JP2003171369A - Method for producing 3-substituted-amino-5-hydroxy-1 h-1,2,4-triazole derivative - Google Patents
Method for producing 3-substituted-amino-5-hydroxy-1 h-1,2,4-triazole derivativeInfo
- Publication number
- JP2003171369A JP2003171369A JP2001374751A JP2001374751A JP2003171369A JP 2003171369 A JP2003171369 A JP 2003171369A JP 2001374751 A JP2001374751 A JP 2001374751A JP 2001374751 A JP2001374751 A JP 2001374751A JP 2003171369 A JP2003171369 A JP 2003171369A
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- Japan
- Prior art keywords
- group
- substituted
- hydroxy
- compound
- formula
- Prior art date
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- -1 3-substituted-amino-5-hydroxy-1 h-1,2,4-triazole Chemical class 0.000 title claims abstract description 24
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 10
- DOQQTKLDEQSKIE-UHFFFAOYSA-N silver;isocyanate Chemical compound [Ag+].[N-]=C=O DOQQTKLDEQSKIE-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000002723 alicyclic group Chemical group 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims abstract description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 6
- 125000005018 aryl alkenyl group Chemical group 0.000 claims abstract description 5
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 4
- 125000003147 glycosyl group Chemical group 0.000 claims abstract description 4
- 125000001424 substituent group Chemical group 0.000 claims description 10
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical class N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 7
- 239000003905 agrochemical Substances 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 13
- 238000004896 high resolution mass spectrometry Methods 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229910052946 acanthite Inorganic materials 0.000 description 4
- XUARKZBEFFVFRG-UHFFFAOYSA-N silver sulfide Chemical compound [S-2].[Ag+].[Ag+] XUARKZBEFFVFRG-UHFFFAOYSA-N 0.000 description 4
- 229940056910 silver sulfide Drugs 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical class C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000004566 IR spectroscopy Methods 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 150000003852 triazoles Chemical class 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012847 fine chemical Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000002363 herbicidal effect Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 description 2
- XIOUDVJTOYVRTB-UHFFFAOYSA-N 1-(1-adamantyl)-3-aminothiourea Chemical compound C1C(C2)CC3CC2CC1(NC(=S)NN)C3 XIOUDVJTOYVRTB-UHFFFAOYSA-N 0.000 description 1
- PEWKSNLNCRYBNV-UHFFFAOYSA-N 1-amino-3-(2,4-dichlorophenyl)thiourea Chemical compound NNC(=S)NC1=CC=C(Cl)C=C1Cl PEWKSNLNCRYBNV-UHFFFAOYSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000009835 boiling Methods 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
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000005648 plant growth regulator Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000003419 tautomerization reaction Methods 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
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 150000003564 thiocarbonyl compounds Chemical class 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、5-ヒドロキシ-1H-
1,2,4-トリアゾール誘導体の新規な製造方法および該製
法により得られる医薬品や農薬などのファインケミカル
製品の中間原料などとして有用なトリアゾール誘導体に
関する。TECHNICAL FIELD The present invention relates to 5-hydroxy-1H-
The present invention relates to a novel method for producing a 1,2,4-triazole derivative and a triazole derivative useful as an intermediate raw material for fine chemical products such as pharmaceuticals and agricultural chemicals obtained by the method.
【０００２】[0002]
【従来の技術】トリアゾール誘導体の中には除草剤・植
物成長調整剤などとして既に市販されているものも幾つ
かあり、各種の生理活性が期待できる興味深い化合物で
ある。例えば、３−置換アミノ−１，２，４−トリアゾ
ノリン−５−オンのＮ置換体（5-ヒドロキシ-1H-1,2,4-
トリアゾールの５位の酸素原子は、ケト、エノールの互
変異性を生ずる。）、好ましい除草活性を有する化合物
として知られ（特開平５−１１２５３８号公報、特開平
３−１３３９６６号等）、また、同様の化合物は、心臓
血管障害の治療用化合物として知られ（特願平５−５０
６４４３号公報）、カルシウムイオンによって誘発され
る動脈の収縮に対して拮抗作用を有し、冠動脈の血管を
拡張させる効果があるものも報告されている。（J. Me
d. Chem., 1989, 32(3), 562 - 568）一方、これらのト
リアゾール環化合物に関する従来の製造方法は（チオ）
尿素誘導体等をヒドラジンと処理することにより専ら行
われているが、ヒドラジンと長時間加熱するので、副反
応が多く、目的とする化合物の収率の低下を招き、効率
よく得ることは難しい。また、3および5-位に導入でき
る置換基の種類にも極めて限定されるため、現在までに
合成されているトリアゾール誘導体の種類は極めて少な
い。2. Description of the Related Art Some of the triazole derivatives are already on the market as herbicides and plant growth regulators, and they are interesting compounds that can be expected to have various physiological activities. For example, N-substituted 3-substituted amino-1,2,4-triazonoline-5-one (5-hydroxy-1H-1,2,4-
The oxygen atom at the 5-position of triazole causes tautomerism of keto and enol. ), A compound having a preferable herbicidal activity (JP-A-5-112538, JP-A-3-133966, etc.), and a similar compound is known as a compound for treatment of cardiovascular disorders (Japanese Patent Application No. Hei 10 (1999) -135242). 5-50
No. 6443), it is also reported that it has an antagonistic effect on the contraction of arteries induced by calcium ions and has an effect of expanding the blood vessels of coronary arteries. (J. Me
d. Chem., 1989, 32 (3), 562-568) On the other hand, the conventional manufacturing method for these triazole ring compounds is (thio)
It is exclusively carried out by treating a urea derivative or the like with hydrazine, but since it is heated with hydrazine for a long time, there are many side reactions, which leads to a decrease in the yield of the target compound and is difficult to obtain efficiently. In addition, since the types of substituents that can be introduced at the 3- and 5-positions are also extremely limited, the types of triazole derivatives that have been synthesized so far are extremely small.
【０００３】[0003]
【発明が解決しようとする課題】 本発明の課題は、従
来とは全く異なる新規な製造方法で、容易に入手できる
化合物を原料として用い、簡便な操作で効率よく3-置換
アミノ-5-ヒドロキシ-1H-1,2,4-トリアゾール誘導体を
製造する方法を提供するとともに、該方法により、有用
な新規化合物を得ることを目的とするものである。The problem to be solved by the present invention is a novel production method which is completely different from the conventional one, and a compound which is easily available is used as a raw material, and a 3-substituted amino-5-hydroxy group is efficiently produced by a simple operation. The present invention aims to provide a method for producing a -1H-1,2,4-triazole derivative, and to obtain a useful novel compound by the method.
【０００４】[0004]
【課題を解決するための手段】本発明者らは前記の課題
に取り組むべく、鋭意研究を重ねた結果、チオカルボニ
ル化合物の硫黄は銀のような金属イオンによって容易に
脱硫することを見いだし、この知見に基づいて本発明を
完成するに至った。As a result of intensive studies to solve the above problems, the present inventors have found that sulfur of a thiocarbonyl compound is easily desulfurized by a metal ion such as silver. The present invention has been completed based on the findings.
【０００５】すなわち、本発明は、下記一般式（I）That is, the present invention provides the following general formula (I)
【化１】
（ただし、式中のＲは、アリール基、アルキル基、アル
ケニル、アラルキル基、アリールアルケニル基、脂環式
基、複素環式基、またはグリコシル基を表すが、これら
置換基は置換されていてもよい。）で表される4-置換チ
オセミカルバジド類と、シアン酸銀（ＡｇＯＣＮ）と反
応させることを特徴とする、下記一般式（II）[Chemical 1] (However, R in the formula represents an aryl group, an alkyl group, an alkenyl, an aralkyl group, an arylalkenyl group, an alicyclic group, a heterocyclic group, or a glycosyl group, and these substituents may be substituted. A 4-substituted thiosemicarbazide represented by the following general formula (II), characterized by reacting with silver cyanate (AgOCN)
【化２】
（式中Ｒは前記と同じ意味を持つ）で表される3-置換ア
ミノ-5-ヒドロキシ-1H-1,２,4-トリアゾール誘導体の製
造方法に関するものであり、また、該方法により得られ
た、上記一般式（II）で表される化合物中、Ｒがアリー
ル基、アルキル基、アラルキル基、または脂環式基（但
し、これらは置換されていてもよい。）である新規化合
物に関するものである。[Chemical 2] The present invention relates to a method for producing a 3-substituted amino-5-hydroxy-1H-1,2,4-triazole derivative represented by the formula (wherein R has the same meaning as described above), and is obtained by the method. In addition, the present invention relates to a novel compound in which R is an aryl group, an alkyl group, an aralkyl group, or an alicyclic group (which may be substituted) among the compounds represented by the general formula (II). Is.
【０００６】[0006]
【発明の実施の形態】 本発明においては、原料の一つ
として、前記一般式（Ｉ）で表される４−置換チオセミ
カルバジド化合物が用いられる。この一般式（Ｉ）にお
いて、Ｒとしては、アリール基、アルキル基、アルケニ
ル基、アラルキル基、アリールアルケニル基脂環式基、
複素環式基またはグリコシル基が挙げられる。これら置
換基を具体的に示すと、アリール基としては、例えば、
フェニル基、ナフチル基、アズレニル基、フェナントレ
ン基、ビフェニル基等が挙げられ、アルキル基として
は、メチル基、エチル基、ブチル基、ラウリル基、セチ
ル基、ステアリル基等が挙げられ、アルケニル基として
は、例えば、ビニル基、プロペニル基、ブチニル基、へ
キセニル基等が挙げられ、アラルキル基としては、アリ
ールアルケニル基としては、スチリル基等が挙げられ
る。例えば、ベンジル基、フェニルエチル基、クミル
基、シンナミル基、トリチル基等が挙げられ、脂環式基
としては、シクロプロピル基、シクロペンチル基、シク
ロヘキシル基、アダマンチル基等が挙げられ、複素環式
基としては、フリル基、チエニル基、ピリジル基、キノ
リル基、チアゾリル基、オキサゾリル基、カルバゾリル
基等が挙げられ、グリコシル基としては、例えば、グル
コシル基、マンノシル基、リボフラノシル基、デオキシ
リボフラノシル基、あるいはこれらの誘導体が挙げられ
る。また、これら置換基は例えば、アルコキシル基、エ
ステル基、ニトロ基、シアノ基、複素環式基、ハロゲン
原子、ジ置換アミノ基、ジ置換カルバモイル基、アシル
基、アロイル基、チオアルコキシル基、ジ置換スルファ
モイル基等により置換されていてもよく。置換基が目的
とする反応に対して不活性であるならば、上記以外の置
換基でもよい。さらに、置換基が目的とする反応に対し
て活性であっても、例えばシリル基、アシル基等の周知
の保護基で保護しておき、反応終了後該保護基を脱離さ
せてもよい。また、それらの置換基を、一つ又は複数個
有してもよいし、一種又は複数の種類の置換基を有して
もよい。本発明の製造方法は、極めて汎用性に富み、原
料化合物の種類には本来限定されない。本発明で用いる
原料、４−置換チオセミカルバジド誘導体の入手に関し
ては、対応するイソチオシアナート類をヒドラジンと処
理する方法が最も簡便で、収率よく得られる。BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, a 4-substituted thiosemicarbazide compound represented by the above general formula (I) is used as one of the raw materials. In this general formula (I), R is an aryl group, an alkyl group, an alkenyl group, an aralkyl group, an arylalkenyl group alicyclic group,
Heterocyclic or glycosyl groups may be mentioned. When these substituents are specifically shown, examples of the aryl group include:
Examples thereof include a phenyl group, a naphthyl group, an azulenyl group, a phenanthrene group, and a biphenyl group.Examples of the alkyl group include a methyl group, an ethyl group, a butyl group, a lauryl group, a cetyl group, and a stearyl group. Examples thereof include a vinyl group, a propenyl group, a butynyl group, and a hexenyl group. Examples of the aralkyl group include an arylalkenyl group and a styryl group. For example, a benzyl group, a phenylethyl group, a cumyl group, a cinnamyl group, a trityl group and the like, and the alicyclic group includes a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, an adamantyl group and the like, a heterocyclic group. Examples of the furyl group, thienyl group, pyridyl group, quinolyl group, thiazolyl group, oxazolyl group, carbazolyl group, etc. These derivatives are mentioned. Further, these substituents are, for example, an alkoxyl group, an ester group, a nitro group, a cyano group, a heterocyclic group, a halogen atom, a disubstituted amino group, a disubstituted carbamoyl group, an acyl group, an aroyl group, a thioalkoxyl group, a disubstituted group. It may be substituted with a sulfamoyl group or the like. Substituents other than the above may be used as long as the substituents are inert to the intended reaction. Furthermore, even if the substituent is active for the intended reaction, it may be protected with a known protecting group such as a silyl group or an acyl group and the protecting group may be eliminated after the reaction is completed. Moreover, you may have one or more of those substituents and may have one or more types of substituents. The production method of the present invention is extremely versatile and is not essentially limited to the type of raw material compound. Regarding the acquisition of the starting material and the 4-substituted thiosemicarbazide derivative used in the present invention, the method of treating the corresponding isothiocyanates with hydrazine is the simplest and can be obtained in good yield.
【０００７】本発明方法においては、前記４−置換チオ
セミカルバジド化合物にシアン酸銀と反応させるが、有
機溶媒中で実施するのが好ましい。有機溶媒としては、
例えば、アセトニトリル、テトラヒドロフラン、酢酸エ
チル、N,N-ジメチルホルムアミド、ピリジン、クロロベ
ンゼン、トルエンなどが挙げられ、これらは単独で用い
てもよいし、２種以上混合して使用してもよい。In the method of the present invention, the 4-substituted thiosemicarbazide compound is reacted with silver cyanate, but it is preferably carried out in an organic solvent. As an organic solvent,
Examples thereof include acetonitrile, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine, chlorobenzene, and toluene. These may be used alone or in combination of two or more.
【０００８】次に本発明の好適な実施態様について説明
すると、まず有機溶媒中に、前記一般式（Ｉ）で表され
る４−置換チオセミカルバジド類を溶解した後、シアン
酸銀を、チオセミカルバジド化合物１モルに対して通常
２当量以上、好ましくは2.2〜2.5当量の割合で加え、室
温でかき混ぜて反応させる。この際、必要に応じて溶媒
の沸点まで加熱し、反応を促進させてもよい。また、助
剤としてトリエチルアミン、ピリジンなどの三級アミン
を加えることにより、さらに反応を促進させることもで
きる。反応の終了時には反応液が透明になり、黒色の硫
化銀が析出することにより確認できる。反応終了後、析
出した不溶物の硫化銀をろ過などの手段で除去した後、
溶媒を減圧下で留去させる。生成した目的化合物は、水
洗、乾燥した後、必要ならば再結晶あるいはカラムクロ
マトグラフィーなどの方法で精製することができる。ま
た、生成物が弱酸性物質であることを利用して、粗生成
物をアルカリ性の水溶液とし、酢酸などの弱酸で中和し
て再び析出させて精製することもできる。このようにし
て、前記一般式（ＩＩ）で表される3-置換アミノ-5-ヒ
ドロキシ-1H-1,2,4-トリアゾール化合物が得られる。A preferred embodiment of the present invention will be described. First, after dissolving the 4-substituted thiosemicarbazide represented by the general formula (I) in an organic solvent, silver cyanate is added to thiosemicarbazide. The compound is added usually in an amount of 2 equivalents or more, preferably 2.2 to 2.5 equivalents, relative to 1 mol of the compound, and stirred at room temperature to react. At this time, if necessary, the reaction may be promoted by heating to the boiling point of the solvent. The reaction can be further promoted by adding a tertiary amine such as triethylamine or pyridine as an auxiliary agent. It can be confirmed that the reaction liquid becomes transparent at the end of the reaction and black silver sulfide is deposited. After completion of the reaction, the precipitated insoluble silver sulfide is removed by means such as filtration,
The solvent is distilled off under reduced pressure. The produced target compound can be purified by a method such as recrystallization or column chromatography after washing with water and drying. Further, by utilizing the fact that the product is a weakly acidic substance, the crude product can be purified by making it an alkaline aqueous solution, neutralizing it with a weak acid such as acetic acid, and precipitating it again. Thus, the 3-substituted amino-5-hydroxy-1H-1,2,4-triazole compound represented by the general formula (II) is obtained.
【０００９】本発明における反応機構としては、上記一
般式（Ｉ）で表される4-置換チオセミカルバジド化合物
が２当量のシアン酸銀と反応して上記一般式（II）で表
される3-置換アミノ-5-ヒドロキシ-1H-1,2,4-トリアゾ
ール化合物を生成する経路を以下に示すように推定でき
る。As the reaction mechanism in the present invention, the 4-substituted thiosemicarbazide compound represented by the general formula (I) is reacted with 2 equivalents of silver cyanate and represented by the general formula (II) The pathway for producing a substituted amino-5-hydroxy-1H-1,2,4-triazole compound can be estimated as shown below.
【化３】 [Chemical 3]
【００１０】また、該方法により得られた、上記一般式
（II）で表される化合物中、Ｒがアリール基、アルキル
基、アラルキル基または脂環式基（但し、これらは置換
されていてもよい。）である化合物は、新規であり、上
記した３−置換アミノ−１，２，４−トリアゾノリン−
５−オンのＮ置換体からなる除草活性を有する化合物、
あるいは心臓血管障害の治療用化合物を製造する際の有
用な中間体となる。In the compound represented by the above general formula (II) obtained by the method, R is an aryl group, an alkyl group, an aralkyl group or an alicyclic group (provided that these are substituted. Is a novel compound, which is a novel 3-substituted amino-1,2,4-triazonoline-
A compound having herbicidal activity, which comprises a 5-substituted N-substituted compound,
Alternatively, it is a useful intermediate in the production of a compound for treating cardiovascular disorders.
【００１１】以下に、本発明の実施例を示すが、本発明
はこれら実施例に限定されるものではない。なお、下記
実施例において得られた化合物の同定は、赤外吸収スペ
クトル、高分解能質量分析（ＨＲＭＳ）の測定によって
行った。実施例の各生成物においては、赤外吸収スペク
トルにおいて3300〜3100 cm-1付近にNH またはOHの伸縮
振動が、1730〜1530cm-1においてトリアゾール環に帰属
する三本の吸収がそれぞれ観測された。また、高分解能
質量分析でそれぞれの分子式と分子量が確認できた。Examples of the present invention will be shown below, but the present invention is not limited to these examples. The compounds obtained in the following examples were identified by infrared absorption spectrum and high resolution mass spectrometry (HRMS). In each of the products of Examples, stretching vibrations of NH or OH in the vicinity of 3300 to 3100 cm -1 in the infrared absorption spectrum, and three absorptions attributable to the triazole ring were observed at 1730 to 1530 cm -1 , respectively. . In addition, each molecular formula and molecular weight could be confirmed by high resolution mass spectrometry.
【００１２】[0012]
【実施例１】アセトニトリル４ml中に4-(1´-ナフチル)
チオセミカルバジド220 mg (1 mmol)とトリエチルアミ
ン300 mg を溶解した溶液をかき混ぜながら、これにシ
アン酸銀 360 mg (2.4 mmol)を少しずつ加えた。この反
応液を加熱し、還流下で１時間保持した。反応終了後、
析出した硫化銀を熱時に濾別した。濾液中の溶媒を減圧
留去したのち、残留物を１Ｍ水酸化ナトリウム水溶液に
溶解させ、さらに、不溶物を濾別した水溶液に希酢酸水
溶液を加え、中和すると、目的とする生成物が析出し
た。これをフィルターで集め、110℃、減圧下で乾燥さ
せたところ、176 mg(収率78%)の3-(1´-ナフチルアミ
ノ)-5-ヒドロキシ-1H-1,2,4-トリアゾール（ＩＩ-a）を
得た。この化合物の融点（ｍｐ）、赤外吸収スペクトル
（ＩＲ）および、高分解能質量分析（ＨＲＭＳ）の結果
は下記のとおりである。ｍｐ158℃、ＩＲ（cm-1）3364
〜3055 (OH または NH), 1732, 1691, 1626, 1574, 140
2。 HRMS (m / z) C12H10N4Oとしての計算値： 226.0
855。 測定値： 226.0852 (M+)。
得られた化合物の化学構造を以下に示す。Example 1 4- (1'-naphthyl) in 4 ml of acetonitrile
While stirring a solution prepared by dissolving 220 mg (1 mmol) of thiosemicarbazide and 300 mg of triethylamine, 360 mg (2.4 mmol) of silver cyanate was added little by little to this. The reaction was heated and kept under reflux for 1 hour. After the reaction,
The deposited silver sulfide was filtered off when heated. After distilling off the solvent in the filtrate under reduced pressure, the residue was dissolved in a 1 M aqueous sodium hydroxide solution, and the aqueous solution from which the insoluble matter was filtered off was diluted with a dilute acetic acid aqueous solution and neutralized to precipitate the desired product. did. This was collected by a filter and dried under reduced pressure at 110 ° C., and 176 mg (yield 78%) of 3- (1′-naphthylamino) -5-hydroxy-1H-1,2,4-triazole ( II-a) was obtained. The melting point (mp), infrared absorption spectrum (IR) and high resolution mass spectrometry (HRMS) results of this compound are as follows. mp158 ° C, IR (cm -1 ) 3364
~ 3055 (OH or NH), 1732, 1691, 1626, 1574, 140
2. Calculated as HRMS (m / z) C 12 H 10 N 4 O: 226.0
855. Found: 226.0852 (M + ). The chemical structure of the obtained compound is shown below.
【化４】 [Chemical 4]
【００１３】[0013]
【実施例２】実施例１において、4-(1´-ナフチル)チオ
セミカルバジドの代わりに、4-クミルチオセミカルバジ
ド（210 mg）を用いた以外は、実施例１と同様にして、
183 mg(収率84%) の3-クミルアミノ-5-ヒドロキシ-1H-
1,2,4-トリアゾール（ＩＩ-b）を得た。この化合物のｍ
ｐ、ＩＲ、およびＨＲＭＳは下記の通りである。mp 115
℃。IR (cm-1) 3317 (NH または OH), 2980 (CH), 173
2, 1639, 1566, 1386。HRMS (m / z) C11H14N4Oとして
の計算値： 218.1168。測定値：218.1167 (M +)。
得られた化合物の化学構造を以下に示す。Example 2 In Example 1, 4- (1'-naphthyl) thio
4-cumylthiosemicarbazide instead of semicarbazide
In the same manner as in Example 1 except that de (210 mg) was used,
183 mg (84% yield) of 3-cumylamino-5-hydroxy-1H-
1,2,4-triazole (II-b) was obtained. M of this compound
p, IR, and HRMS are as follows. mp 115
° C. IR (cm-1) 3317 (NH or OH), 2980 (CH), 173
2, 1639, 1566, 1386. HRMS (m / z) C11H14NFourAs O
Calculated for: 218.1168. Measurements: 218.1167 (M +).
The chemical structure of the obtained compound is shown below.
【化５】 [Chemical 5]
【００１４】[0014]
【実施例３】実施例１において、4-(1´-ナフチル)チオ
セミカルバジドの代わりに、4-アダマンチルチオセミカ
ルバジド（240 mg）を用いた以外は、実施例１と同様に
して、206 mg (収率88%)の3-アダマンチルアミノ-5-ヒ
ドロキシ-1H-1,2,4-トリアゾール（ＩＩ-ｃ）を得た。
この化合物のｍｐ、ＩＲ、および、ＨＲＭＳは下記の通
りである。mp 230℃ (昇華)。IR (cm-1) 3177 (NHまた
はOH), 2906 (CH), 2851 (CH), 1709, 1620, 1535, 135
9, 800, 736。 HRMS (m / z) C12H18N4O としての計算
値：234.1481。測定値：234.1492 (M+)。
得られた化合物の化学構造を以下に示す。Example 3 In the same manner as in Example 1 except that 4-adamantylthiosemicarbazide (240 mg) was used in place of 4- (1′-naphthyl) thiosemicarbazide, 206 mg ( 88% yield of 3-adamantylamino-5-hydroxy-1H-1,2,4-triazole (II-c) was obtained.
The mp, IR and HRMS of this compound are as follows. mp 230 ℃ (sublimation). IR (cm -1 ) 3177 (NH or OH), 2906 (CH), 2851 (CH), 1709, 1620, 1535, 135
9, 800, 736. HRMS (m / z) C 12 H 18 N 4 calculated for O: 234.1481. Found: 234.1492 (M + ). The chemical structure of the obtained compound is shown below.
【化６】 [Chemical 6]
【００１５】[0015]
【実施例４】アセトニトリル４ml中に4-(2´,4´-ジク
ロロフェニル)チオセミカルバジド236mg (1 mmol)とト
リエチルアミン300 mg を溶解した溶液をかき混ぜなが
ら、これにシアン酸銀 360 mg (2.4 mmol)を少しずつ加
えた。この反応液を加熱し、還流下で１時間保持した。
反応終了後、析出した硫化銀を熱時に濾別した。濾液中
の溶媒を減圧留去したのち、残留物をエタノールで再結
晶して精製すると、160 mg(65%)の3-(2´,4´-ジクロロ
フェニルアミノ)-5-ヒドロキシ-1H-1,2,4-トリアゾール
（ＩＩ-d）を得た。この化合物のｍｐ、ＩＲ、およ
び、ＨＲＭＳは下記の通りである。ｍｐ 298 ℃。IR (c
m-1) 3487〜3186 (NHまたはOH), 1755, 1635, 1606, 15
52,1386。HRMS (m / z) C8H5Cl2N4O+ としての計算
値：242.9840。測定値：242.9856 ([M - H]+)。
得られた化合物の化学構造を以下に示す。Example 4 While stirring a solution in which 236 mg (1 mmol) of 4- (2 ', 4'-dichlorophenyl) thiosemicarbazide and 300 mg of triethylamine were dissolved in 4 ml of acetonitrile, 360 mg (2.4 mmol) of silver cyanate was added thereto. Was added little by little. The reaction was heated and kept under reflux for 1 hour.
After the reaction was completed, the precipitated silver sulfide was filtered off while heating. After the solvent in the filtrate was distilled off under reduced pressure, the residue was recrystallized from ethanol and purified to give 160 mg (65%) of 3- (2 ', 4'-dichlorophenylamino) -5-hydroxy-1H-1. 1,2,4-triazole (II-d) was obtained. The mp, IR and HRMS of this compound are as follows. mp 298 ° C. IR (c
m -1 ) 3487 to 3186 (NH or OH), 1755, 1635, 1606, 15
52,1386. HRMS (m / z) C 8 H 5 Cl 2 N 4 O + as Calculated: 242.9840. Found: 242.9856 ([M-H] + ). The chemical structure of the obtained compound is shown below.
【化７】 [Chemical 7]
【００１６】[0016]
【発明の効果】本発明によれば、入手が容易な4-置換チ
オセミカルバジド化合物及びシアン酸銀を原料として用
い、穏和な条件下で、従来知られていない新規な反応形
式によって、新規な3-置換アミノ-5-ヒドロキシ-1H-1,
2,4-トリアゾール化合物を簡便且つ収率よく製造するこ
とができる。また、本発明方法で得られるトリアゾール
化合物は医薬や農薬などのファインケミカル製品の中間
原料として有用である。INDUSTRIAL APPLICABILITY According to the present invention, a 4-substituted thiosemicarbazide compound and silver cyanate, which are easily available, are used as raw materials and, under mild conditions, a novel reaction method which is not known so far is used. -Substituted amino-5-hydroxy-1H-1,
The 2,4-triazole compound can be produced easily and in good yield. Further, the triazole compound obtained by the method of the present invention is useful as an intermediate raw material for fine chemical products such as pharmaceuticals and agricultural chemicals.
Claims (2)
ル、アラルキル基、アリールアルケニル基、脂環式基、
複素環式基、またはグリコシル基を表すが、これら置換
基は置換されていてもよい。）で表される4-置換チオセ
ミカルバジド類と、シアン酸銀と反応させることを特徴
とする、下記一般式（II） 【化２】 （式中Ｒは前記と同じ意味を持つ）で表される3-置換ア
ミノ-5-ヒドロキシ-1H-1,２,4-トリアゾール誘導体の製
造方法。1. The following general formula (I): (In the formula, R represents an aryl group, an alkyl group, an alkenyl, an aralkyl group, an arylalkenyl group, an alicyclic group,
It represents a heterocyclic group or a glycosyl group, but these substituents may be substituted. ) A 4-substituted thiosemicarbazide represented by the formula (I) and silver cyanate are reacted with each other, and the following general formula (II): A method for producing a 3-substituted amino-5-hydroxy-1H-1,2,4-triazole derivative represented by the formula (wherein R has the same meaning as described above).
または脂環式基を表すが、これらは置換されていてもよ
い。）で表される3-置換アミノ-5-ヒドロキシ-1H-1,２,
4-トリアゾール誘導体。2. The following general formula (II): (In the formula, R is an aryl group, an alkyl group, an aralkyl group,
Or, it represents an alicyclic group, which may be substituted. ) 3-substituted amino-5-hydroxy-1H-1,2, represented by
4-triazole derivative.
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|---|---|---|---|
| JP2001374751A JP2003171369A (en) | 2001-12-07 | 2001-12-07 | Method for producing 3-substituted-amino-5-hydroxy-1 h-1,2,4-triazole derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001374751A JP2003171369A (en) | 2001-12-07 | 2001-12-07 | Method for producing 3-substituted-amino-5-hydroxy-1 h-1,2,4-triazole derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2003171369A true JP2003171369A (en) | 2003-06-20 |
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ID=19183267
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
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| Country | Link |
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2001
- 2001-12-07 JP JP2001374751A patent/JP2003171369A/en active Pending
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