JPH0418090A - Production of bisazolylpyrimidine derivative - Google Patents
Production of bisazolylpyrimidine derivativeInfo
- Publication number
- JPH0418090A JPH0418090A JP12211290A JP12211290A JPH0418090A JP H0418090 A JPH0418090 A JP H0418090A JP 12211290 A JP12211290 A JP 12211290A JP 12211290 A JP12211290 A JP 12211290A JP H0418090 A JPH0418090 A JP H0418090A
- Authority
- JP
- Japan
- Prior art keywords
- derivative
- bisazolylpyrimidine
- producing
- formula
- tetra
- 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
- 238000004519 manufacturing process Methods 0.000 title claims description 41
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims abstract description 21
- 150000003230 pyrimidines Chemical class 0.000 claims abstract description 17
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 15
- 150000007980 azole derivatives Chemical class 0.000 claims abstract description 12
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims abstract description 11
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 4
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 150000001450 anions Chemical class 0.000 claims abstract description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- -1 4,6-diimidazolylpyrimidine Chemical compound 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 10
- XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical compound ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 claims description 9
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 8
- QWDCDVFIUVZMTO-UHFFFAOYSA-N 4,6-bis(1H-pyrazol-5-yl)pyrimidine Chemical group N1N=C(C=C1)C1=NC=NC(=C1)C1=NNC=C1 QWDCDVFIUVZMTO-UHFFFAOYSA-N 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical group ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- 125000003943 azolyl group Chemical group 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 2
- SYZCZDCAEVUSPM-UHFFFAOYSA-M tetrahexylazanium;bromide Chemical compound [Br-].CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC SYZCZDCAEVUSPM-UHFFFAOYSA-M 0.000 claims description 2
- TWAVLAUIQVYLOR-UHFFFAOYSA-N 1-pyrrol-1-ylpyrrole Chemical group C1=CC=CN1N1C=CC=C1 TWAVLAUIQVYLOR-UHFFFAOYSA-N 0.000 claims 1
- HRIKTQDEGIPHJH-UHFFFAOYSA-N 2,4-bis(1H-pyrazol-5-yl)pyrimidine Chemical compound N1N=C(C=C1)C1=NC(=NC=C1)C1=NNC=C1 HRIKTQDEGIPHJH-UHFFFAOYSA-N 0.000 claims 1
- 239000006227 byproduct Substances 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 239000002904 solvent Substances 0.000 description 17
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 239000013076 target substance Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- BTLKROSJMNFSQZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyrimidine Chemical compound CC1=CC(Cl)=NC(Cl)=N1 BTLKROSJMNFSQZ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 2
- WGZYVHFXLPDNDL-UHFFFAOYSA-N 4-benzoyl-2-phenylpyrazole-3-carbonitrile Chemical compound C=1C=CC=CC=1C(=O)C(=C1C#N)C=NN1C1=CC=CC=C1 WGZYVHFXLPDNDL-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GKQHIYSTBXDYNQ-UHFFFAOYSA-M 1-dodecylpyridin-1-ium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+]1=CC=CC=C1 GKQHIYSTBXDYNQ-UHFFFAOYSA-M 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 101100313097 Caenorhabditis elegans tba-8 gene Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- GEYBMYRBIABFTA-UHFFFAOYSA-N O-methyltyrosine Chemical compound COC1=CC=C(CC(N)C(O)=O)C=C1 GEYBMYRBIABFTA-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 1
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- IUSOXUFUXZORBF-UHFFFAOYSA-N n,n-dioctyloctan-1-amine;hydrochloride Chemical compound [Cl-].CCCCCCCC[NH+](CCCCCCCC)CCCCCCCC IUSOXUFUXZORBF-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 description 1
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (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)
本発明は、ピリミジン誘導体を出発物質としたビスアゾ
リルピリミジン誘導体の製造方法に関ずろ。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a method for producing a bisazolylpyrimidine derivative using a pyrimidine derivative as a starting material.
(従来の技術)
ビスアゾリルピリミジン誘導体は、低毒性で細胞保護作
用を有する抗潰瘍薬としてその有用性が認められている
化合物である。(Prior Art) Bisazolylpyrimidine derivatives are compounds that have been recognized for their usefulness as anti-ulcer drugs with low toxicity and cytoprotective effects.
従来、このビスアゾリルピリミジン誘導体の製造方法と
して、アゾール誘導体(例えば、イミダゾール、ピラゾ
ール、トリアゾール)と水素化アルカリ金属とを反応さ
せてアゾール誘導体のアルカリ塩を生成させ、次に該ア
ルカリ塩と2.4−ジクロロピリミジン、あるいは4,
6−ジクロロピリミジンとの反応によりビスアゾリルピ
リミジン誘導体を製造する方法(特開昭63−3987
5号)等が提案されていた。Conventionally, as a method for producing bisazolylpyrimidine derivatives, an azole derivative (e.g., imidazole, pyrazole, triazole) and an alkali metal hydride are reacted to form an alkali salt of the azole derivative, and then the alkali salt and 2 .4-dichloropyrimidine, or 4,
Method for producing bisazolylpyrimidine derivatives by reaction with 6-dichloropyrimidine (Japanese Patent Application Laid-Open No. 63-3987
No. 5) etc. were proposed.
(発明が解決しようとする課題〉
しかしながら、前記従来技術での製造方法では、目的物
質(ビスアゾリルピリミジン誘導体)を70〜85%の
収率で得られる反面、その製造工程において高価な水素
化アルカリ金属を使用しなければならない上に、有機溶
媒、試薬、窒素ガスを用いた一連の化学反応を、無水の
条件下で行う必要があり、また、製造工程で強引火性の
水素ガスが発生するなど、かねてからその製法上、保安
上の不利な点が指摘されていた。(Problems to be Solved by the Invention) However, in the production method using the above-mentioned conventional technology, the target substance (bisazolylpyrimidine derivative) can be obtained with a yield of 70 to 85%, but on the other hand, expensive hydrogenation is required in the production process. In addition to the use of alkali metals, a series of chemical reactions using organic solvents, reagents, and nitrogen gas must be conducted under anhydrous conditions, and highly flammable hydrogen gas is generated during the manufacturing process. Disadvantages in terms of safety have been pointed out for some time due to the manufacturing method.
しかも、前記従来技術の製造方法の追試実験によれば、
加水分解されたモノヒドロキシピリミジン体が製造工程
で著聞副生ずるため、目的とするビスアゾリルピリミジ
ン誘導体を高純度かつ高収率に得るのが困難であるとい
う欠点があった。すなわち、目的とするビスアゾリルピ
リミジン誘導体の純度をあげようとすると収率が低下す
るという現象を招いていたため、ビスアゾリルピリミジ
ン誘導体の工業的生産は経済的に見合うものではなかっ
た。Moreover, according to a follow-up experiment of the manufacturing method of the prior art,
Since a significant amount of hydrolyzed monohydroxypyrimidine is produced as a by-product during the manufacturing process, it is difficult to obtain the desired bisazolylpyrimidine derivative with high purity and high yield. That is, an attempt to increase the purity of the target bisazolylpyrimidine derivative resulted in a decrease in yield, and therefore, industrial production of the bisazolylpyrimidine derivative was not economically viable.
このような状況下、当該業界では、短時間に、効率よく
、安全に、しかも簡便にビスアゾリルピリミジン誘導体
が得られるところの製造方法が切望されているのが実情
であった。Under these circumstances, there has been a real need in the industry for a production method that allows bisazolylpyrimidine derivatives to be obtained easily, efficiently, and safely in a short period of time.
(課題を解決するための手段)
本発明者は、上記の従来技術において指摘されていた欠
点を改善すべく鋭意研究を重ねた結果、相間移動触媒存
在下、ピリミジン誘導体とアゾール誘導体とを反応させ
ることにより、効率よく、かつ高純度のビスアゾリルピ
リミジン誘導体が製造できることを見出し本発明を完成
せしめたものであ一す、その要旨とするところは、化学
式〔I〕 :
〔式中、X及びYは一方がNで他方がCHであり、Zは
水素原子またはメチル基である〕で表されるピリミジン
誘導体と、アゾール誘導体とを、化学式〔■〕 :
!(3
〔式中、R1、R2、R3、及びR4は、アルキル基、
アラルキル基、または窒素原子を伴う複素環であり、A
Oはアニオンである]で表される相間移動触媒の存在下
で反応させることを特徴とする
化学式[■] :
N /)S−X
3M8 [m]
(式中、χ及びYは一方がNで他方がCHであり、Zは
水素原子またはメチル基であり、Sはアゾリル基である
)で表されるビスアゾリルピリミジン誘導体の製造方法
である。(Means for Solving the Problems) As a result of intensive research to improve the drawbacks pointed out in the above-mentioned prior art, the present inventors have discovered that a pyrimidine derivative and an azole derivative are reacted in the presence of a phase transfer catalyst. The present invention has been completed by discovering that bisazolylpyrimidine derivatives can be produced efficiently and with high purity by the following steps: One Y is N, the other is CH, and Z is a hydrogen atom or a methyl group.] A pyrimidine derivative represented by the formula [■] and an azole derivative are represented by the chemical formula [■]: ! (3 [wherein, R1, R2, R3, and R4 are alkyl groups,
is an aralkyl group or a heterocycle with a nitrogen atom, and A
A chemical formula [■] characterized in that the reaction is carried out in the presence of a phase transfer catalyst represented by [O is an anion]: N /) S-X 3M8 [m] (wherein χ and Y are one of N and the other is CH, Z is a hydrogen atom or a methyl group, and S is an azolyl group).
ピリミジン誘導体(1)としては、2,4−ジクロロピ
リミジン、4.6−ジクロロピリミジン、及び2.4−
ジクロロ−6−メチルピリミジン等が挙げられる。Examples of the pyrimidine derivative (1) include 2,4-dichloropyrimidine, 4,6-dichloropyrimidine, and 2,4-dichloropyrimidine.
Examples include dichloro-6-methylpyrimidine.
一方、アゾール誘導体としては、ピラゾール、・イミダ
ゾール、及び1,2.4−トリアゾール等が挙げられる
。このアゾール誘導体のピリミジン誘導体CI)に対す
るモル比は、2.0〜3.0の範囲で、特に2.0〜2
.2のほぼ等モルが好ましい。On the other hand, examples of azole derivatives include pyrazole, imidazole, and 1,2,4-triazole. The molar ratio of this azole derivative to the pyrimidine derivative CI) is in the range from 2.0 to 3.0, in particular from 2.0 to 2.
.. Approximately equimolar amounts of 2 are preferred.
さらに、相間移動触媒(Il)として適当なものは、い
わゆる四級アンモニウム塩、例えば、塩化ベンジルトリ
エチルアンモニウム、臭化ベンジルトリエチルアンモニ
ウム、塩化フェニルトリエチルアンモニウム、臭化テト
ラ−n−ブチルアンモニウム、塩化テトラ−n−ブチル
アンモニウム、硫酸水素テトラ−n−ブチルアンモニウ
ム、臭化テトラエチルアンモニウム、塩化テトラエチル
アンモニウム、塩化トリオクチルアンモニウム、塩化セ
チルピリジニウム、及び塩化ラウリルピリジニウム等で
ある。この内、臭化テトラ−n−ブチルアンモニウムと
硫酸水素テトラ−n−ブチルアンモニウムは本発明の製
造方法における使用にあっては好ましい触媒である。Furthermore, suitable phase transfer catalysts (Il) are so-called quaternary ammonium salts, such as benzyltriethylammonium chloride, benzyltriethylammonium bromide, phenyltriethylammonium chloride, tetra-n-butylammonium bromide, tetra- These include n-butylammonium, tetra-n-butylammonium hydrogen sulfate, tetraethylammonium bromide, tetraethylammonium chloride, trioctylammonium chloride, cetylpyridinium chloride, and laurylpyridinium chloride. Among these, tetra-n-butylammonium bromide and tetra-n-butylammonium hydrogen sulfate are preferred catalysts for use in the production method of the present invention.
該触媒の使用量は、ピリミジン誘導体CI)に対し、1
〜20モル%の範囲であるが、好ましくは1〜5モル%
である。The amount of the catalyst used is 1 for the pyrimidine derivative CI).
-20 mol%, preferably 1-5 mol%
It is.
本発明の反応の形態としては、液−液、あるいは固−液
の二相系の反応を意味し、完全な非水系から触媒、試薬
、及び溶媒中に含まれる水は許容されるものであり、さ
らには加水することも許容される形態である。The reaction mode of the present invention refers to a liquid-liquid or solid-liquid two-phase system reaction, and water contained in a completely non-aqueous system or a catalyst, reagent, and solvent is acceptable. It is also an acceptable form to add water.
本反応で使用される有機溶媒は、芳香族炭化水素、例え
ば、ベンゼン、トルエン、キシレン等、もしくは非プロ
トン系の極性溶媒、例えば、アセトニトリル、ジオキサ
ン、クロロホルム、エーテル、アセトン、メチルエチル
ケトン、ジメチルホルムアミF、テトラヒドロフラン等
が好ましく、特に、ベンゼン、メチルエチルケトン、ア
セトニトリルが好ましい。溶媒量は、ピリミジン誘導体
に対して5〜1 、000倍量が好適である。The organic solvent used in this reaction is an aromatic hydrocarbon such as benzene, toluene, xylene, etc., or an aprotic polar solvent such as acetonitrile, dioxane, chloroform, ether, acetone, methyl ethyl ketone, dimethylformamide F. , tetrahydrofuran, etc. are preferred, and benzene, methyl ethyl ketone, and acetonitrile are particularly preferred. The amount of solvent is preferably 5 to 1,000 times the amount of the pyrimidine derivative.
反応温度は、室温から還流温度までの間で、特に50〜
80℃が好ましく、反応時間は、反応温度、使用する触
媒によって異なるが、1〜10時間で充分である。The reaction temperature is between room temperature and reflux temperature, especially 50 to reflux temperature.
The temperature is preferably 80°C, and the reaction time varies depending on the reaction temperature and the catalyst used, but 1 to 10 hours is sufficient.
以下の実施例にて本発明のビスアゾリルピリミジン誘導
体の製造方法、ならびに本発明の製造方法の至適反応条
件の設定を説明するが、本発明はこれら実施例に限定さ
れて解釈されるべきものではない。The following examples will explain the method for producing bisazolylpyrimidine derivatives of the present invention and the setting of optimal reaction conditions for the production method of the present invention, but the present invention should be construed as being limited to these examples. It's not a thing.
(実施例)
A%J+ 1 : 4,6L−ジピラヅリルピリミジ
ンベンゼン1.5ρに4,6−ジクロロピリミジン10
0.0g (0,67mo+)とピラゾール113.9
g (1,675m01)を室温で溶解し、該溶液に水
酸化カリウム93.8g (1,675mol)、次い
で臭化テトラ−n−ブヂルアンモニウム21.6g(0
,067mol)を加え、50℃で6時間撹拌した。得
られた反応溶液に水500m1を加えて2回水洗した。(Example) A%J+ 1: 4,6L-dipyrazulylpyrimidine 1.5ρ to 4,6-dichloropyrimidine 10
0.0g (0.67mo+) and pyrazole 113.9
g (1,675 mol) at room temperature, and to this solution was added 93.8 g (1,675 mol) of potassium hydroxide, and then 21.6 g (0 mol) of tetra-n-butylammonium bromide.
,067 mol) and stirred at 50°C for 6 hours. 500 ml of water was added to the resulting reaction solution and washed twice.
ベンゼン層を無水硫酸ナトリウムで乾燥後、溶媒を減圧
濃縮して得られる残渣をアセトン中で活性炭で処理した
後、エタノールより再結晶すると下記の分析値を示す4
,6−ジピラゾリルピリミジン130;6g(0,61
6mol)が得られた。After drying the benzene layer over anhydrous sodium sulfate and concentrating the solvent under reduced pressure, the resulting residue was treated with activated carbon in acetone and then recrystallized from ethanol, giving the following analytical values 4.
,6-dipyrazolylpyrimidine 130; 6g (0,61
6 mol) was obtained.
生゛物゛のン鴫と収率
白色粉末結晶 (収率91.9%)
N M R(CDC1x)、δ:
8.80 (IH,d、 J=1.0Hz)、8.60
(2H,dd、 J=2.711z、 0.7Hz)
、8.49 (IH,d、 J=1.0Hz)、7.8
2 (2H,dd、 J=0.711z)、6.52
(2)!、 dd、 J=2.7H2)、元素分析:
C,oH,N6(212,21)として、計算値(%)
:
C,56,60; H,3,80; N、 39.
60分析イ直 (%) :
C,56,67; H,3,76; N、
39.89M5 (m/z) : 212 (
M’ )。Yield of white powder crystals (yield 91.9%) NMR (CDC1x), δ: 8.80 (IH, d, J=1.0Hz), 8.60
(2H, dd, J=2.711z, 0.7Hz)
, 8.49 (IH, d, J=1.0Hz), 7.8
2 (2H, dd, J=0.711z), 6.52
(2)! , dd, J=2.7H2), elemental analysis:
Calculated value (%) as C, oH, N6 (212, 21)
: C, 56,60; H, 3,80; N, 39.
60 analysis straight (%): C, 56,67; H, 3,76; N,
39.89M5 (m/z): 212 (
M').
145 (M” Ci N3 N2 )B支
アj: 134−137 ℃
ゞ°7111:4,6−ジピラゾリルピリミジン窒素雰
囲気下、水素化ナトリウム(鉱油中60%含有) 16
1g (4,02mol)を乾燥テトラヒドロフラン(
200Il+ 1 )に懸濁した溶液に、ピラゾール2
28g(3,35mol)を溶解した乾燥テトラヒドロ
フラン(500ml)を1時間かけて滴加し、水冷下で
2時間反応させた後、該反応液に4,6−ジクロロピリ
ミジン200.0g(1,34mol)の乾燥テトラヒ
ドロフラン溶液(500ml)を水冷下で1時間かけて
滴加し、約70℃で一晩反応させた。145 (M” Ci N3 N2 ) B branch: 134-137 °C ゞ°7111: 4,6-dipyrazolylpyrimidine Sodium hydride (containing 60% in mineral oil) under nitrogen atmosphere 16
1 g (4.02 mol) of dry tetrahydrofuran (
Pyrazole 2 was added to a solution suspended in 200Il+ 1).
Dry tetrahydrofuran (500 ml) in which 28 g (3.35 mol) of 4,6-dichloropyrimidine was dissolved was added dropwise over 1 hour, and the reaction was allowed to proceed for 2 hours under water cooling. ) was added dropwise over 1 hour under water cooling, and the mixture was reacted overnight at about 70°C.
反応混液を減圧留去して得られた残渣をジクロロメタン
に溶解後、飽和炭酸水素すトリウム水溶液、次いで飽和
塩化ナトリウム水溶液で有機層を洗浄した。有機層を無
水硫酸ナトリウムで乾燥後、溶媒を減圧濃縮して得られ
る残渣をクロロホルムに溶解してシリカゲルで吸着処理
した。その後、溶媒を減圧留去して得られる残渣をエタ
ノールより再結晶、及び活性炭による脱色操作を各々2
回線り返すことにより、4,6ジピラゾリルビリミジン
135.0g(0,646mof収率47.8%)が得
られた。After the reaction mixture was distilled off under reduced pressure and the resulting residue was dissolved in dichloromethane, the organic layer was washed with a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution. After drying the organic layer over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform and adsorbed on silica gel. Thereafter, the solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from ethanol and decolorized using activated carbon for two times each.
By repeating the line, 135.0 g (0,646 mof yield: 47.8%) of 4,6 dipyrazolylpyrimidine was obtained.
上記比較例1に示したように、従来法に従った4、6−
ジピラヅリルピリミジンの製造方法では、ピラゾールと
水素化ナトリウムを乾燥テトラハイドロフラン中で、ピ
ラゾールのナトリウム塩を合成し、これにビスクロロピ
リミジンの乾燥テトラハイドロフランを徐々に滴下し、
さらに長時間加熱還流する必要がある。As shown in Comparative Example 1 above, 4,6-
In the method for producing dipyrazurylpyrimidine, pyrazole and sodium hydride are mixed in dry tetrahydrofuran to synthesize the sodium salt of pyrazole, and to this, dry tetrahydrofuran of bischloropyrimidine is gradually added dropwise.
It is necessary to heat and reflux for an even longer time.
また、暗褐色を厘した反応液は、テ[ラハイドロフラン
を減圧留去で除いた後、ジクロロメタンで抽出し、つい
で反応液の澄明化と純度の向上のために、脱色と再結晶
を数回操り返す必要がある。In addition, the reaction solution, which had turned dark brown, was extracted with dichloromethane after removing the tetrahydrofuran under reduced pressure, and then decolorized and recrystallized several times in order to clarify the reaction solution and improve its purity. It is necessary to repeat the process.
このように、従来法では本発明の製造方法と比較してビ
スアゾリルピリミジン誘導体の収率が極端に悪い上に、
各工程の処理時間が長(、かつ反復操作を必要とするた
め、その製造方法を生産ラインへ通用することは困難を
伴うものであった。As described above, in the conventional method, the yield of bisazolylpyrimidine derivatives is extremely poor compared to the production method of the present invention, and
Because each process takes a long time (and requires repeated operations), it was difficult to apply this manufacturing method to a production line.
−12: ・ するr峠の重類によるヒ゛スア4,6−
ジピラゾリルピリミジンの製法上における、使用する溶
媒の種類によるビスアゾリルピリミジン誘導体の収率に
与える影響を高速クロマトグラフィー(HPLCカラム
:μmBONDASP−)IERE 5 p C18、
流速: O−5ml/min、移動相:メタノールと水
(70: 30)の混液)を用いて調べた。-12: ・Heavy damage caused by heavy substances at Suru Pass 4,6-
In the production process of dipyrazolylpyrimidine, the influence of the type of solvent used on the yield of bisazolylpyrimidine derivatives was investigated by high performance chromatography (HPLC column: μm BONDASP-) IERE 5 p C18,
The investigation was conducted using a flow rate of 0-5 ml/min and a mobile phase of a mixture of methanol and water (70:30).
拭験方広二
室温下、反応開始後、30分、1時間、2時間、3時間
、4時間、6時間、8時間、及び10時間目の反応液1
0μlを移動相溶媒で100倍希釈して、その2μlを
HP LCカラムに注入し、生成しているビスアゾリル
ピリミジン誘導体の100%収率に対する生成割合(%
)を算出した。Reaction solution 1 at 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, and 10 hours after the start of the reaction at room temperature
0 μl was diluted 100 times with a mobile phase solvent, 2 μl of it was injected into an HP LC column, and the production ratio (%
) was calculated.
拭果上
・ピリミジン誘導体として、
4.6−ジク00ピリミジン2.OOg (0,013
4mol)・ピラゾール 2.2h (0,
0335mol)・相間移動触媒として、
TBAB (臭化テトラ−n−ブチルアンモニウム)0
.43g (0,0013mol)
・K OH2,21g (0,0335mol)・溶媒
40m1
■狂詰又上
各種溶媒ごとの4,6−ジピラゾリルピリミジン生成効
果の試験結果を下記第1表に示した。As a pyrimidine derivative, 4.6-diku00pyrimidine2. OOg (0,013
4mol)・Pyrazole 2.2h (0,
0335 mol)・TBAB (tetra-n-butylammonium bromide)0 as a phase transfer catalyst
.. 43 g (0,0013 mol) ・KOH2, 21 g (0,0335 mol) ・Solvent 40 ml ■Kazume Mata The test results of the 4,6-dipyrazolylpyrimidine production effect of each solvent are shown in Table 1 below.
上記試験結果からも明らかなように、アセトニトリルを
溶媒として用いた場合において、速やかに4,6−ジピ
ラゾリルピリミジンが生成されており、アセトニトリル
が本発明の製法においては好適な溶媒であることが判明
した。As is clear from the above test results, when acetonitrile is used as a solvent, 4,6-dipyrazolylpyrimidine is rapidly produced, indicating that acetonitrile is a suitable solvent for the production method of the present invention. did.
4.6−ジピラゾリルピリミジンの製法上における、使
用する相間移動触媒の種類によるビスアゾリルピリミジ
ン誘導体の収率に与える影響を高速クロマトグラフィー
(HPLCカラム:μmBONDASPHERE 5
u C18、流速: 0.5 ml/min、移動相:
メタノールと水(70: 30)の混液)を用いて調べ
た。4. In the production process of 6-dipyrazolylpyrimidine, the influence of the type of phase transfer catalyst used on the yield of bisazolylpyrimidine derivatives was investigated by high performance chromatography (HPLC column: μm BONDASPHERE 5
u C18, flow rate: 0.5 ml/min, mobile phase:
The results were investigated using a mixture of methanol and water (70:30).
拭辰方豊工 実施例2に同じ。Toyoko Futatsukata Same as Example 2.
拭里二
・ピリミジン誘導体として、
4.6−ジクロロピリミジン2.00g (0,013
4mol)・ピラゾール 2.28g (
0,0335mol)・相間移動触媒 それぞ
れ0.0013mol−K OH2,21g (0,0
335mo+)・溶媒として、ベンゼン 40m1
拭Y猪果工
各種相間移動触媒ごとの4.6−ジピラゾリルビリミジ
ン生成効果の試験結果を下記第2表に示した。As a pyrimidine derivative, 2.00 g of 4,6-dichloropyrimidine (0,013
4mol)・Pyrazole 2.28g (
0,0335 mol)・Phase transfer catalyst 0.0013 mol-K OH2,21g (0,0
335 mo+) Benzene 40 ml as a solvent Test results of the 4,6-dipyrazolylbyrimidine production effect of various phase transfer catalysts are shown in Table 2 below.
注)#l:臭化テトラーn−ブチルアンモニウム+12
:硫酸水素テトラ−n−ブチルアンモニウム
#3:塩化テトラーn−ブチルアンモニウム14:臭化
テトラ−n−ヘキシルアンモニウム
上記試験結果より、臭化テトラ−n−ブチルアンモニウ
ムが他の三者と比較して、極めて効率よく目的物質の4
,6−ジビラゾリルビリミジンを生成しており、該触媒
が本発明の製法においては好適であることがうかがえる
。Note) #l: Tetra n-butylammonium bromide +12
: Tetra-n-butylammonium hydrogen sulfate #3: Tetra-n-butylammonium chloride 14: Tetra-n-hexylammonium bromide From the above test results, tetra-n-butylammonium bromide is superior to the other three. , very efficiently target substance 4
, 6-dibyrazolylbyrimidine was produced, indicating that this catalyst is suitable for the production method of the present invention.
4.6−ジピラゾリルピリミジンの製法上における、各
種反応温度条件下におけるビスアゾリルピリミジン誘導
体の収率に与える影響を高速クロマトグラフィー(HP
LC力ラム二う−BONOA−SPHERE 5 u
C18、流速: 0.5 ml/min、移動相:メタ
ノールと水(70: 30)の混液)を用いて調べた。4. In the production process of 6-dipyrazolylpyrimidine, the influence of various reaction temperature conditions on the yield of bisazolylpyrimidine derivatives was investigated using high performance chromatography (HP
LC Power Ram Two-BONOA-SPHERE 5 u
C18, flow rate: 0.5 ml/min, mobile phase: a mixture of methanol and water (70:30)).
芯上び戸り二 実施例2に同じ。core top door ri 2 Same as Example 2.
■東二
・ピリミジン誘導体として、
4.6−ジクロロピリミジン 2.OOg(0,013
4mol)・ピラゾール 2 、28g
(0、0335mo l)・相間移動触媒として、
TBA8 (臭化テトラ−n−ブチルアンモニウム)2
.28g(0,OO13mo+)
・K OH2,21g(0,0335mol)・溶媒と
して、ベンゼン 40m1
拭慧払果工
各種反応温度条件ごとの4.6−ジピラゾリルピリミジ
ン生成効果の試験結果を下記第3表に示した。■As a Toni-pyrimidine derivative, 4.6-dichloropyrimidine 2. OOg(0,013
4mol)・Pyrazole 2, 28g
(0,0335mol)・As a phase transfer catalyst, TBA8 (tetra-n-butylammonium bromide)2
.. 28g (0,OO13mo+) ・K OH2,21g (0,0335mol) ・Benzene as solvent 40ml It was shown to.
下記試験結果より、反応温度を80℃付近にに設定して
反応を行えば、目的物質の4.6一ジピ実施例1に記載
のビスアゾリルピリミジン誘導体(4,6−ジピラゾリ
ルピリミジン)の類似物質を下記手順に従って製造した
。From the test results below, if the reaction temperature is set around 80°C and the reaction is carried out, the target substance is 4.6-dipyrazolylpyrimidine derivative (4,6-dipyrazolylpyrimidine) described in Example 1. A similar substance was prepared according to the following procedure.
有機?8媒のアセトニトリル50m I中に、2.4−
ジクロロピリミジン、4,6−ジクロロピリミジン、も
しくは2,4−ジクロロ−6−メチルピリミジンのいず
れかのジクロロピリミジン(0,05mo+)とピラゾ
ール、イミダゾール、もしくは1,2.4−トリアゾー
ルのいずれかのアゾ−ノロ0.12mol)を室温で溶
解した溶液に水酸化カリウム(0,12m01)を加え
、次いで相間移動触媒の臭化テトラ−n−ブチルアンモ
ニウム(0,024mo+)を加え、温度80℃で4時
間撹拌した。得られた反応液を減圧乾固して得られる残
渣にベンゼン200m l、及び水500m1を加えて
2回洗浄し、さらに飽和食塩水300m lを加えて2
回洗浄した。ベンゼン層を無水硫酸ナトリウムで乾燥後
、溶媒を減圧濃縮して得られた残渣をエタノールと水(
1:1体積比)の混液から、再結晶すると反応物質に対
応する下記81重類のビスアゾリルピリミジン誘導体が
得られた。Organic? In 50 mI of acetonitrile, 2.4-
Dichloropyrimidine (0,05mo+) of dichloropyrimidine, 4,6-dichloropyrimidine, or 2,4-dichloro-6-methylpyrimidine and azo of pyrazole, imidazole, or 1,2,4-triazole Potassium hydroxide (0.12 mol) was dissolved at room temperature, and then tetra-n-butylammonium bromide (0.024 mol) as a phase transfer catalyst was added. Stir for hours. The resulting reaction solution was dried under reduced pressure, and the resulting residue was washed twice by adding 200 ml of benzene and 500 ml of water, and then washed twice with 300 ml of saturated brine.
Washed twice. After drying the benzene layer over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure and the resulting residue was mixed with ethanol and water (
When recrystallized from the mixed solution (1:1 volume ratio), the following 81-class bisazolylpyrimidine derivative corresponding to the reactant was obtained.
すなわち、3種のジクロロピリミジン及び3種のアゾー
ルそれぞれを逐次組み合わすことにより実施例1に記載
の4.6−ジピラゾリルピリミジン以外の下記8種類の
ビスアゾリルピリミジン誘導体を上記操作手順に従って
製造したのである。That is, by sequentially combining three types of dichloropyrimidines and three types of azoles, the following eight types of bisazolylpyrimidine derivatives other than 4,6-dipyrazolylpyrimidine described in Example 1 were produced according to the above operating procedure. It is.
(1) 4.6−ジイミダゾリルピリミジン・ 4.
6−ジクロロピリミジン
・イミダゾール
生 8の 多“旨と ニー
淡黄色粉末結晶 (収率72%)
N M R(DMSO−d6)、δ:
8.99 (IH,d、 J=1.0Hz)、8.72
(2H,d、 J=1.0Hz)、8.21 (II
L d、 J=1.0)lz)、8.09 (2H,d
、 J=0.7Hz)、7.22 (211,d、 J
=1.0IIz)、立案分析:C6゜H−IIN6(2
12,21)として、計算値(%):
C,56,60; H,3,80; N、 39.
60分析値(%):
C,56,62; H,’ 3.89; N、
39.49M5 (m/z) : 212 (M’
)。(1) 4.6-diimidazolylpyrimidine 4.
6-dichloropyrimidine imidazole raw 8 polyester pale yellow powder crystals (yield 72%) NMR (DMSO-d6), δ: 8.99 (IH, d, J=1.0Hz), 8.72
(2H, d, J=1.0Hz), 8.21 (II
L d, J=1.0)lz), 8.09 (2H, d
, J=0.7Hz), 7.22 (211,d, J
=1.0IIz), planning analysis: C6゜H-IIN6(2
12,21), calculated values (%): C, 56,60; H, 3,80; N, 39.
60 analysis value (%): C, 56,62; H,'3.89; N,
39.49M5 (m/z): 212 (M'
).
(2) 4.6−ジ(L2,4− )リアヅリル)ピ
リミジン・ 4.6−ジクロロピリミジン
・ 1,2.4− )リアゾール
生成物 の形態と収率
淡黄色針状結晶 (収率75%)
Σ琶R(DMSO−d6)、δ:
9.56 (211,s)、
9.15 (ltl、 d、 J=1.0tlz)、8
.44 (2H,s)、
8.12 (LH,d、 J=1.0)1z)、元木分
販: Ca H6N8(214,18) として、計算
値(%):
C,44,86; H,2,82,N、 52.32
分析値(%):
C,44,56; H,2,95; N、 52.
49M5 (m/z) : 214 (M゛)+数
点: 222−223℃
(3) 2.4−ジピラゾリルピリミジン・ 2,4
−ジクロロピリミジン
・ピラゾール
生 の多しと ;
無色針状結晶 (収率93%)
N M R(DMSO−d、)、δ:
8.87 (3H,m)、
7.97 (III、 d、 J=1.0tlz)、7
.89 (LH,d、 J=1.0Hz)、7.80
(ill、 d、 J=2.7Hz)、6.70 (L
H,d、 J=1.0Hz)、(i、62 (III、
d、 J=1.0Ilz)、元1析: C,6H,N
、 (212,21)として、計算値(%):
C,56,60; H,3,80; N、 39.
60分析値(%):
C,56,59; H,3,77; N、 39.
32M5 (m/z) : 212 (M” )。(2) Morphology and yield of 4,6-di(L2,4-)riazulyl)pyrimidine/4,6-dichloropyrimidine/1,2,4-)lyazole product Pale yellow needle crystals (yield 75%) ) Σ琶R(DMSO-d6), δ: 9.56 (211,s), 9.15 (ltl, d, J=1.0tlz), 8
.. 44 (2H, s), 8.12 (LH, d, J=1.0) 1z), Motoki distribution: Ca H6N8 (214,18), calculated value (%): C, 44,86; H, 2, 82, N, 52.32
Analysis value (%): C, 44,56; H, 2,95; N, 52.
49M5 (m/z): 214 (M゛) + several points: 222-223℃ (3) 2.4-dipyrazolylpyrimidine 2,4
- Dichloropyrimidine pyrazole raw material; colorless needle crystals (yield 93%) NMR (DMSO-d,), δ: 8.87 (3H, m), 7.97 (III, d, J=1.0tlz), 7
.. 89 (LH, d, J=1.0Hz), 7.80
(ill, d, J=2.7Hz), 6.70 (L
H, d, J=1.0Hz), (i, 62 (III,
d, J=1.0Ilz), element 1 analysis: C, 6H, N
, (212,21), calculated value (%): C, 56,60; H, 3,80; N, 39.
60 Analysis value (%): C, 56,59; H, 3,77; N, 39.
32M5 (m/z): 212 (M”).
散点: 147−148℃
(4) 2.4−ジイミダゾリルピリミジン・ 2,
4−ジクロロピリミジン
・イミダゾール
生J のニ能と 率
淡赤色粉末結晶 (収率88%)
N M R(DMSO−d6)、δ:
8.90 (2H,m)、
8.74 (LH,s)、
8.19 (IH,s)、
8.07 (IIL s)、
7.81 (III、 d、 J=1.0IIz)、7
.20 (1tL s)、
7.14 (LH,s)、
兄Q : C+oHe N& (212,21)とし
て、計算値(%):
C,56,60; H,、3,80; N、 39
.60分析値(%):
C,56,71; H,3,85; N、 39.
45M5 (m/z) : 212 (M” )。Scattered points: 147-148℃ (4) 2.4-diimidazolylpyrimidine 2,
Pale red powder crystals (yield 88%) of 4-dichloropyrimidine imidazole raw J NMR (DMSO-d6), δ: 8.90 (2H, m), 8.74 (LH, s ), 8.19 (IH,s), 8.07 (IIL s), 7.81 (III, d, J=1.0IIz), 7
.. 20 (1tL s), 7.14 (LH,s), Brother Q: C+oHe N& (212,21), calculated value (%): C, 56,60; H, 3,80; N, 39
.. 60 Analysis value (%): C, 56,71; H, 3,85; N, 39.
45M5 (m/z): 212 (M”).
n立: 138−140 ℃
・ 2.4−ジクロロピリミジン
・ L2,4− トリアゾール
生 のニー詭と収〉・・
無色粉末結晶 (収率71%)
NMR(DMSO−d6)、δ:
9.78 (III、 s)、
9.74 (11(、s)、
9.09 (11(、d、 J=1.0Hz)、8.4
5 (IH,s)、
8.35 (IH,s)、
7.90 (18,d、 J=1.011z)、兄i分
捉:C自H−,N、 (214,18)として、計算
値(%):
C,44,86; H,2,82: N、 52.
32分析値(%):
C,44,86; I(+’ 2.83; N、
51.69M5 (m/z) : 214 (M
’ )。Temperature: 138-140 °C 2,4-dichloropyrimidine L2,4-triazole raw knee and yield...Colorless powder crystals (yield 71%) NMR (DMSO-d6), δ: 9.78 (III, s), 9.74 (11(,s), 9.09 (11(,d, J=1.0Hz), 8.4
5 (IH, s), 8.35 (IH, s), 7.90 (18, d, J=1.011z), as Calculated value (%): C, 44,86; H, 2,82: N, 52.
32 analysis value (%): C, 44,86; I(+'2.83; N,
51.69M5 (m/z): 214 (M
).
散点: 270−271 ”C
02,4−ジクロロ−6−メチルピリミジン・ピラゾー
ル
生 物でのり態と収゛
無色針状結晶 (収率95%)
N M R(DMSO−d6)、δ:
8.84 (2H,m)、
7.95 (LH,s)、
7.86 (III、 s)、
7.71 (IH,s)、
6.68 (18,m)、
6.60 (IH,m)、
2.60 (3tl、 s)、
丘i芳頁: C,、H,。N& (226,23)と
して、計算値(%):
C,58,40; H,4,46; N、 37.
15分析値(%):
C,58,54; H,4,35; N、 36.
62M5 (m/ z) : 226 (M”
)+鉱: 115−118 ℃
・ 2,4〜ジクロロ−6−メチルピリミジン・イミダ
ゾール
の多能と ;・
無色粉末結晶 (収率89%)
N M R(DMSO−d6)、δ:
8.83 (IH,S)、
8.71 (IH,s)、
8.15 (Ill、 S)、
8.04 (ltl、 s)、
7.74 (18,s)、
7.19 (LH,s)、
7.13 (18,S)、
2.57 (3H,s)、
1分tJ?:C,,H,oN6 (226,23)と
して、計算値(%):
C,58,40; H,4,46; N+ 37.
15分析値(%):
C,58,48; H,4,47; N、 37.
13M5 (m/z) : 226 (M” )。Scattered points: 270-271 "C 02,4-dichloro-6-methylpyrimidine pyrazole Form and aggregation in living organisms Colorless needle crystals (yield 95%) NMR (DMSO-d6), δ: 8 .84 (2H, m), 7.95 (LH, s), 7.86 (III, s), 7.71 (IH, s), 6.68 (18, m), 6.60 (IH, m), 2.60 (3tl, s), Calculated value (%) as: C,, H,.N & (226,23): C, 58,40; H, 4,46; N , 37.
15 Analysis value (%): C, 58,54; H, 4,35; N, 36.
62M5 (m/z): 226 (M”
) + ore: 115-118 ℃ ・ 2,4-dichloro-6-methylpyrimidine imidazole multipotency ; ・ colorless powder crystal (yield 89%) NMR (DMSO-d6), δ: 8.83 (IH,S), 8.71 (IH,s), 8.15 (Ill, S), 8.04 (ltl, s), 7.74 (18,s), 7.19 (LH,s) , 7.13 (18,S), 2.57 (3H,s), 1 minute tJ? :C,,H,oN6 (226,23), calculated value (%): C, 58,40; H, 4,46; N+ 37.
15 Analysis value (%): C, 58,48; H, 4,47; N, 37.
13M5 (m/z): 226 (M”).
殿点: 183−184℃
(8) 2.4−ジ(1,2,4−)リアゾリル −
6−メチ土ピリミジン
困クロロピリミジン びア・ゾール云式薬・ 2,4−
ジクロロ−6−メチルピリミジン・ L2,4− トリ
アゾール
生 のtと 率
淡黄色粉末結晶 (収率74%)
NMR(DMSO−d6)、δ:
9.74 (ltl、 s)、
9.70 (IL s)、
8.42 (IH,s)、
8.32 (IFI、 s)、
7.81 (01,s)、
2.67 (3)1. s)、
云↑立捉: Cq He No (228,21)と
して、計算値(%):
C,47,36; H,3,53; N、 49.
10分析値(%):
C,47,55; H,3,54; N、 49.
08M5 (m/z) : 228 (M” )。Temperature point: 183-184℃ (8) 2.4-di(1,2,4-)riazolyl -
6-methoxypyrimidine-chloropyrimidine biazole drug, 2,4-
Dichloro-6-methylpyrimidine/L2,4-triazole raw t and ratio pale yellow powder crystals (yield 74%) NMR (DMSO-d6), δ: 9.74 (ltl, s), 9.70 (IL s), 8.42 (IH, s), 8.32 (IFI, s), 7.81 (01, s), 2.67 (3)1. s), 云↑ rise: Cq He No (228,21), calculated value (%): C, 47,36; H, 3,53; N, 49.
10 Analysis value (%): C, 47,55; H, 3,54; N, 49.
08M5 (m/z): 228 (M”).
n点: 220−223℃
(効果)
本発明の製造方法においては、ピリミジン誘導体とアゾ
ール誘導体を適当な溶媒中に混和し、これに苛性アルカ
リ(例えば、KO)I)及び相間移動触媒を加えること
によって反応が速やかに開始され、室温の条件下で数時
間の内に反応は完結する。Point n: 220-223°C (Effect) In the production method of the present invention, a pyrimidine derivative and an azole derivative are mixed in a suitable solvent, and a caustic alkali (e.g., KO) and a phase transfer catalyst are added thereto. The reaction is rapidly initiated and completed within several hours at room temperature.
なお、反応時間の短縮は、溶媒、反応温度、及び相間移
動触媒等を考慮・選択することによって容易に達成され
うるちのである。Note that shortening of the reaction time can be easily achieved by considering and selecting the solvent, reaction temperature, phase transfer catalyst, etc.
また、副生成物(モノヒドロキシピリミジン体)の生成
は従来法に比べ激減し、反応液は澄明で黄色を呈し、か
つ目的物質のビスアゾリルピリミジン誘導体の収率、及
び純度は大幅に向上する。In addition, the production of by-products (monohydroxypyrimidine derivatives) is drastically reduced compared to conventional methods, the reaction solution is clear and yellow, and the yield and purity of the target substance, the bisazolylpyrimidine derivative, are significantly improved. .
さらに、本発明は製造コストの面からも好ましいもので
ある。例えば、溶媒にベンゼンを採用すれば、反応銘了
後の反応釜に水洗用の水を加え、撹拌下で充分水洗すれ
ばピリミジン誘導体とアゾール誘導体、ならびに副生成
物(モノヒドロキシピリミジン体)も水洗で除くことが
でき、最終的にベンゼンを減圧留去した残渣から高純度
の目的物質のビスアゾリルピリミジン誘導体が得られる
という精製工程での利点をも導くものである。Furthermore, the present invention is preferable from the viewpoint of manufacturing cost. For example, if benzene is used as the solvent, pyrimidine derivatives, azole derivatives, and by-products (monohydroxypyrimidine derivatives) can also be washed away by adding water for washing to the reaction vessel after the reaction is complete, and thoroughly washing with water while stirring. This also brings about the advantage in the purification process that a high purity bisazolylpyrimidine derivative, which is the target substance, can be obtained from the residue obtained by distilling off benzene under reduced pressure.
すなわち、本発明は、短時間に、効率よく、安全に、し
かも簡便にビスアゾリルピリミジン誘導体を得られると
いう、すくれた作用・効果を奏するビスアゾリルピリミ
ジン誘導体の製造方法を提供するものである。That is, the present invention provides a method for producing bisazolylpyrimidine derivatives that exhibits excellent actions and effects, such that bisazolylpyrimidine derivatives can be obtained efficiently, safely, and simply in a short time. be.
Claims (11)
水素原子またはメチル基である〕で表されるピリミジン
誘導体と、アゾール誘導体とを、化学式〔II〕: ▲数式、化学式、表等があります▼[II] 〔式中、R_1、R_2、R_3、及びR_4は、アル
キル基、アラルキル基、または窒素原子を伴う複素環で
あり、A^■はアニオンである〕で表される相間移動触
媒の存在下、有機溶媒中で反応させることを特徴とする 化学式〔III〕: ▲数式、化学式、表等があります▼[III] 〔式中、X及びYは一方がNで他方がCHであり、Zは
水素原子またはメチル基であり、Sはアゾリル基である
〕で表されるビスアゾリルピリミジン誘導体の製造方法
。(1) Chemical formula [I]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, one of X and Y is N and the other is CH, and Z is a hydrogen atom or a methyl group.] The represented pyrimidine derivative and azole derivative are represented by the chemical formula [II]: ▲There are numerical formulas, chemical formulas, tables, etc.▼ [II] [In the formula, R_1, R_2, R_3, and R_4 are an alkyl group, an aralkyl group, or a heterocycle with a nitrogen atom, and A^■ is an anion] Chemical formula [III] characterized in that the reaction is carried out in an organic solvent in the presence of a phase transfer catalyst represented by: ▲ Numerical formula, chemical formula, There are tables, etc. ▼ [III] Bisazolyl represented by [In the formula, one of X and Y is N and the other is CH, Z is a hydrogen atom or a methyl group, and S is an azolyl group] A method for producing a pyrimidine derivative.
ロトン性極性溶媒のいずれかである請求項1に記載のビ
スアゾリルピリミジン誘導体の製造方法。(2) The method for producing a bisazolylpyrimidine derivative according to claim 1, wherein the organic solvent is either an aromatic hydrocarbon or an aprotic polar solvent.
に記載のビスアゾリルピリミジン誘導体の製造方法。(3) Claim 2, wherein the aromatic hydrocarbon is benzene.
A method for producing a bisazolylpyrimidine derivative as described in .
メチルエチルケトン、もしくはテトラヒドロフランのい
ずれかである請求項2に記載のビスアゾリルピリミジン
誘導体の製造方法。(4) The aprotic polar solvent is acetonitrile,
The method for producing a bisazolylpyrimidine derivative according to claim 2, which is either methyl ethyl ketone or tetrahydrofuran.
である請求項1から4のいずれかに記載のビスアゾリル
ピリミジン誘導体の製造方法。(5) The method for producing a bisazolylpyrimidine derivative according to any one of claims 1 to 4, wherein the pyrimidine derivative is bischloropyrimidine.
ピリミジン、4,6−ジクロロピリミジン、もしくは2
,4−ジクロロ−6−メチルピリミジンのいずれかであ
る請求項5に記載のビスアゾリルピリミジン誘導体の製
造方法。(6) The bischloropyrimidine is 2,4-dichloropyrimidine, 4,6-dichloropyrimidine, or
, 4-dichloro-6-methylpyrimidine, the method for producing a bisazolylpyrimidine derivative according to claim 5.
ル、もしくは1,2,4−トリアゾールのいずれかであ
る請求項1から6のいずれかに記載のビスアゾリルピリ
ミジン誘導体の製造方法。(7) The method for producing a bisazolylpyrimidine derivative according to any one of claims 1 to 6, wherein the azole derivative is any one of pyrazole, imidazole, or 1,2,4-triazole.
請求項1から7のいずれかに記載のビスアゾリルピリミ
ジン誘導体の製造方法。(8) The method for producing a bisazolylpyrimidine derivative according to any one of claims 1 to 7, wherein the phase transfer catalyst is a quaternary ammonium salt.
チルアンモニウム、硫酸水素テトラ−n−ブチルアンモ
ニウム、塩化テトラ−n−ブチルアンモニウム、もしく
は臭化テトラ−n−ヘキシルアンモニウムのいずれかで
ある請求項8に記載のビスアゾリルピリミジン誘導体の
製造方法。(9) The quaternary ammonium salt is any one of tetra-n-butylammonium bromide, tetra-n-butylammonium hydrogen sulfate, tetra-n-butylammonium chloride, or tetra-n-hexylammonium bromide. A method for producing a bisazolylpyrimidine derivative according to claim 8.
−ジピラゾリルピリミジン、4,6−ジイミダゾリルピ
リミジン、4,6−ジ(1,2,4−トリアゾリル)ピ
リミジン、2,4−ジピラゾリルピリミジン、2,4−
ジイミダゾリルピリミジン、2,4−ジ(1,2,4−
トリアゾリル)ピリミジン、2,4−ジピラゾリル−6
−メチルピリミジン、2,4−ジイミダゾリル−6−メ
チルピリミジン、もしくは2,4−ジ(1,2,4−ト
リアゾリル)−6−メチルピリミジンのいずれかである
請求項1から9のいずれかに記載のビスアゾリルピリミ
ジン誘導体の製造方法。(10) The bisazolylpyrimidine derivative is 4,6
-dipyrazolylpyrimidine, 4,6-diimidazolylpyrimidine, 4,6-di(1,2,4-triazolyl)pyrimidine, 2,4-dipyrazolylpyrimidine, 2,4-
Diimidazolylpyrimidine, 2,4-di(1,2,4-
triazolyl)pyrimidine, 2,4-dipyrazolyl-6
-Methylpyrimidine, 2,4-diimidazolyl-6-methylpyrimidine, or 2,4-di(1,2,4-triazolyl)-6-methylpyrimidine, according to any one of claims 1 to 9. A method for producing the bisazolylpyrimidine derivative described.
で行われることを特徴とする請求項1から10のいずれ
かに記載のビスアゾリルピリミジン誘導体の製造方法。(11) The method for producing a bisazolylpyrimidine derivative according to any one of claims 1 to 10, wherein the reaction is carried out at a reaction temperature of 50°C to 80°C.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2122112A JPH0710859B2 (en) | 1990-05-10 | 1990-05-10 | Process for producing bisazolylpyrimidine derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2122112A JPH0710859B2 (en) | 1990-05-10 | 1990-05-10 | Process for producing bisazolylpyrimidine derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH0418090A true JPH0418090A (en) | 1992-01-22 |
JPH0710859B2 JPH0710859B2 (en) | 1995-02-08 |
Family
ID=14827937
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2122112A Expired - Lifetime JPH0710859B2 (en) | 1990-05-10 | 1990-05-10 | Process for producing bisazolylpyrimidine derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0710859B2 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6339875A (en) * | 1986-08-05 | 1988-02-20 | Nissin Food Prod Co Ltd | Pyrimidine derivative |
-
1990
- 1990-05-10 JP JP2122112A patent/JPH0710859B2/en not_active Expired - Lifetime
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6339875A (en) * | 1986-08-05 | 1988-02-20 | Nissin Food Prod Co Ltd | Pyrimidine derivative |
Also Published As
Publication number | Publication date |
---|---|
JPH0710859B2 (en) | 1995-02-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4698945B2 (en) | Ionic liquid | |
US7759497B2 (en) | Synthesis of diaryl pyrazoles | |
CN105218540B (en) | A kind of preparation method of 3 thiocarbamoyl imidazoles of C simultaneously [1,2 a] pyridine compounds and their | |
EP3941907A1 (en) | A process for synthesis of fipronil | |
JPH0418090A (en) | Production of bisazolylpyrimidine derivative | |
CN113039175B (en) | Method for preparing arylsulfonyl acrylonitrile | |
KR101543667B1 (en) | Optically 2-amino triazole derivatives and preparation method thereof | |
Taib et al. | Click approach to the novel 1, 2, 3-triazolium phosphotungstate organic–inorganic hybrids for the highly promoted synthesis of spirooxindoles | |
RU2248347C2 (en) | Method for preparing acylated 1,3-dicarbonylic compounds | |
Taib et al. | Introduction of Click Synthesized Novel Organic-Inorganic Solid Acid Catalysts for Highly Promoted Synthesis of Substituted Xanthenes | |
JP7001699B2 (en) | 4-[(4,5-Dihydro-3-methoxy-4-methyl-5-oxo-1H-1,2,4-triazole-1-yl) carbonyl) sulfamoyl] -5-methylthiophene-3-carboxylic acid How to prepare methyl | |
EP4249468A1 (en) | A method for synthesis of halide salts | |
US4812566A (en) | Process for preparing 1-dodecylazacycloheptane-2-one | |
CN106432182B (en) | Specially the synthetic method of azoles amine intermediate | |
CN114835646A (en) | Imidazole trifluoromethylthio reagent and synthesis application thereof | |
WO2023280638A1 (en) | Vinyl thianthrenium compound, process for its preparation and its use for transferring a vinyl group | |
WO2022176961A1 (en) | Compound and metal complex | |
CN117327047A (en) | Amide ligand and copper-catalyzed synthesis method of aminothiophene compound | |
JPS61143353A (en) | Production of thiocyanate and/or isothiocyanate | |
JP2001302634A (en) | Method of producing quaternary ammonium salt | |
CN113214224A (en) | Preparation method of polysubstituted 3-methylene isoindolinone derivative | |
JPH09241259A (en) | Production of 2-mercaptoimidazole condensed ring compound | |
KR790001309B1 (en) | Process for prepaing uracil derivatives | |
CN108033924A (en) | A kind of method for efficiently preparing 1,2,3- triazole derivatives | |
CN102295497B (en) | Synthesis method of halogenated aromatic hydrocarbon compound with water as solvent |