JPS62192361A - Pyrazole compound and production thereof - Google Patents
Pyrazole compound and production thereofInfo
- Publication number
- JPS62192361A JPS62192361A JP3432186A JP3432186A JPS62192361A JP S62192361 A JPS62192361 A JP S62192361A JP 3432186 A JP3432186 A JP 3432186A JP 3432186 A JP3432186 A JP 3432186A JP S62192361 A JPS62192361 A JP S62192361A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- phenyl group
- general formula
- group
- carbon atoms
- 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.)
- Pending
Links
- -1 Pyrazole compound Chemical class 0.000 title claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 24
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 23
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 4
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims abstract description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims description 14
- 229910000037 hydrogen sulfide Inorganic materials 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 239000003524 antilipemic agent Substances 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- APXRHPDHORGIEB-UHFFFAOYSA-N 1H-pyrazolo[4,3-d]pyrimidine Chemical class N1=CN=C2C=NNC2=C1 APXRHPDHORGIEB-UHFFFAOYSA-N 0.000 abstract description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 239000007789 gas Substances 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000007664 blowing Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- XFTIKWYXFSNCQF-UHFFFAOYSA-N N,N-dipropylformamide Chemical compound CCCN(C=O)CCC XFTIKWYXFSNCQF-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 235000002597 Solanum melongena Nutrition 0.000 description 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- XBYRMPXUBGMOJC-UHFFFAOYSA-N 1,2-dihydropyrazol-3-one Chemical class OC=1C=CNN=1 XBYRMPXUBGMOJC-UHFFFAOYSA-N 0.000 description 1
- JFZSDNLQDTYVEE-UHFFFAOYSA-N 1,4-dihydropyrazolo[4,3-d]pyrimidin-7-one Chemical compound O=C1N=CNC2=C1NN=C2 JFZSDNLQDTYVEE-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- SLBQRNFFFILCBU-UHFFFAOYSA-N 7-sulfanylidene-2,4-dihydro-1h-pyrazolo[4,3-d]pyrimidin-3-one Chemical compound N1=CN=C2C(O)=NNC2=C1S SLBQRNFFFILCBU-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- IXTQGXZMKDPNMH-UHFFFAOYSA-N OC1=C(N=O)C(C(=O)OCC)=NN1C1=CC=CC=C1 Chemical compound OC1=C(N=O)C(C(=O)OCC)=NN1C1=CC=CC=C1 IXTQGXZMKDPNMH-UHFFFAOYSA-N 0.000 description 1
- UJVJGYQUOOQTAW-UHFFFAOYSA-N Pyrimine Natural products OC(=O)C1CCC(C=2N=CC=CC=2)=N1 UJVJGYQUOOQTAW-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- UNBDDZDKBWPHAX-UHFFFAOYSA-N n,n-di(propan-2-yl)formamide Chemical compound CC(C)N(C=O)C(C)C UNBDDZDKBWPHAX-UHFFFAOYSA-N 0.000 description 1
- IHYNKGRWCDKNEG-UHFFFAOYSA-N n-(4-bromophenyl)-2,6-dihydroxybenzamide Chemical compound OC1=CC=CC(O)=C1C(=O)NC1=CC=C(Br)C=C1 IHYNKGRWCDKNEG-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- ZOCLAPYLSUCOGI-UHFFFAOYSA-M potassium hydrosulfide Chemical compound [SH-].[K+] ZOCLAPYLSUCOGI-UHFFFAOYSA-M 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- DSKLYHDHQJANOE-UHFFFAOYSA-N pyrazolo[4,3-d]pyrimidine Chemical compound C1=NC=N[C]2C=NN=C21 DSKLYHDHQJANOE-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- RCOSUMRTSQULBK-UHFFFAOYSA-N sodium;propan-1-olate Chemical compound [Na+].CCC[O-] RCOSUMRTSQULBK-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、３−ヒドロキシ−４−ニトロソ−５−アルコ
キシカルボニル−ピラゾールから新規化合物３−ヒドロ
キシ−４−ジアルキルアミノメチレンアミノ−５−ピラ
ゾールを経る３−ヒドロキシ−７−メルカプト−ピラゾ
ロ（４，３−ｄ）ピリミジン〔この化合物は、後述のよ
うに抗高脂血剤として有用なピラゾロ（４，３−ｄ）ピ
リミジン誘導体の原料として有用である。〕の製造工程
の一部分およびこれら製造工程に用いられる中間体に関
する。Detailed Description of the Invention [Industrial Application Field] The present invention provides a novel compound 3-hydroxy-4-dialkylaminomethyleneamino-5-pyrazole from 3-hydroxy-4-nitroso-5-alkoxycarbonyl-pyrazole. 3-hydroxy-7-mercapto-pyrazolo(4,3-d)pyrimidine [This compound is useful as a raw material for pyrazolo(4,3-d)pyrimidine derivatives useful as antihyperlipidemic agents as described below. be. ] and intermediates used in these manufacturing steps.
３−ヒドロキシ−７−メルカプト−ピラゾロ〔４゜３−
ｄ〕ピリミジンは特開昭６０−２３１６７９号に示され
たように抗高脂血剤の中間体として有用である。従来、
この３−ヒドロキシ−７−メルカプト−ピラゾロ（４，
３−ｄ）ピリミン（ＩＸ）は、スキーム１ （以下、
余白）
〔スキーム１〕
〔反応式中の一般式において、Ｒ１は水素原子、炭素数
１から４の低級アルキル基、フェニル基または置換フェ
ニル基を意味し、Ｒ３は炭素数１から４のアルキル基を
意味する。〕に示されるように、３−ヒドロキシ−４−
ニトロソ−５−アルコキシカルボニルピラゾール （Ｉ
Ｉ）を還元した後、ホルムアミド中、高温で加熱、環化
させることによって、一旦３．７−シヒドロキシーピラ
ゾロ（４，３−ｄ〕ピリミジン（■）を得て、これをピ
リジン中、ミニ硫化リンと加熱することによって合成さ
れた。 しかしながらこの方法は中間体である３、７
−シヒドロキシーピラゾロ（４，３−ａ）ピリミジン（
■）を得るために環化反応において２５０℃以上の高温
加熱が必要なこと、更にこの３，７−シヒドロキシー
ピラゾロ（４，３−ｄ）ピリミジン（■）とミニ硫化リ
ンの反応は、制御しにいくばかりでなく、収率が低く、
生成する３−ヒドロキシ−７−メルカプト−ピラゾロ（
４，３−ｄ）ピリミジン（ＩＸ）の純度も高くないとい
う問題点があった。3-Hydroxy-7-mercapto-pyrazolo [4゜3-
d] Pyrimidine is useful as an intermediate for antihyperlipidemic agents as shown in JP-A-60-231679. Conventionally,
This 3-hydroxy-7-mercapto-pyrazolo (4,
3-d) Pyrimine (IX) is prepared according to Scheme 1 (hereinafter,
Margin) [Scheme 1] [In the general formula in the reaction formula, R1 means a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, or a substituted phenyl group, and R3 is an alkyl group having 1 to 4 carbon atoms. means. ], 3-hydroxy-4-
Nitroso-5-alkoxycarbonylpyrazole (I
After reducing I), 3,7-hydroxypyrazolo(4,3-d)pyrimidine (■) is obtained by heating and cyclizing in formamide at high temperature, and this is converted into pyridine in pyridine. synthesized by heating with mini-phosphorus sulfide.
-cyhydroxypyrazolo(4,3-a)pyrimidine (
(2) In order to obtain 3,7-hydroxy
The reaction between pyrazolo(4,3-d)pyrimidine (■) and miniphosphorus sulfide is not only difficult to control but also has a low yield.
The resulting 3-hydroxy-7-mercapto-pyrazolo (
There was also a problem that the purity of 4,3-d) pyrimidine (IX) was not high.
本発明者らは、３−ヒドロキシ−７−メルカプトピラゾ
ロ（４，３−ｄｌ ピリミジンの新規な合成法について
鋭意検討した結果、３．７−シヒドロキシーピラゾロ（
４，３−ｄ）ピリミジン（■）を経ない新規な合成法を
見出し、この新規合成法の一部分の工程として本発明を
完成した。As a result of intensive investigation into a new method for synthesizing 3-hydroxy-7-mercaptopyrazolo (4,3-dl pyrimidine), the present inventors discovered that 3,7-hydroxy-pyrazolo (
We found a new synthetic method that does not involve 4,3-d) pyrimidine (■), and completed the present invention as a partial step of this new synthetic method.
以下に本発明の方法を詳細に説明する。本発明の新規合
成法を一部分の工程として含む上記新規な合成法は、下
記のスキーム２に示したようなＡからＤの工程からなり
、本発明の工程はＡからＣまでの工程である。The method of the present invention will be explained in detail below. The above-mentioned novel synthesis method including the novel synthesis method of the present invention as a part of the steps consists of steps A to D as shown in Scheme 2 below, and the steps of the present invention are steps A to C.
〔スキーム２〕
（ＩＸ）
〔式中、Ｒ１は水素原子、炭素数１から４の低級アルキ
ル基、フェニル基または置換フェニル基を意味し、Ｒ２
は炭素数１から３のアルキル基を意味し、Ｒ３は炭素数
１から４のアルキル基を意味する。〕
工程Ａはアルコキシカルボニル基をカルバモイル基に変
換する工程である。従来このものは封管中でアンモニア
水と加熱することにより得られたが（Ｃｈｅｍ、Ｐｈａ
ｒｍ、Ｂｕｌｌ、、 ３１．１２８８（１９８３） ）
、今回更に簡便に、室温でアンモニア水中でかきまぜ
るだけですみやかに、かつ定量的に進行することを見い
だした。[Scheme 2] (IX) [In the formula, R1 means a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a phenyl group or a substituted phenyl group, and R2
means an alkyl group having 1 to 3 carbon atoms, and R3 means an alkyl group having 1 to 4 carbon atoms. ] Step A is a step of converting an alkoxycarbonyl group into a carbamoyl group. Conventionally, this product was obtained by heating with aqueous ammonia in a sealed tube (Chem, Pha
rm, Bull, 31.1288 (1983))
This time, we have found that the process can proceed more easily and quantitatively simply by stirring it in aqueous ammonia at room temperature.
工程Ｂは複数の反応を中間体を単離することなく行わせ
る工程である。まずジアルキルホルムアミド（ジメチル
ホルムアミド、ジエチルホルムアミド、ジプロピルホル
ムアミドまたはジイソプロピルボルムアミド、特に、ジ
メチルホルムアミド）のみ、或いはジアルキルボルムア
ミド（ジメチルホルムアミド、ジエチルホルムアミド、
ジプロピルホルムアミドまたはジイソプロピルホルムア
ミド、特に、ジメチルボルムアミド）とベンゼン、トル
エン、アセトニトリル、クロロホルム、エーテルまたは
ヘキサノなどとの混合溶媒中において、化合物（ＩＩＩ
）のニトロソ基を還元する。Step B is a step in which multiple reactions are performed without isolating intermediates. First, only dialkylformamides (dimethylformamide, diethylformamide, dipropylformamide or diisopropylformamide, especially dimethylformamide) or dialkylformamides (dimethylformamide, diethylformamide,
The compound (III
) to reduce the nitroso group of
この還元反応はたとえばパラジウム−炭素などの触媒の
存在下に水素雰囲気下で容易に行なわせることができる
。生成するアミノ体は酸化されやすく、空気中ではすみ
やかに青紫色の未知物質を与えるので単離することなく
、溶液状態のまま更に反応させる。This reduction reaction can be easily carried out under a hydrogen atmosphere in the presence of a catalyst such as palladium-carbon. The resulting amino compound is easily oxidized and quickly gives a bluish-purple unknown substance in the air, so it is not isolated and is allowed to react further in a solution state.
すなわち、還元の終った溶液を氷冷し、オキシ塩化リン
を滴下するか、オキシ塩化リン、チオニルクロリドまた
はホスゲンとジアルキルホルムアミド（ジメチルホルム
アミド、ジエチルホルムアミドマたはジプロピルホルム
アミド、特に、ジメチルホルムアミド）とからなる混合
物を滴下し１、更に水冷下あるいは室温で反応を完結さ
せる。That is, the reduced solution is ice-cooled, and phosphorus oxychloride is added dropwise, or phosphorus oxychloride, thionyl chloride, or phosgene is mixed with dialkylformamide (dimethylformamide, diethylformamide, or dipropylformamide, especially dimethylformamide). A mixture consisting of (1) is added dropwise, and the reaction is completed under water cooling or at room temperature.
この際カルバモイル基の脱水反応によるシアン基の生成
とアミノ基のジアルキルアミノメチレン基による保護が
同時に進行する。このあと少量の水を添加し、加水分解
することにより、化合物（Ｖｌ）が結晶として収率よく
得られる。At this time, the production of a cyan group by the dehydration reaction of the carbamoyl group and the protection of the amino group by the dialkylaminomethylene group proceed simultaneously. Thereafter, by adding a small amount of water and performing hydrolysis, compound (Vl) can be obtained as crystals in a good yield.
ＣとＤ工程は、Ｈ２Ｓの付加を経由する環化工程である
。この工程は種々の条件下で行なうことができる。塩基
性条件下で化合物（ＶＴ）を懸濁あるいは溶解させた溶
液に硫化水素ガスを吹きこみ、更に４０〜８０℃に加熱
しながらかきまぜるが、室温で長時間かきまぜることに
より環化反応が進行する。硫化水素をふきこんだ後で化
合物（Ｖｌ）を加えても、反応は同様に進行する。Steps C and D are cyclization steps via addition of H2S. This step can be carried out under various conditions. Hydrogen sulfide gas is blown into a solution in which compound (VT) is suspended or dissolved under basic conditions, and the mixture is further stirred while heating to 40 to 80°C, but the cyclization reaction proceeds by stirring for a long time at room temperature. . Even if compound (Vl) is added after hydrogen sulfide is bubbled in, the reaction proceeds in the same way.
塩基としては水酸化ナトリウム、水酸化カリウム、アン
モニア、あるいはナトリウムメトキシド、ナトリウムエ
トキシドまたはナトリウムプロポオキシド等のアルカリ
金属アルコラード、あるいはピリジン、トリエチルアミ
ンまたはトリエタノ−ルアミンなどの三級アミンを用い
ることが出来る。As the base, sodium hydroxide, potassium hydroxide, ammonia, alkali metal alcoholades such as sodium methoxide, sodium ethoxide or sodium propoxide, or tertiary amines such as pyridine, triethylamine or triethanolamine can be used.
水酸化ナトリウム、ナトリウムエトキシドなどの塩基を
用いる場合は化合物（Ｖｌ）に対して大過剰用いる方が
よい収率を与える。When using a base such as sodium hydroxide or sodium ethoxide, it is better to use it in large excess relative to compound (Vl) to give a better yield.
？容媒としてはメタノ−Ｊし、エタノール、プロパツー
ル、ブタノールなどのアルコール性溶媒のほか、水も用
いることが出来る。硫化水素を吹き込むかわりに試薬と
して入手可能な水硫化ナトリウム、あるいは水硫化カリ
ウムを用いることも出来る。? As a medium, in addition to methanol, alcoholic solvents such as ethanol, propatool, butanol, and water can also be used. Instead of blowing in hydrogen sulfide, it is also possible to use sodium bisulfide or potassium bisulfide, which are available as reagents.
この反応の中間体として、まず化合物（■）が生成する
ことが、薄層クロマトグラフィーにより確かめられ、ま
た単離することが出来る。しかし、通常は単離する必要
はなく、加熱により環化反応した目的物を容易に得るこ
とが出来る。It was confirmed by thin layer chromatography that the compound (■) is produced as an intermediate in this reaction, and it can be isolated. However, isolation is usually not necessary, and the target product subjected to the cyclization reaction can be easily obtained by heating.
以上述べたＣおよびＤ工程は更に簡便に、連続して行な
うことが出来、化合物（Ｖ［）を単離する必要がない。Steps C and D described above can be carried out more conveniently and continuously, and there is no need to isolate compound (V[).
すなわち、工程Ｂ２において、ビルスマイヤー試薬によ
る反応が完結した後、水を滴下し、触媒を濾別する。That is, in step B2, after the reaction with the Vilsmeier reagent is completed, water is added dropwise and the catalyst is filtered off.
更に濾液に冷却下で、水酸化ナトリウム、水酸化カリウ
ムなどの濃厚水溶液を滴下して、溶液をアルカリ性とす
る。このあと工程ＣとＤについて述べたのと同様に、硫
化水素ガス吹きこみなどの処理を行なうことにより、一
旦化合物（Ｖｌ）を単離した場合とほぼ同様の収率で化
合物（ＩＸ）を得ることが出来る。Furthermore, a concentrated aqueous solution of sodium hydroxide, potassium hydroxide, or the like is added dropwise to the filtrate under cooling to make the solution alkaline. After this, in the same way as described for steps C and D, by performing treatments such as blowing hydrogen sulfide gas, compound (IX) is obtained in almost the same yield as when compound (Vl) is isolated. I can do it.
以上、本発明の製造法を用いることにより、抗高脂制剤
として有用な化合物の中間体である３−ヒドロキシ−７
−メルカプト−ピラゾロ〔４，３−ｄ）ピリミジン（■
）が取扱いにくい３．７−シヒドロキシーピラゾロ（４
，３−ｄ）ピリミジン（■）を経由することなく簡単な
操作で、より高い総合収率で得られる。As described above, by using the production method of the present invention, 3-hydroxy-7, which is an intermediate of a compound useful as an antihyperlipidemic agent, can be produced.
-Mercapto-pyrazolo[4,3-d)pyrimidine (■
) is difficult to handle, 3,7-hydroxy-pyrazolo (4
, 3-d) can be obtained in a higher overall yield by simple operations without going through pyrimidine (■).
さらにこの新規合成法で得られた化合物（ＩＸ）は従来
法で得られるものより格段に純度が高く、はとんど精製
の必要がない。Furthermore, the compound (IX) obtained by this new synthesis method has a much higher purity than that obtained by the conventional method, and there is almost no need for purification.
また、さらに本発明はこの製造法に用いられる新規な有
用な中間体を提供するものである。Furthermore, the present invention provides a new and useful intermediate for use in this production method.
なお、ここで述べた３−ヒドロキシピラゾール類はたと
えば化合物（ＩＩＩ）についていえばピラゾロン型
○
の互変異性体の構造を、また１、化合物（ＩＸ）につい
ていえば、３−ヒドロキシ−ピラゾロ〔４゜３−ｄ〕ピ
リミジン−７−チオン型
の互変異性体の構造もとりうると考えられるが、本特許
出願明細書では簡単のためヒドロキシ型、メルカプＩ・
型で統一して表記した。The 3-hydroxypyrazoles mentioned here are, for example, the structure of the pyrazolone type ○ tautomer for compound (III), and the structure of the tautomer of pyrazolone type 1, and 3-hydroxy-pyrazolo[4] for compound (IX). It is thought that a tautomer structure of the ゜3-d]pyrimidine-7-thione type is also possible, but for the sake of simplicity in this patent application specification, the hydroxy type, mercap I.
It is written in a unified manner.
次に本発明を実施例と参考例を挙げて更に具体的に説明
するが、本発明は、以下の実施例によって限定されるも
のではない。EXAMPLES Next, the present invention will be described in more detail with reference to examples and reference examples, but the present invention is not limited to the following examples.
実施例１
１００ｍｎフラスコに２−メチル−３−ヒドロキシ−４
−ニトロソ−５−エトキシカルボニルーピラゾール（Ｉ
ｔ ａ） （Ｒ’＝ＣＩ＋３） １０ ｇ１２８％アン
モニア水５０ｍ７！を入れ、室温で３時間攪拌する。Example 1 2-methyl-3-hydroxy-4 in a 100 mn flask
-Nitroso-5-ethoxycarbonylupyrazole (I
t a) (R'=CI+3) 10 g128% ammonia water 50m7! and stir at room temperature for 3 hours.
室温、減圧でアンモニアを留去し、さらに塩酸水を加え
て、酸性とし、析出してくる黄色結晶を濾別、水洗する
。Ammonia is distilled off at room temperature under reduced pressure, and hydrochloric acid water is added to make the mixture acidic. The precipitated yellow crystals are separated by filtration and washed with water.
収率：９６％
融点２２０〜２２５℃（分解）
ｐｍｒスペクトル（ｄ６−ＤＭＳＯ中）δｐｐｍ； （
３，３０（ｓ）：３．３５（ｓ）＝２：３．３Ｈ）（７
，４３（ｂｒ、ｓ）：８．４０（ｂｒ、５）＝２：３．
３１１ ）ＭＳ（ｍ／ｅ）： １７０ （Ｍ′″）実
施例２
実施例１と同様にして２−エチル−３−ヒドロキシ−４
−ニトロソ−５−エトキシカルボニル−ピラゾール（Ｕ
ｂ ） （Ｒ’＝ＣＪｓ）より、表記化合物を得た。Yield: 96% Melting point 220-225°C (decomposition) PMR spectrum (in d6-DMSO) δppm; (
3,30(s):3.35(s)=2:3.3H)(7
,43(br,s):8.40(br,5)=2:3.
311) MS (m/e): 170 (M''') Example 2 2-ethyl-3-hydroxy-4 was prepared in the same manner as in Example 1.
-Nitroso-5-ethoxycarbonyl-pyrazole (U
b) The title compound was obtained from (R'=CJs).
収率；６１％
融点 １７８．０〜１７９．５℃
ｐｍｒスペクトル（ＣＤＣｊ２３中）
δｐｐｍ； １．３６（ｔ、 ３１１． Ｊ＝７．２Ｈ
ｚ）１．６Ｈｂｒ、ｓ、 ２Ｈ）
３．９２（ｑ、 ２１Ｌ Ｊ・７．２１１ｚ）実施例３
（ＶＩａ）（−設工 （Ｖｌ）によ 表される化会惣２
００ｍｎのナスフラスコに化合物（Ｉｌｌａ）２０ ｇ
（０，１１８ｍｏｌ）、ジメチホルムアミド６０ｍ１
を入れ攪拌した。窒素置換した後５％パラジウム−炭素
、１ｇを加え、常温、常圧で水素雰囲気下、水素還元し
た。還元終了後、水冷下、オキシ塩化リン２９．４ｍｊ
！（化合物（Ｉｌｌａ）に対し２．５倍モル当量）をジ
メチルホルムアミド３０ｍ１！に溶かした溶液を徐々に
滴下した。水冷下さらに３０分攪拌した後、室温にて１
５時間攪拌した。次に水冷下、水５ｍｌを徐々に加え、
過剰のオキシ塩化リンを分解した。約１時間抜メタノー
ル２０ｍＩ！、加え、パラジウム−炭素を濾別した。メ
タノールを低温で留去した後、２日間冷蔵庫に保存し、
析出した結晶を濾別、アセトン洗浄することにより、目
的とする化合物（Ｖｉａ） 、１９．９ ｇ （収率：
８７．２％）を得た。Yield: 61% Melting point: 178.0-179.5°C PMR spectrum (in CDCj23) δppm: 1.36 (t, 311. J=7.2H
z) 1.6Hbr, s, 2H) 3.92 (q, 21L J・7.211z) Example 3 (VIa) (-construction (Vl)
20 g of compound (Illa) in a 00 mm eggplant flask
(0,118 mol), dimethyformamide 60 ml
and stirred. After purging with nitrogen, 1 g of 5% palladium on carbon was added, and hydrogen reduction was carried out in a hydrogen atmosphere at room temperature and pressure. After completion of reduction, add 29.4 mj of phosphorus oxychloride under water cooling.
! (2.5 times the molar equivalent of compound (Illa)) in 30ml of dimethylformamide! A solution dissolved in water was gradually added dropwise. After stirring for another 30 minutes under water cooling,
Stirred for 5 hours. Next, while cooling with water, gradually add 5 ml of water.
Excess phosphorus oxychloride was destroyed. 20 mI of methanol removed for about 1 hour! , and palladium-carbon was filtered off. After distilling off methanol at low temperature, store it in the refrigerator for 2 days,
The precipitated crystals were filtered and washed with acetone to obtain the desired compound (Via), 19.9 g (yield:
87.2%).
融点 ２２０〜２２５° （分解）
ｐｍｒスペクトル（ｄ６−ＤＭＳＯ中）δｐｐｍ ３
．２０（６Ｈ，ｓ） ３．６２（３Ｈ，ｓ）８．２
６（ｉｌｌ、 ｓ）
ＭＳ（ｍ／ｅ）； １９３ （Ｍ’）実施例４
実施例３と同様にして化合物（Ｉｌｌｂ）０．５ｇより
表記化合物０．３１ｇを得た。Melting point 220-225° (decomposition) PMR spectrum (in d6-DMSO) δppm 3
．． 20 (6H, s) 3.62 (3H, s) 8.2
6 (ill, s) MS (m/e); 193 (M') Example 4 In the same manner as in Example 3, 0.31 g of the title compound was obtained from 0.5 g of compound (Illb).
収率：５４％
融点 １９５−２０５° （分解）
ｐｍｒスペクトル（ｄ６−ＤＭＳＯ中）δｐｐｍ １
．３０（ｔ、 ３Ｈ，Ｊ＝７．２Ｈｚ）３．２０（ｓ、
３Ｈ） ３．２７（ｓ、 ３１１）４．０２（ｑ、
２Ｌ Ｊ＝７．２１＋ｚ）８．３７（ｓ、ＩＨ）
ＭＳ（ｍ／ｅ）； ２０７ （Ｍ”） 、 １６３（
Ｍ” −ＭｅｚＮ）参考例１
（合成例１）
５０ｎｌのナスフラスコにエタノール２０ｍ７！、金属
ナトリウム０．９１ｇ（化合物（ＶＩａ）に対して７．
６倍モル当量）を入れ加熱しながら溶解させた。室温に
戻し、化合物（■ａ） １ ｇ （５，１８ｍｍｏ＋
＞をエタノール５ｍｌに懸濁した溶液を加えた。この
懸濁液に硫化水素ガスを室温で５時間吹込んだ後、８０
°で１．５時間加熱した。この後室温に戻し不溶の黄色
固体を濾別した。これを水６ｍ１ｌに溶解させ、微量の
不溶物を濾別した。濾液に濃塩酸を加え、酸性とし析出
した化合物（ＩＸａ ）を濾過、水洗、乾燥した。０．
７１ｇ（収率： ７５．３％）
融点 ３２０℃以上
ｐｍｒスペクトル（ｄ、−ＤＭＳＯ中）δｐｐｍ
３．７１（ｓ、 ３１１） ７．８０（ｓ、
Ｉｌｌ）ＭＳ（ｍ／ｅ）； １８２ （Ｍ”）（合
成例２）
５０ｍＡ’のコルベンで苛性ソーダ１．５７ｇ（化合物
（Ｖｌ ａ ）に対して７．６倍グラム当量）を水６ｍ
βに溶解させ、硫化水素ガスを室温で５時間吹込んだ。Yield: 54% Melting point 195-205° (decomposition) PMR spectrum (in d6-DMSO) δppm 1
．． 30(t, 3H, J=7.2Hz) 3.20(s,
3H) 3.27 (s, 311) 4.02 (q,
2L J=7.21+z)8.37(s, IH) MS(m/e); 207(M”), 163(
M''-MezN) Reference Example 1 (Synthesis Example 1) In a 50 nl eggplant flask, 20 m7 of ethanol and 0.91 g of metallic sodium (7.7 g for compound (VIa)) were added.
6 times molar equivalent) was added and dissolved while heating. Return to room temperature and add 1 g of compound (■a) (5,18 mmo+
> was suspended in 5 ml of ethanol. After blowing hydrogen sulfide gas into this suspension at room temperature for 5 hours,
Heated for 1.5 hours at °C. Thereafter, the temperature was returned to room temperature and the insoluble yellow solid was filtered off. This was dissolved in 6 ml of water, and trace amounts of insoluble matter were filtered off. Concentrated hydrochloric acid was added to the filtrate to make it acidic, and the precipitated compound (IXa) was filtered, washed with water, and dried. 0.
71g (Yield: 75.3%) Melting point: 320°C or higher PMR spectrum (d, in -DMSO) δppm
3.71 (s, 311) 7.80 (s,
Ill) MS (m/e); 182 (M'') (Synthesis Example 2) 1.57 g of caustic soda (7.6 times the gram equivalent of compound (Vla)) was added to 6 m of water using a 50 mA' Kolben.
β and hydrogen sulfide gas was blown into the solution at room temperature for 5 hours.
次に、化合物（Ｖｌａ）Ｉｇを加え、溶解させた後、硫
化水素ガスを室温でさらに３０分間吹込んだ。薄層クロ
マトグラフにて原料の化合物（Ｖｉａ）が消失し、チオ
アミド体（■ａ）が生成しているのを確認した後、硫化
水素ガスの吹込みを続けながら６０℃で１．５時間加熱
した。室温に戻し、濃塩酸を加えて溶液を酸性にし析出
してきた黄色固体を濾別した。これを重曹水９１１７！
に熔かし、微量の不溶物を濾別した後、濾液を濃塩酸で
酸性として、析出した固体を濾別、水洗、乾燥して、化
合物（ＩＸａ） 、０．７３ ｇ （収率： ７７．４
％）を得た。Next, compound (Vla) Ig was added and dissolved, and then hydrogen sulfide gas was further blown in at room temperature for 30 minutes. After confirming by thin layer chromatography that the raw material compound (Via) has disappeared and the thioamide compound (■a) has been produced, heat at 60°C for 1.5 hours while continuing to blow hydrogen sulfide gas. did. The temperature was returned to room temperature, the solution was made acidic by adding concentrated hydrochloric acid, and the precipitated yellow solid was separated by filtration. This is baking soda water 9117!
After filtering off trace amounts of insoluble matter, the filtrate was acidified with concentrated hydrochloric acid, and the precipitated solid was filtered off, washed with water, and dried to obtain compound (IXa), 0.73 g (yield: 77 .4
%) was obtained.
（合成例３）
〔化合物（■ａ）の単離を行なわない、化合物（Ｉ［［
ａ）からの直接合成）
５０ｍ７！コルベンに化合物（Ｉ［［ａ）Ｉｇとジメチ
ルボルムアミド４ｍｌを入れ、攪拌し、窒素置換してか
ら、パラジウム−炭素０．０５ ｇを加えた。(Synthesis Example 3) [Compound (■a) is not isolated, compound (I[[
Direct synthesis from a)) 50m7! Compound (I [[a) Ig and 4 ml of dimethylbormamide were placed in a Kolben, stirred, and replaced with nitrogen, and then 0.05 g of palladium-carbon was added.
常温、常圧で水素還元を行なった後、水冷下、オキシ塩
化リン１．４７ｎｌ（化合物（ＴＩＩａ）に対し２．５
倍モル当量）を徐々に滴下し、３０分間攪拌した。室温
で１４時間攪拌した後水冷下で水４ｍｌをゆっくりと加
え、過剰のオキシ塩化リンを分解した。パラジウム−炭
素を濾別した後、水冷下で濾液に濃苛性ソーダ水溶液（
４，８ｇを水８ｍ７！に溶かした溶液）を加えた。この
溶液に硫化水素ガスを室温で５時間吹き込んだ後、６０
°で１時間加熱した。室温に戻した後塩酸酸性として析
出してきた黄色固体について合成例２と同様の処理をし
て化合物（ＩＸａ） ０．６３ ｇ （収率：５８．９
％）を得た。After hydrogen reduction at room temperature and pressure, under water cooling, 1.47 nl of phosphorus oxychloride (2.5 nl for compound (TIIa))
2 molar equivalents) was gradually added dropwise, and the mixture was stirred for 30 minutes. After stirring at room temperature for 14 hours, 4 ml of water was slowly added under water cooling to decompose excess phosphorus oxychloride. After the palladium-carbon was filtered off, the filtrate was mixed with a concentrated aqueous solution of caustic soda (
4.8g in 8m7 of water! solution) was added. After blowing hydrogen sulfide gas into this solution at room temperature for 5 hours,
Heated for 1 hour at °C. After returning to room temperature, the yellow solid precipitated as acidified with hydrochloric acid was treated in the same manner as in Synthesis Example 2 to obtain 0.63 g of compound (IXa) (yield: 58.9
%) was obtained.
（合成例４）
ピリジン０．４１ｇと化合物（Ｖｉａ）１．０ｇをエタ
ノール１０ｍｊ！中に加え、かきまぜながら硫化水素ガ
スを室温で３．５時間吹き込んだ。沈殿した黄色固体を
濾別した。これを合成例１と同様に処理して化合物（Ｉ
Ｘａ） ０．５８ ｇ （収率：６１．４％）を得た。(Synthesis Example 4) 0.41 g of pyridine and 1.0 g of compound (Via) were added to 10 mj of ethanol! Hydrogen sulfide gas was blown into the solution at room temperature for 3.5 hours while stirring. The precipitated yellow solid was filtered off. This was treated in the same manner as in Synthesis Example 1 to obtain compound (I
Xa) 0.58 g (yield: 61.4%) was obtained.
ピリジンのかわりにトリエチルアミン、トリエタノール
アミンを用いても化合物（ＩＸａ）が得られた。Compound (IXa) was also obtained using triethylamine or triethanolamine instead of pyridine.
実施例５
実施例４の合成例１において室温で５時間硫化水素ガス
を吹き込んだ。薄層クロマトグラフィーにおいて、原料
（Ｖｌ ａ ）が消失し、新しいスポットのみが生成し
ているのを確かめた後、低温でエタノールを一部留去し
た。この新しいスポットを分取薄層クロマトグラフィー
で分離し、メタノールにより抽出した。メタノールを留
去して目的とする（■ａ）を黄色油状物として得た。Example 5 In Synthesis Example 1 of Example 4, hydrogen sulfide gas was blown at room temperature for 5 hours. After confirming in thin layer chromatography that the raw material (Vla) had disappeared and only new spots were generated, ethanol was partially distilled off at low temperature. This new spot was separated by preparative thin layer chromatography and extracted with methanol. Methanol was distilled off to obtain the desired product (■a) as a yellow oil.
ｐｍｒスペクトクル（ｄ、−ＤＭＳＯ中）δｐｐｍ
２．７４（３８，ｓ） ２．９０（３Ｈ，ｓ）３．３
２（３Ｈ，ｓ） ７．９５（ＩＨ，ｓ）ＭＳ（ＦＤ）
（ｍ／ｅ）； ２２７ （Ｍ”）実施例６
実施例１と同様にして、２−フェニル−３−ヒドロキシ
−４−ニトロソ−５−エトキシカルボニル−ピラゾール
（Ｉｌｃ）より表記化合物を得た。pmr spectrum (d, in -DMSO) δppm
2.74 (38, s) 2.90 (3H, s) 3.3
2 (3H, s) 7.95 (IH, s) MS (FD)
(m/e); 227 (M'') Example 6 In the same manner as in Example 1, the title compound was obtained from 2-phenyl-3-hydroxy-4-nitroso-5-ethoxycarbonyl-pyrazole (Ilc).
収率 ９９％。 融点 ２２０〜２２２℃ｐｍｒスペク
トル（ｄ６−ＤＭＳＯ中）δｐｐｍ ； ７．２９〜７
．９３（ｍ、５Ｈ）８．４０．８．６３（ｂｒ、ｓ、
ｘ２＋ ＬＨ）ＭＳ（ｍ／ｅ）； ２３２（Ｍ ” ）
、１８Ｂ（Ｍ ” −ＣＯＮｌｌｚ）参考例２
２−エチル−３−ヒドロキシ−７−メルカプト参考例１
の合成例２と同様の方法で３−ヒドロキシ−４−ジメチ
ルアミノメチレンアミノ−５−シアノ−ピラゾール（■
ｂ）０．４ｇより表記化合物０．２０ｇ（収率 ５２．
９％）を得た。Yield 99%. Melting point 220-222℃pmr spectrum (in d6-DMSO) δppm; 7.29-7
．． 93 (m, 5H) 8.40.8.63 (br, s,
x2+ LH) MS (m/e); 232 (M ”)
, 18B(M''-CONllz) Reference Example 2 2-Ethyl-3-hydroxy-7-mercapto Reference Example 1
3-hydroxy-4-dimethylaminomethyleneamino-5-cyano-pyrazole (■
b) 0.20g of the title compound from 0.4g (yield 52.
9%).
融点 ２７５〜２７９℃
ｐｎ＋ｒスペクトル（ｄａ−ＤＭＳＯ中）δｐｐｍ ：
１．３５（ｔ、３８．Ｊ＝７．２１１ｚ）４．１１（
ｑ、２Ｈ，Ｊ＝７．２１１ｚ） ７．７６（ｓ、 Ｉ
Ｈ）１３、Ｈｂｒ、ｓ、、 ＩＭ）
ＭＳ（ｎ＋／ｅ）； １９６（Ｍ ” ）、 １６８（
Ｍ ” −ＣＨｚ＝ＣＨｚ）参考例３
参考例１の合成例３とほぼ同様の方法で、３−ヒドロキ
シ−４−ニトロソ−５−カルバモイル−ピラゾール（Ｉ
［［ｃ）より直接合成した。Melting point 275-279°C pn+r spectrum (in da-DMSO) δppm:
1.35(t, 38.J=7.211z)4.11(
q, 2H, J=7.211z) 7.76(s, I
H) 13, Hbr, s,, IM) MS (n+/e); 196 (M ”), 168 (
M ” -CHz=CHz) Reference Example 3 3-Hydroxy-4-nitroso-5-carbamoyl-pyrazole (I
[Synthesized directly from [c].
ただし、オキシ塩化リンを加えた後の室温での攪拌時間
を１４時間から１時間に短縮した。However, the stirring time at room temperature after adding phosphorus oxychloride was shortened from 14 hours to 1 hour.
化合物（Ｉ［［ｃ）Ｉｇより化合物（ＩＸｃ）０．８８
ｇ（収率 ７８．６％）を得た。Compound (I[[c) Compound (IXc) from Ig 0.88
g (yield 78.6%) was obtained.
融点 ＞３００℃
ｐｍｒスペクトル（ｄｉ−ＤＭＳＯ中）δｐｐｍ ；
７．３９〜７．９１（ｍ、６Ｈ）１３．６７（ｂｒ、ｓ
、、ＬＨ）
ＭＳ（ｍ／ｅ）； ２４４（Ｍ ” ）。Melting point >300℃ PMR spectrum (in di-DMSO) δppm;
7.39-7.91 (m, 6H) 13.67 (br, s
,,LH) MS (m/e); 244 (M'').
Claims (5)
基、フェニル基または置換フェニル基を意味し； Ｘはニトロソ基、アミノ基または（Ｒ＾２）＿２ＮＣＨ
＝Ｎ−（Ｒ＾２は炭素数１から３のアルキル基を意味す
る）を意味し； Ｒ＾１が炭素数１から４のアルキル基、フェニル基また
は置換フェニル基であり かつＸがニトロソ基であると
きＹは−Ｃ（Ｏ）ＮＨ＿２を意味し；Ｒ＾１が水素原子
、炭素数１から４のアルキル基、フェニル基または置換
フェニル基でありかつＸがアミノ基であるときＹは−Ｃ
（Ｏ）ＮＨ＿２を意味し；Ｒ＾１が水素原子、炭素数１
から４のアルキル基、フェニル基または置換フェニル基
でありかつＸが（Ｒ＾２）＿２ＮＣＨ＝Ｎ−（Ｒ＾２は
上述と同意味である）であるときＹはＣＮまたは−Ｃ（
Ｓ）ＮＨ＿２を意味する。〕で表されるピラゾール系化
合物。(1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 means a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, or a substituted phenyl group. ; X is a nitroso group, an amino group or (R^2)_2NCH
=N- (R^2 means an alkyl group having 1 to 3 carbon atoms); R^1 is an alkyl group having 1 to 4 carbon atoms, a phenyl group, or a substituted phenyl group, and X is a nitroso group When R^1 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group or a substituted phenyl group, and X is an amino group, Y means -C(O)NH_2; C
(O) means NH_2; R^1 is a hydrogen atom, carbon number is 1
is an alkyl group, phenyl group or substituted phenyl group of 4 and X is (R^2)_2NCH=N- (R^2 has the same meaning as above), Y is CN or
S) means NH_2. ] A pyrazole compound represented by
；Ｒ＾１は水素原子、炭素数１から４のアルキル基、フ
ェニル基または置換フェニル基を意味する。〕で表され
るピラゾール系化合物に、常圧下、アンモニアを反応さ
せることを特徴とする一般式（III） ▲数式、化学式、表等があります▼（III） 〔式中、Ｒ＾１は一般式（II）の説明と同意味である。 〕で表されるピラゾール系化合物の製法。(2) General formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) [In the formula, R^3 means an alkyl group having 1 to 4 carbon atoms; R^1 is a hydrogen atom, a carbon number It means 1 to 4 alkyl groups, phenyl groups or substituted phenyl groups. General formula (III) characterized by reacting a pyrazole compound represented by ] with ammonia under normal pressure ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula, R^1 is the general formula It has the same meaning as the explanation in (II). ] A method for producing a pyrazole compound represented by
キル基、フェニル基または置換フェニル基を意味する。 〕で表されるピラゾール系化合物を還元することを特徴
とする一般式（IV） ▲数式、化学式、表等があります▼（IV） 〔式中、Ｒ＾１は一般式（III）の説明と同意味である
。〕で表されるピラゾール系化合物の製法。(3) General formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) [In the formula, R^1 means a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, a phenyl group, or a substituted phenyl group. . ] General formula (IV) characterized by reducing the pyrazole compound represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) [In the formula, R^1 is the explanation of general formula (III) They have the same meaning. ] A method for producing a pyrazole compound represented by
キル基、フェニル基または置換フェニル基を意味する。 〕で表されるピラゾール系化合物に、一般式（Ｖ） （Ｒ＾２）＿２ＮＣ（Ｏ）Ｈ （Ｖ） 〔式中、Ｒ＾２は炭素数１から３のアルキル基を意味す
る。〕で表されるジアルキルホルムアミドとオキシ塩化
リン、チオニルクロライドまたはホスゲンとの混合物を
反応させることを特徴とする一般式（VI） ▲数式、化学式、表等があります▼（VI） 〔式中、Ｒ＾１とＲ＾２は一般式（IV）および（Ｖ）の
説明と同意味である。〕で表されるピラゾール系化合物
の製法。(4) General formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) [In the formula, R^1 means a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, or a substituted phenyl group. . [In the formula, R^2 means an alkyl group having 1 to 3 carbon atoms. ] General formula (VI) characterized by reacting a mixture of dialkylformamide represented by phosphorus oxychloride, thionyl chloride or phosgene ▲There are numerical formulas, chemical formulas, tables, etc.▼(VI) [In the formula, R ^1 and R^2 have the same meanings as in the general formulas (IV) and (V). ] A method for producing a pyrazole compound represented by
キル基、フェニル基または置換フェニル基を意味し、Ｒ
＾２は炭素数１から３のアルキル基を意味する。〕で表
されるピラゾール系化合物に、塩基存在下硫化水素を反
応させるか、水硫化塩を反応させることを特徴とする一
般式（VII） ▲数式、化学式、表等があります▼（VII） 〔式中、Ｒ＾１とＲ＾２は一般式（VI）の説明と同意味
である。〕で表される化合物の製法。(5) General formula (VI) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (VI) [In the formula, R^1 means a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, a phenyl group, or a substituted phenyl group. ,R
^2 means an alkyl group having 1 to 3 carbon atoms. General formula (VII) characterized by reacting a pyrazole compound represented by ] with hydrogen sulfide or a hydrosulfide salt in the presence of a base ▲There are mathematical formulas, chemical formulas, tables, etc. ▼ (VII) [ In the formula, R^1 and R^2 have the same meaning as explained in general formula (VI). ] A method for producing a compound represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3432186A JPS62192361A (en) | 1986-02-19 | 1986-02-19 | Pyrazole compound and production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3432186A JPS62192361A (en) | 1986-02-19 | 1986-02-19 | Pyrazole compound and production thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS62192361A true JPS62192361A (en) | 1987-08-22 |
Family
ID=12410894
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3432186A Pending JPS62192361A (en) | 1986-02-19 | 1986-02-19 | Pyrazole compound and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62192361A (en) |
-
1986
- 1986-02-19 JP JP3432186A patent/JPS62192361A/en active Pending
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