反応後、反応液の有機層を分液し、溶媒を留去すること
により、目的とする環状イミド誘導体〔■〕を通常の有
機化学的手法により、高い収率で単離することができる
。After the reaction, the organic layer of the reaction solution is separated and the solvent is distilled off, thereby making it possible to isolate the desired cyclic imide derivative [■] with a high yield by a conventional organic chemical method.
さらに環状イミド誘導体（１１は、所望に応じて、各種
の無機酸又は有機酸、例えば、塩酸，蓚酸．クエン酸，
リンゴ酸．酒石酸，フマール酸．マレイン酸等と酸付加
塩を形成することができる。Further, the cyclic imide derivative (11 is optionally selected from various inorganic or organic acids, such as hydrochloric acid, oxalic acid, citric acid,
Malic acid. Tartaric acid, fumaric acid. Acid addition salts can be formed with maleic acid and the like.
次に実施例をあげて、本発明を詳細に説明するが、本発
明はこの実施例に限定されるものではない。EXAMPLES Next, the present invention will be explained in detail with reference to Examples, but the present invention is not limited to these Examples.
実施例
水１１７ｋｇ．｝ルエン２ ９． ３ ｋｇにビシクロ
［２，２．１３へブタン−２．３−ジーエキソーカルポ
キシイミド１９．５ｋｇ．無水炭酸カリウム２４．４８
ｋｇ．硫酸水素テトラ−ｎ−プチルアンモニウム４．０
１ｋｇ．１−ブロモー４−クロロブタン２ ６． ３
１ ｋｇを加え、６０〜７０℃を保ちながら、２時間撹
拌した。反応液を冷却し、１−（２−ピリミジル） ピ
ベラジン２７．１４ｋｇ．ヨウ化カリウム１９．６ｋｇ
．無水炭酸カリウム８． １ ６ ｋｇを加え、加熱還
流下、５時間撹拌した。Example water 117 kg. }Ruen 2 9. 3 kg of bicyclo[2,2.13butane-2.3-di-exocarpoximide 19.5 kg. Anhydrous potassium carbonate 24.48
kg. Tetra-n-butylammonium hydrogen sulfate 4.0
1kg. 1-bromo 4-chlorobutane 2 6. 3
1 kg was added thereto, and the mixture was stirred for 2 hours while maintaining the temperature at 60 to 70°C. The reaction solution was cooled and 27.14 kg of 1-(2-pyrimidyl)piverazine was added. Potassium iodide 19.6kg
．． Anhydrous potassium carbonate8. 16 kg was added thereto, and the mixture was stirred for 5 hours under heating under reflux.
反応液にトルエン１ ３ ６． ５ ｋｇを注入し、７
０℃で分液し、有機相をｐＨ６．７５のリン酸緩衝液１
１７ｋｇで３回、水１１７ｋｇで１回洗浄した。Add toluene 1 3 6. to the reaction solution. Inject 5 kg, 7
Separate the layers at 0°C, and add the organic phase to phosphate buffer solution 1, pH 6.75.
It was washed three times with 17 kg of water and once with 117 kg of water.
無水硫酸マグネシウム９．７５ｋｇ．活性炭０． ８
ｋｇを加え、３０分間撹拌後、濾過し、トルエン３ ２
． ５ ｋｇで洗浄した。得られたトルエン溶液を、ク
エン酸一水和物２５．０４ｋｇ，イソプロビルアルコー
ル１ ６ ３． １ ３ ｋｇよりなる溶液に滴下し、
生成した結晶を濾取、乾燥したところ６ １． ４ ｋ
ｇのへキサヒド口−２− Ｃ４− ｛４− （２−ピリ
ミジニル）−１−ビペラジニル｝ブチル〕−４．７−メ
タノーＩＨ−イソインドール−１．３（２Ｈ）−ジオン
（クエン酸塩）を得た。収率９０．５％融点１７４−１
７５℃
実施例２
水１１０ｋｇ．｝ルエン２ ７． ２ ｋｇにシクロヘ
キサン−１．２−ジーカルボキシイミド１ ６． ９
ｋｇ無水炭酸カリウム２２．９ｋｇ．硫酸水素テトラ−
ｎ−プチルアンモニウム３．８ｋｇ．１−ブロモー４−
クロロブタン２ ０． ９ ｋｇを加え、６０−６５℃
に保ちながら、２時間撹拌した。反応液を冷却し、３−
（１−ピベラジニル）−１．２−ペンズイソチアゾール
２ ５． ４ ｋｇヨウ化カリウム１８１ｋｇ，無水炭
酸カリウム７． ６ ｋｇを加え加熱還流下５時間撹拌
した。反応液にトルエン１０２ｋｇを注入し、７０−８
０℃で分液し、水１１０ｋｇで２回洗浄を行った。トル
エン層へ無水硫酸マグネシウム３． ２ ｋｇを加え、
４０分間撹拌後、濾過し、トルエン２５ｋｇで洗浄した
。得られたトルエン溶液を減圧下、濃縮を行い、残渣ヘ
イソブロビルアルコール２ ８ ３ ｋｇを加え６０℃
まで加熱し、冷却後、生成した結晶を濾取した。Anhydrous magnesium sulfate 9.75 kg. Activated carbon 0. 8
kg, stirred for 30 minutes, filtered, and added 3.2 kg of toluene.
．． Washed with 5 kg. The obtained toluene solution was mixed with 25.04 kg of citric acid monohydrate and 16.3 kg of isopropyl alcohol. Dropped into a solution consisting of 13 kg,
The formed crystals were collected by filtration and dried.6 1. 4k
g of hexahydride-2-C4-{4-(2-pyrimidinyl)-1-biperazinyl}butyl]-4.7-methanol IH-isoindole-1.3(2H)-dione (citrate) Obtained. Yield 90.5% Melting point 174-1
75°C Example 2 110 kg of water. }Ruen 2 7. 2 kg of cyclohexane-1,2-dicarboximide 1 6. 9
kg Anhydrous potassium carbonate 22.9 kg. hydrogen sulfate tetra-
n-butylammonium 3.8kg. 1-bromo4-
Chlorobutane 2 0. Add 9 kg and heat to 60-65℃
The mixture was stirred for 2 hours while maintaining the temperature. Cool the reaction solution, 3-
(1-piverazinyl)-1,2-penzisothiazole 2 5. 4 kg potassium iodide 181 kg, anhydrous potassium carbonate 7. 6 kg was added thereto, and the mixture was stirred for 5 hours under heating and reflux. Inject 102 kg of toluene into the reaction solution and add 70-8
The liquid was separated at 0°C and washed twice with 110 kg of water. 3. Add anhydrous magnesium sulfate to the toluene layer. Add 2 kg,
After stirring for 40 minutes, it was filtered and washed with 25 kg of toluene. The obtained toluene solution was concentrated under reduced pressure, and 283 kg of heisobrobil alcohol was added to the residue at 60°C.
After cooling, the formed crystals were collected by filtration.
イソブロビルアルコール４７ｋｇで洗浄後、得られた結
晶を乾燥し、シスー２− （４− （４一（１．２−ペ
ンズイソチアゾール−３−イル）−１−ピペラジニル〕
ブチル〕へキサヒドロ−１｝｛−イソインドール−１．
３ （２Ｈ）ジオン３ ５． ４ ｋｇを得た。収率
７５．３％、融点５３−５６℃
代理人 弁理士 細 田 芳 徳After washing with 47 kg of isobrobyl alcohol, the obtained crystals were dried to give cis-2-(4-(4-(1.2-penzisothiazol-3-yl)-1-piperazinyl)
butyl]hexahydro-1}{-isoindole-1.
3 (2H)dione 3 5. Obtained 4 kg. Yield 75.3%, melting point 53-56℃ Agent: Patent attorney Yoshinori Hosoda
Claims (3)
式、化学式、表等があります▼、 ▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼、▲数式、化学式、表等があります▼
、 ▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼または▲数式、化学式、表等がありま
す▼ で示される基を表わす。〕 で表わされる化合物を、一般式 Ｑ＾＋Ｘ＾− 〔式中、Ｘ＾−はハロゲンイオン、ヒドロキシイオンま
たは硫酸水素イオンを表わし、Ｑ＾＋は一般式 Ｒ＿１Ｒ＿２Ｒ＿３Ｒ＿４Ｗ＾＋ （式中、Ｒ＿１、Ｒ＿２、Ｒ＿３およびＲ＿４はそれぞ
れ炭素数１から２０よりなる直鎖又は分枝状のアルキル
基を表わし、Ｗは窒素原子または、リン原子を表わす。 ）で示される基を表わす。〕で示される４級オニウム塩
および塩基の存在下に１−ブロモ−４−クロロブタンと
反応させ、さらに一般式 ▲数式、化学式、表等があります▼ 〔式中、Ｒは置換又は無置換のフェニル基、置換又は無
置換の２−ピリジル基、置換又は無置換のピリミジル基
、置換又は無置換の１，２−ベンゾ−３−イソチアゾリ
ル基を表わし、前記の置換基は、ハロゲン原子、炭素数
１から４のアルコキシ基またはシアノ基を表わす。〕 で表わされるピペラジン誘導体を加えて反応させること
を特徴とする一般式 ▲数式、化学式、表等があります▼ 〔式中、▲数式、化学式、表等があります▼、Ｒは前述
と同じ意味を表 わす。〕で表わされる環状イミド誘導体またはそれらの
酸付加塩の製造方法。(1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ is the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas, tables, etc. There are ▼, ▲mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼ or ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ Represents the group shown. ] The compound represented by the general formula Q^+X^- [wherein, X^- represents a halogen ion, hydroxy ion or hydrogen sulfate ion, and Q^+ represents the general formula R_1R_2R_3R_4W^+ (wherein, R_1, R_2 , R_3 and R_4 each represent a straight chain or branched alkyl group having 1 to 20 carbon atoms, and W represents a nitrogen atom or a phosphorus atom. [In the formula, R is substituted or unsubstituted phenyl]. represents a substituted or unsubstituted 2-pyridyl group, a substituted or unsubstituted pyrimidyl group, a substituted or unsubstituted 1,2-benzo-3-isothiazolyl group, and the above substituent has a halogen atom, a carbon number of 1 4 represents an alkoxy group or a cyano group. ] A general formula characterized by adding and reacting a piperazine derivative represented by ▲ There are mathematical formulas, chemical formulas, tables, etc. represent ] A method for producing a cyclic imide derivative or an acid addition salt thereof.
化学式、表等があります▼で表わされ る基であり、Ｒが２−ピリミジル基である請求項（１）
の製造方法。(2) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ is a formula ▲ Mathematical formula,
There are chemical formulas, tables, etc.Claim (1) which is a group represented by ▼, and R is a 2-pyrimidyl group
manufacturing method.
モニウムである請求項（１）又は請求項（２）の製造方
法。(3) The manufacturing method according to claim (1) or claim (2), wherein Q^+X^- is tetra-n-butylammonium hydrogen sulfate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1056583A JP2918899B2 (en) | 1989-03-09 | 1989-03-09 | Method for producing cyclic imide derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1056583A JP2918899B2 (en) | 1989-03-09 | 1989-03-09 | Method for producing cyclic imide derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02235865A true JPH02235865A (en) | 1990-09-18 |
| JP2918899B2 JP2918899B2 (en) | 1999-07-12 |
Family
ID=13031193
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1056583A Expired - Lifetime JP2918899B2 (en) | 1989-03-09 | 1989-03-09 | Method for producing cyclic imide derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2918899B2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996006827A1 (en) * | 1994-08-27 | 1996-03-07 | Research Institute Of Chemical Processing And Utilization Of Forest Products, Chinese Academy Of Forestry | N-alkylimide and process for preparation thereof |
| CN1073990C (en) * | 1997-06-17 | 2001-10-31 | 中国林业科学研究院林产化学工业研究所 | Process for preparing (inner) N-alkyl imide |
| US6914064B2 (en) | 2000-11-30 | 2005-07-05 | Ranbaxy Laboratories Limited | 1,4-Disubstituted piperazine derivatives useful as uro-selective α1-adrenoceptor blockers |
-
1989
- 1989-03-09 JP JP1056583A patent/JP2918899B2/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996006827A1 (en) * | 1994-08-27 | 1996-03-07 | Research Institute Of Chemical Processing And Utilization Of Forest Products, Chinese Academy Of Forestry | N-alkylimide and process for preparation thereof |
| CN1073990C (en) * | 1997-06-17 | 2001-10-31 | 中国林业科学研究院林产化学工业研究所 | Process for preparing (inner) N-alkyl imide |
| US6914064B2 (en) | 2000-11-30 | 2005-07-05 | Ranbaxy Laboratories Limited | 1,4-Disubstituted piperazine derivatives useful as uro-selective α1-adrenoceptor blockers |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2918899B2 (en) | 1999-07-12 |
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