TWI373468B - Method for preparation of amido pyrazole - Google Patents
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- TWI373468B TWI373468B TW99102990A TW99102990A TWI373468B TW I373468 B TWI373468 B TW I373468B TW 99102990 A TW99102990 A TW 99102990A TW 99102990 A TW99102990 A TW 99102990A TW I373468 B TWI373468 B TW I373468B
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1373468 t、發明說明: 【發明所屬之技術領域】 本發明係關於一種製備醯胺基吡唑衍生物之方法,尤其關於 以一鍋法製備醯胺基吡唑衍生物。 【先前技術】 麩胺酸(glutamate )於哺乳類動物的中樞神經系統中,係作 為一種興奮性神經傳導物質,而哺乳類動物腦中之中枢神經系 統内的代謝型麩胺酸受體(metabotropic glutamate receptor, mGluRs ),則係扮演於神經細胞中結合及傳輸麩胺酸之角色, 其藉由傳輸麩胺酸至細胞内,以控制神經細胞之神經衝動。因 此,代謝型麩胺酸受體涉及許多腦部或神經之生理機制,例如 記憶、學習、及痛覺等,其亦與憂慮或憂鬱等情緒感受有關, 是故,臨床上許多關於神經性及精神性疾病之研究或治療,皆 係針對代謝型麩胺酸受體來進行。 已有文獻指出,醯胺基吡唑衍生物可與第五型代謝型麩胺酸 受體(metabotropic glutamate receptor 5,mGluRs)結合,達 成治療精神分裂症之效果,此可參見Lindsley α/., J. Med. Chem., 2004, 47, 5825 A Paulis et al., Med. Chem., 2006, 49, 3332,該等文獻全文倂於此處以供參考。迄今,豕(1,3-二苯基 -1//-吡唑-5-基)苯曱醯胺類之衍生物已被開發為第五型代謝型 麩胺酸受體之正向異位調控之活化物質,以作為治療精神分裂 症之藥物。 習知之製備醯胺基吡唑衍生物的方法主要有二種。第一種製 5 1373468 備方法係利用如下反應製程(此可參見Chen ei α/_, Tetrahedron Lett·, 1998, 39, 8229 ,該文獻全文併於此處以供參考): 〇1373468 t, DISCLOSURE OF THE INVENTION: FIELD OF THE INVENTION The present invention relates to a process for preparing a guanamine-based pyrazole derivative, and more particularly to the preparation of a guanamine-based pyrazole derivative in a one-pot process. [Prior Art] Glutamate is an excitatory neurotransmitter in the central nervous system of mammals, and metabotropic glutamate receptors in the central nervous system of mammalian brains. , mGluRs), plays a role in the binding and transport of glutamate in nerve cells by controlling the nerve impulses of nerve cells by transporting glutamate into the cells. Therefore, metabotropic glutamate receptors are involved in many physiological mechanisms of the brain or nerves, such as memory, learning, and pain, which are also related to emotional feelings such as anxiety or depression. Therefore, many clinical and neurological and spiritual effects. The study or treatment of sexually transmitted diseases is carried out against metabotropic glutamate receptors. It has been pointed out that guanamine pyrazole derivatives can be combined with metabotropic glutamate receptor 5 (mGluRs) to achieve the effect of treating schizophrenia. See Lindsley α/., J. Med. Chem., 2004, 47, 5825 A Paulis et al., Med. Chem., 2006, 49, 3332, the entire disclosure of which is hereby incorporated by reference. To date, derivatives of guanidine (1,3-diphenyl-1//-pyrazol-5-yl)benzamide have been developed as positive ectopics of the fifth type of metabotropic glutamate receptor. Activating substances that are regulated as drugs for the treatment of schizophrenia. There are two main methods for preparing guanamine-based pyrazole derivatives. The first system 5 1373468 is prepared by the following reaction process (see, for example, Chen ei α/_, Tetrahedron Lett., 1998, 39, 8229, the entire disclosure of which is hereby incorporated by reference):
於此習知方法中,係使2’-溴苯乙酮(2’-Bromoacetophenone, 化合物2 )與酿酿亞胺鉀(potassium phthalimide )進行取代反 應,以得到化合物3,接著化合物3與'苯肼(phenylhydrazine) 進行環化反應而得到化合物4。然後,化合物4再與聯胺水合 物進行開環反應,以得到化合物5。最後進行胺基醯化反應, 而得到終產物化合物6。此合成方法之步驟繁瑣,且其使用之 試劑昂貴,終產物之產率僅為約11至17%,完全不符合經濟 效益。 6 1373468 第二種合成方法則係如下所示之反應製程(此可參見Paulis β/.,Med. C/zew., 2006, 49, 3332,該文獻全文倂於此處以供 參考):In this conventional method, 2'-Bromoacetophenone (Compound 2) is substituted with potassium phthalimide to obtain Compound 3, followed by Compound 3 and 'Benzene Phenylhydrazine is subjected to a cyclization reaction to give a compound 4. Then, Compound 4 is further subjected to a ring opening reaction with a hydrazine hydrate to obtain Compound 5. Finally, the amine oximation reaction is carried out to obtain the final product compound 6. The procedure of this synthetic method is cumbersome and the reagents used are expensive, and the yield of the final product is only about 11 to 17%, which is completely uneconomical. 6 1373468 The second synthetic method is the reaction process shown below (see Paulis β/., Med. C/zew., 2006, 49, 3332, the entire disclosure of which is hereby incorporated by reference):
總產率:2至38%Total yield: 2 to 38%
於此習知方法中,係使用氰苯(benzonitrile,化合物7 )與乙 氰(acetonitrile)反應,以得到化合物8。接著,化合物8與 苯肼鹽酸鹽(phenylhydrazine hydrochloride)進行環化反應而 得到化合物9。最後,進行胺基醯化反應,以得到終產物化合 物10,其產率為約2至38%。 上述兩種製備醯胺基吡唑衍生物之方法皆須經歷至少三至 四個步驟,且於各步驟完成後,尚須經萃取及層析等繁複之純 化程序,故於藥廠之製程放大過程中,相當耗費人力、物力及 財力。因此,業界極須一種可降低製造成本之合成方法,以方 便、快速且大量地製備醯胺基°比σ坐衍生物。 1373468 本發明即係針對上述需求所為之研究成果,經由使用酿乙氛 化合物(acy丨acetonitri〗e)'肼類(⑽㈣⑷化合物與_醯化 試劑,可快速且方便地合成醯胺基。比唑衍生物。 【發明内容】 本發明之-目的在於提供—種製備下式⑴酿胺基。比唾衍 生物之方}纟係包3扣合乙氰化合物與一肼類化合物, 以進行縮合環化反應,得到_第_反應產物;以及添加一酿化 試劑至該第-反應產物中,以進行胺基醢化反應,得到式⑴ 胺基α比β坐衍生物: X1-ΝIn this conventional method, benzonitrile (Compound 7) is reacted with acetonitrile to give Compound 8. Next, the compound 8 is subjected to a cyclization reaction with phenylhydrazine hydrochloride to obtain a compound 9. Finally, an amine oximation reaction is carried out to obtain a final product compound 10 in a yield of about 2 to 38%. The above two methods for preparing the guanamine-based pyrazole derivative have to undergo at least three to four steps, and after completion of each step, a complicated purification procedure such as extraction and chromatography is required, so that the process of the pharmaceutical factory is enlarged. In the process, it is quite labor-intensive, material and financial. Therefore, there is a need in the art for a synthetic method which can reduce the manufacturing cost, and to prepare a guanamine-based ratio σ sitting derivative in a convenient, rapid and large-scale manner. 1373468 The present invention is directed to the research results of the above requirements, and the guanamine group can be synthesized quickly and conveniently by using a compound of acy 丨 oni oni oni oni ( ( ( ( ( ( ( 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨[Description of the Invention] The present invention has an object to provide a method for preparing an amine group of the following formula (1), which is a compound of a salino derivative, and a ruthenium compound, a ruthenium compound, and a ruthenium compound, to carry out a condensation ring. The reaction is carried out to obtain a _th reaction product; and a brewing agent is added to the first reaction product to carry out an amine oximation reaction to obtain an amine group α-β-supplement derivative of the formula (1): X1-Ν
⑴。 本發明之詳細技術及較佳實施態樣,將描述於以下内容令, 以供本發明所屬領域具通常知識者據以明瞭本發明 【實施方式】 1 除非文中有另外說明,於本說明書中(尤其是在後述專利申請 範圍40所使用之「-」、「該」及類似用語應理解為包含單數及 複數形式。 根據世界衛生組織於2001年的心理衛生報告書,全球每四人就 有一人於一生中可能罹患精神性疾病或神經性疾病。如上所述, 腦内中樞神經系統的神經性或精神性疾病與代謝型麵胺酸受體有 1373468 關,且可利用醯胺基吡唑衍生物與第 一 土代6射型麵胺酸受體之專 性結合特性,使其作為第五型代 '项2麩胺酸党體之促效劑 l ag〇mst),以治療神經性或精神性疾病。 本發明提供一種製備下式⑴酿胺基。比。坐衍生物之方法 0 X1(1). DETAILED DESCRIPTION OF THE INVENTION The present invention will be described in the following description of the present invention in order to provide a description of the present invention. In particular, the use of "-", "the" and similar terms in the scope of the patent application 40 will be understood to include the singular and plural forms. According to the World Health Organization's 2001 Mental Health Report, there are one in every four people in the world. May be suffering from mental illness or neurological disease in one lifetime. As mentioned above, the neurological or psychiatric diseases of the central nervous system in the brain are related to the metabotropic partial receptors of 1373,468 and can be derived from amidinopyrazole. The obligate binding properties of the substance to the first-generation 6-shot type of alanine receptor, making it a fifth-generation 'item 2 glutamate agonist l ag〇mst) to treat neuropathic or Mental illness. The present invention provides a preparation of the amine group of the following formula (1). ratio. How to sit on a derivative 0 X1
R-NR-N
、X3 X2 (I) ,其係包含以下步驟: (1)混合式(II)肼類(hydrazine)化合物與式(ΠΙ)醯乙氰 (acylacetonitrile)化合物,以進行縮合環化反應,得到一第一 反應產物;以及 X1-NHNH2 ( II) 0 (III) (2)添力σ式(IV)及式(v)醯化試劑之至少一者至該第一反應產 物中,以進行胺基醯化反應,得到式(I)醯胺基吡唑衍生物: 1373468, X3 X2 (I), which comprises the following steps: (1) mixing a compound of formula (II) with a compound of formula (ΠΙ) acetonitrile (acylacetonitrile) to carry out a condensation cyclization reaction to obtain a first a reaction product; and X1-NHNH2(II)0(III) (2) at least one of the σ (IV) and formula (v) deuteration reagents are added to the first reaction product to carry out an amine hydrazine The reaction gives the guanamine pyrazole derivative of formula (I): 1373468
其中: ο ο R 為 Η、-ί-Χ3 或-&Χ3,; χ及χ2係獨立為:¾基、齒素、氰基、石肖基硫基、由烧基烧氧 基、環烷基、•基烷氧基、芳基、雜芳基、或雜環基; X3與χ3係、不同且獨立Μ基、芳基、續醯基、環院基、雜芳基、 或雜丨辰基;以及 L為離去基。 特定言之,於本發明之方法中,係先使式⑻肼類化合物與 式(III)醯乙氰化合物進行縮合環化反應,以得到一第一反應產 物。於鈿合環化反應完成後’再於該第一反應產物中添加一式() 及式(V)醯化試劑之至少一者,以進行胺基醯化反應,從而製得 酿胺基α比唾衍生物。 於本發明方法步驟(1)中,可視所欲式(τ)醯胺基吡唑衍生物, 選用合宜之式(II)化合物及式(ΠΙ)化合物。較佳地,係於步驟 (1)選用使用符合以下條件之式(II)化合物及式(ΙΠ)化合物, 以製備對應之式(I)醯胺基吡唑衍生物:ΧΙ及X2係獨立為鹵素、 氰基、硝基、硫基、C3至Qo環烷基、C5至(:2〇芳基、或視需要具 一或夕個齒素取代基之C|至C2〇烧基或Cl至C2〇烧氧基,該環烧 基或芳基之環中之一或多個碳原子可視需要獨立被N、〇或S置 1373468 換1更佳地,所使用之式⑻化合物及式㈤)化合物係符合以 下t件l及X2係獨立為…-芳基,該芳基之環中之-或多 们炭原子可視需要獨立被Ν、〇或s置換。Where: ο ο R is Η, -ί-Χ3 or -&Χ3,; χ and χ2 are independently: 3⁄4 base, dentate, cyano, schlossylthio, alkoxy groups, alkylene groups, • alkoxy, aryl, heteroaryl, or heterocyclic; X3 and χ3, different and independently fluorenyl, aryl, fluorenyl, cyclohetero, heteroaryl, or fluorenyl; And L is the leaving group. Specifically, in the process of the present invention, a sulfonium compound of the formula (8) and a ruthenium cyanide compound of the formula (III) are first subjected to a condensation cyclization reaction to obtain a first reaction product. After the completion of the cyclization reaction, at least one of the formula () and the deuteration reagent of the formula (V) is added to the first reaction product to carry out an amine oximation reaction, thereby preparing a ratio of the amine group to the α. Saliva derivatives. In the step (1) of the process of the present invention, a desired compound of the formula (II) and a compound of the formula (ΠΙ) can be selected according to the desired formula (τ). Preferably, in the step (1), a compound of the formula (II) and a compound of the formula (ΙΠ) are used to prepare a corresponding amide-based pyrazole derivative of the formula (I): oxime and X2 are independently Halogen, cyano, nitro, thio, C3 to Qo cycloalkyl, C5 to (: 2 aryl, or, if desired, a C or a C dentate substituent or C to C2 oxime alkoxy, one or more carbon atoms in the ring of the cycloalkyl or aryl group may be independently replaced by N, 〇 or S by 1373468, more preferably, the compound of formula (8) and formula (5) are used. The compound is consistent with the following t-forms and X2 are independently ...-aryl groups, and the carbon atoms in the ring of the aryl group may be independently replaced by hydrazine, hydrazine or s.
八對本發二方法而言,步驟⑴中之式⑻化合物與式(1„)化 。物之用ϊ配比,並非發明重點所在。然而,基於經濟效益考量, 步驟⑴中之式(η)化合物與式㈤)化合物之莫耳數用量,式 (111 ) . S ( II)通常為至少約〇 9 : i,較佳係至少約^ : ^。 於本發明方法t,係可於不使用溶劑之情形下進行式(II)化 合物及式(III)化合物之縮合環化反應,提供高產率之第一反應 產物。故可於完成步驟⑴之後,直接進行第⑺步驟,毋須中間純 化v V。經分析確認,該第一反應產物係具下式(v〗):For the eight methods of the present invention, the compounding ratio of the compound of the formula (8) in the step (1) and the formula (1) is not the focus of the invention. However, based on economic considerations, the formula (η) in the step (1) The molar amount of the compound and the compound of the formula (5)), the formula (111). S (II) is usually at least about 9: i, preferably at least about ^: ^. In the method t of the present invention, it can be used without The condensation cyclization reaction of the compound of the formula (II) and the compound of the formula (III) is carried out in the presence of a solvent to provide a first reaction product in a high yield. Therefore, after the completion of the step (1), the step (7) can be directly carried out without intermediate purification of v V It is confirmed by analysis that the first reaction product has the following formula (v):
步驟(1)之操作溫度並非本發明方法之關鍵所在,視所選用之式 (1〇化合物及式(ΙΠ )化合物而定。舉例言之,當使用χι及X2 為笨基之式(II)化合物及式(in)化合物時,可於不使用溶劑之 情形下,在約215至220°C之溫度進行步驟(1)縮合環化反應,提 供#-(1,3-二苯基-1//-吼。坐·5-基)胺(即,第一反應產物)。 於本發明方法步驟(2)中,可視所欲式(I)酿胺基°比嗤衍生物之 物種,選用合宜之醯化試劑。較佳地,係於步驟(2)使用符合以下 條件之式(IV)及式(V) &化試劑之至少一者:X3與X3’係獨立 1373468 為視需要具-或多個取代基之c2。烧基、[至c2。續醒基、 C3至c20環烧基、或C』c2〇芳基,其令,該取代基係獨立為齒 素、氰基、硝基、c2i C,。環針基、€5至C2a芳基、或視需要具— 或多個齒素取代基之C,至C4烷基或C|至q烷氧基,且該環烷基 或芳基之環中之一或多個碳原子可視需要獨立被N 〇或S置換。 更佳地’所使用之式(IV)及/或式(V)醯化試劑係符合以下條 件.X與X3係獨立為視需要具一或多個取代基之Cl至Go烷基、 心至(:|()磺醯基、q至C|G環烷基、或匕至C|〇芳基,其中該 取代基係獨立為i素、甲基、三氟甲基、甲氧基、氰基、硝基、 C2 %酐基、苯基、或喹啉基,且該環烷基或芳基之環中之—或多 個碳原子可視需要獨立被N、〇或s置換。 可於步驟(2)所使用之式(IV)及/或式(v)醯化試劑中,含任 ^合宜之離去基L。舉例言之,L可選自_素、&至〜统氧基、 或C|至C2〇酯基之離去基。較佳地,L係選自鹵素、C|至烷 氧基、或(^至C|()酯基之離去基,具體態樣如c卜乙氧基、及乙 醋基。 對本發明方法而言,步騾(2)之醯化試劑用量亦非關鍵所在。一 知·而S,步驟(2)所使用醯化試劑之莫耳數,至少等於式(11)化 物之莫耳數,較佳為式(II)化合物莫耳數之約15倍或更高(如: 約1·5倍至約3·〇倍),以使式(VI)第一反應產物之胺基上之氫 的至少一者被醯基取代,從而製得所欲之醯胺基吡唑衍生物。 同樣地,視所選用之醯化試劑物種,可於不同溫度下進行本發 /方法步驟(2)。舉例言之,當於步驟(2)使用l為氯之氯醯類醯化 式劑時,可於低溫下(如:約〇至1〇。〇進行胺基醯化反應。可 12 1373468 . . 作為本發明方法步驟(2)醯氣類醯化試劑之例子,包括:氣化乙臨、 • 2_呋喃甲醯氣、2-噻吩甲醯氣、異噁唑-5-氣化碳醯氣、2-笨呋喃曱 • 醯氣、偏苯三曱醯氯、喹啉-8-磺醯氣、及前述之組合。相對地, 若於步驟(2)中使用酯類或酸酐類醯化試劑時,則須於較高溫度下 進行胺基醯化反應。 已知可使用W-(l,3-二苯基-1//-吡唑_5_基)苯曱醯胺類之衍生 物’作為治療神經性及精神性疾病之藥物。因此,於本發明方法 之一實施態樣中,係於步驟(1)使用χ|為苯基之式(11)化合物(即, 鲁笨肼)以及X2為苯基之式(HI)化合物(即,苯甲醯乙氰(benzoyl_ acetonitrile))以進行縮合環化反應。其後,步驟⑺中,至少使用 式(IV )醯化έ式劑以進行胺基酿化反應,其中,X3為視需要具一 或多個取代基之笨基,該苯基上之取代基係獨立為鹵素、氰基、 硝基、C2至C10環酐基、C5至C2〇芳基、或視需要具一或多個鹵素 取代基之(^至C4烷基或(:!至C4烷氧基,且該環烷基或芳基之環 中之一或多個碳原子可視需要獨立被N、〇或s置換;較佳地, ^ 6亥X笨基上之取代基係獨立為鹵素、甲基、三氟甲基、甲氧基、 氰基、硝基、C2環酐基、笨基、或喹啉基,且該環烷基或芳基之 環中之一或多個碳原子可視需要獨立被N、〇或s置換。 • 另有文獻私出,含雜芳環取代基之7V~(1,3-二苯基-1-//-。比吐-5- « 基)醯胺衍生物,亦具有第五型代謝型麩胺酸受體之正向異位調控 的活性(此可參見 Paulis ei 从,j· 2006, 49, 3332,該 文獻全文倂於此處以供參考)。此等具第五型代謝型麩胺酸受體之 正向異位調控活性之衍生物,則可經由在本發明方法之步驟(〗)中 使用X與X為苯基之式(H)及式(ΙΠ)化合物,且於步驟(2) 13 1373468 中使用X3/X3:為雜芳環之式(IV)及/或式(V)醯化試劑而提供。 經由本發明方法,可製得以下化合物:The operating temperature of the step (1) is not critical to the method of the present invention, depending on the selected formula (1 〇 compound and formula (ΙΠ) compound. For example, when χι and X2 are used as the stupid formula (II) In the case of the compound and the compound of the formula (in), the condensation cyclization reaction of the step (1) can be carried out at a temperature of about 215 to 220 ° C without using a solvent to provide #-(1,3-diphenyl-1). //-吼. Sodium 5-amino)amine (ie, the first reaction product). In the step (2) of the method of the present invention, the species of the formula (I) can be used as the amine species. Preferably, the deuteration reagent is preferably used in step (2) using at least one of formula (IV) and formula (V) & reagent: X3 and X3' are independent of 1373468. Or a plurality of substituents c2. an alkyl group, [to c2. a renewed group, a C3 to c20 cycloalkyl group, or a C"c2 aryl group, which is independently a dentate, a cyano group, Nitro, c2i C, cycloacyl, €5 to C2a aryl, or optionally C, or a plurality of dentate substituents, to C4 alkyl or C| to q alkoxy, and the naphthenic Ring of aryl or aryl One or more carbon atoms may be independently replaced by N 〇 or S. More preferably, the formula (IV) and/or formula (V) oximation reagent used is in accordance with the following conditions: X and X3 are independent. A Cl to Go alkyl group having one or more substituents, a core to (:|()sulfonyl group, a q to C|G cycloalkyl group, or a fluorene to a C|indenyl group, wherein the substituent is independent Is i, methyl, trifluoromethyl, methoxy, cyano, nitro, C 2 % anhydride, phenyl, or quinolyl, and - or more in the ring of the cycloalkyl or aryl The carbon atoms may be independently replaced by N, 〇 or s. The formula (IV) and/or the formula (v) used in the step (2) may contain any suitable leaving group L. In general, L may be selected from the group consisting of _ 素, & to oxy, or C | to C 2 oxime ester group. Preferably, L is selected from halogen, C | to alkoxy, or ( ^ to the leaving group of the C|() ester group, such as c ethoxy group, and ethyl acetate. For the method of the present invention, the amount of the hydrazine reagent of step (2) is not critical. Knowing that S, the number of moles of the deuteration reagent used in step (2) is at least equal to 11) The molar number of the compound, preferably about 15 times or more the molar number of the compound of the formula (II) (e.g., about 1.5 times to about 3 times), so that the formula (VI) is first At least one of the hydrogen on the amine group of the reaction product is substituted with a mercapto group to obtain the desired mercaptopyrazole derivative. Similarly, depending on the selected deuteration reagent species, the present invention can be carried out at different temperatures. Method / method step (2). For example, when the step (2) is used as the chlorine chlorination type chlorinating agent of chlorine, the amine group can be carried out at a low temperature (for example, about 〇 to 1 〇. The reaction can be 12 1373468 . As an example of the method (2) helium gas deuteration reagent of the method of the present invention, including: gasification, 2, furan, helium, 2-thiophene oxime, isoxazole -5- gasified carbon helium, 2-p-furan oxime • helium, trimellitic chloride, quinoline-8-sulfonium, and combinations thereof. In contrast, when an ester or acid anhydride deuteration reagent is used in the step (2), the amine group deuteration reaction is carried out at a relatively high temperature. It is known that a derivative of W-(l,3-diphenyl-1//-pyrazol-5-phenyl)benzamine can be used as a drug for treating neurological and psychiatric diseases. Therefore, in one embodiment of the method of the present invention, a compound of the formula (11) wherein χ| is a phenyl group (ie, ruthenium) and a compound of the formula (HI) wherein X2 is a phenyl group are used in the step (1) ( That is, benzoyl acetonitrile is subjected to a condensation cyclization reaction. Thereafter, in the step (7), at least the oxime agent of the formula (IV) is used to carry out an amine-based brewing reaction, wherein X3 is a stupid group having one or more substituents as necessary, and a substituent on the phenyl group Is independently halogen, cyano, nitro, C2 to C10 cyclic anhydride, C5 to C2 aryl, or, if desired, one or more halogen substituents (^ to C4 alkyl or (:! to C4 alkane) An oxy group, and one or more carbon atoms in the ring of the cycloalkyl or aryl group may be independently substituted by N, hydrazine or s; preferably, the substituent on the ^ 6 X X-based group is independently halogen a methyl group, a trifluoromethyl group, a methoxy group, a cyano group, a nitro group, a C2 cyclic anhydride group, a stupid group, or a quinolyl group, and one or more carbon atoms in the ring of the cycloalkyl group or the aryl group It can be replaced by N, 〇 or s as needed. • Another document is privately available, 7V~(1,3-diphenyl-1-//-. Indoleamine derivatives also have positive ectopic regulation of the fifth type of metabotropic glutamate receptor (see Paulis ei from, j. 2006, 49, 3332, the entire disclosure of which is hereby incorporated by reference. ). These have the fifth type A derivative of the forward ectopically regulated activity of a metabotropic glutamate receptor can be obtained by using a compound of the formula (H) and a formula (ΙΠ) wherein X and X are a phenyl group in the step (〖) of the method of the present invention. And using X3/X3: is a heterocyclic ring of formula (IV) and/or formula (V) deuteration reagent in step (2) 13 1373468. By the method of the invention, the following compounds can be obtained:
14 137346814 1373468
於本發明方法中,由於步驟(1)與步驟(2)之間的純化操作並非必 需,故可以一鋼合成法(one-pot synthesis )之方式進行,亦即, 於一單一反應器中進行縮合環化反應與胺基醯化反應。因此,相 較於習知之製備醯胺基吡唑衍生物的方法,本發明方法不僅步驟 少、製程簡單,且因可免除反應過程中之繁複純化步驟,故可以 較低成本且相對簡易之方式來製得所欲之醯胺基吡唑衍生物。如 下述實施例顯示,利用本發明方法製備醯胺基吡唑衍生物,其產 率通常可達70%,甚至90%以上。 綜上,本發明提供一種低成本且簡易之製備醯胺基吡唑衍生物 的方法,其可應用於藥廠中:v以大量且經濟地製備供治療精神性 15 1373468 疾病或神經性疾病的藥物。 茲以下列具體實施態樣以進一步例示說明本發明製備醯胺基。比 唑衍生物的方法。其中該些實施態樣僅提供作為說明,而非用以 限制本發明之範疇。 [實施例1]合成5-胺基-1,3-二苯基吡唑 直接混合苯肼與苯甲醯乙氰(化合物11),並加熱混合物至215 至220°C,進行縮合環化反應達2小時,以製備5-胺基-1,3-二苯基 吡唑,供後續之胺基醯化反應用,其反應流程係如下圖所示。之 後,利用薄層層析法進行監測,可知反應已完成,且不需萃取、 乾燥、過濾及濃縮等程序,即可製得產率為94%的5-胺基-1,3-二 笨基。比嗤(化合物5 )。 分析數據:5-胺基-1,3-二苯基吡唑(化合物5):熔點:129至131°C ; W NMR (CDC13, 200 MHz) δ 3.82 (s, 2 H, NH2), 5.88 (s, 1 H, Py-H), 7.32-7.49 (m, 10 H, ArH), 7.58 (dd, 2 H, J= 6.6, 1.2 Hz, ArH), 7.80 (dd, 2 H, J= 6.6, 1.2 Hz, ArH); l3CNMR(50MHz, CDC13)8 88.1, 124.2,125.6, 127.5, 127.8, 128.5, 129.5, 133.5, 138.7, 145.8, 151.5 ; IR (KBr) 3427 (brs, NH), 3337 (brs, NH), 3059, 1616, 1598, 1558, 1505, 1456, 1375, 1070, 952, 758, 698 cm-1 ; MS m/z (相對強度)235 (M+, 100),207 (20),192 (3),180 (3),131 (7),117 (4), 104 (11),102(10),92 (7),77 (17),65 (3),51 (8). C丨5H13N3 分析計算值:C· 76.57; Η: 5.57; Ν: 17.86 ;實際值:C: 76.14; Η:5·81;Ν: 18·05。 16 1373468In the method of the present invention, since the purification operation between the steps (1) and (2) is not essential, it can be carried out by one-pot synthesis, that is, in a single reactor. The condensation cyclization reaction is carried out with an amine oximation reaction. Therefore, compared with the conventional method for preparing a guanamine-based pyrazole derivative, the method of the invention has not only fewer steps, simple process, but also can eliminate the complicated purification steps in the reaction process, so that the method can be carried out in a relatively low cost and relatively simple manner. To obtain the desired guanamine pyrazole derivative. As shown in the following examples, the preparation of the amide-based pyrazole derivative by the method of the present invention has a yield of usually 70% or more. In summary, the present invention provides a low-cost and simple method for preparing a guanamine-based pyrazole derivative, which can be used in a pharmaceutical factory: v is prepared in a large amount and economically for the treatment of psychotic 15 1373468 disease or neurological disease. drug. The present invention is further illustrated by the following specific embodiments to further illustrate the preparation of the guanamine group. A method of thiazole derivatives. The embodiments are provided by way of illustration only and are not intended to limit the scope of the invention. [Example 1] Synthesis of 5-amino-1,3-diphenylpyrazole Directly mixing phenylhydrazine with benzamidine cyanide (Compound 11), and heating the mixture to 215 to 220 ° C for condensation cyclization For 2 hours, to prepare 5-amino-1,3-diphenylpyrazole for subsequent amine oximation reaction, the reaction scheme is shown in the following figure. After that, it was monitored by thin layer chromatography, and it was found that the reaction was completed, and without extraction, drying, filtration and concentration, a yield of 94% of 5-amino-1,3-diphenyl was obtained. base. Than 化合物 (Compound 5). Analytical data: 5-Amino-1,3-diphenylpyrazole (Compound 5): Melting point: 129 to 131 ° C; W NMR (CDC13, 200 MHz) δ 3.82 (s, 2 H, NH2), 5.88 (s, 1 H, Py-H), 7.32-7.49 (m, 10 H, ArH), 7.58 (dd, 2 H, J = 6.6, 1.2 Hz, ArH), 7.80 (dd, 2 H, J= 6.6 , 1.2 Hz, ArH); l3CNMR (50MHz, CDC13) 8 88.1, 124.2, 125.6, 127.5, 127.8, 128.5, 129.5, 133.5, 138.7, 145.8, 151.5 ; IR (KBr) 3427 (brs, NH), 3337 (brs , NH), 3059, 1616, 1598, 1558, 1505, 1456, 1375, 1070, 952, 758, 698 cm-1 ; MS m/z (relative intensity) 235 (M+, 100), 207 (20), 192 (3), 180 (3), 131 (7), 117 (4), 104 (11), 102 (10), 92 (7), 77 (17), 65 (3), 51 (8). C丨5H13N3 Analytical calculations: C· 76.57; Η: 5.57; Ν: 17.86 ; Actual value: C: 76.14; Η: 5·81; Ν: 18.05. 16 1373468
1111
PhNHNH2 ------ 迴流達2至3小時〖,94〇/〇 [實施例2至4] [實施例2]以氣化乙醯作為胺基醯化試劑 於氮氣系統下,於一反應瓶中,將實施例1所製得之5_胺基_ 1,3-φ 二苯基°比唑(化合物5 )溶解於無水四氫呋喃,再以冰浴降溫至0 至10°C ’接著將氯化乙醯緩慢逐滴添加至反應瓶中。待氣化乙醯 - 添加完成後’撤除冰浴,並回溫至室溫,再攪拌約2小時,並以 • 薄層層析法監測反應進行。當反應終止後,以濃縮乾燥移除四氫 呋喃,再加入二氣曱烷溶解反應混合物,經水萃取洗滌後,收集 有機層’再以飽和食鹽水洗滌,經過濾及濃縮,最後進行層析純 化’即製得產率為85%的7V-(1,3-二苯基-1//-吡唑-5-基)乙醯胺(化 合物12 )產物,如表1所示。PhNHNH2 ------ reflux for 2 to 3 hours, 94 〇 / 〇 [Examples 2 to 4] [Example 2] gasification of acetamidine as an amine sulfonating reagent under a nitrogen system, in a reaction In the bottle, the 5-amino-1,3-1,3-diphenylpyrazole (Compound 5) prepared in Example 1 was dissolved in anhydrous tetrahydrofuran, and then cooled to 0 to 10 ° C in an ice bath. Ethyl chloride was slowly added dropwise to the reaction flask. Wait for gasification of acetonitrile - after the addition is completed, remove the ice bath, warm it to room temperature, stir for about 2 hours, and monitor the reaction by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved by adding dioxane. After washing with water, the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally purified by chromatography. That is, a 7V-(1,3-diphenyl-1//-pyrazol-5-yl)acetamide (Compound 12) product was obtained in a yield of 85%, as shown in Table 1.
® 分析數據:7V-(1,3-二笨基-1//-吡唑-5-基)乙醯胺(化合物I2 ):熔點(經 矽膠管柱層析純化,黃色固體)148至150°C ; WNMROCDCbJOOMHzM 2.06 (s, 3 H, Me), 6.95 (s, 1 Hs Py-H), 7.32-7.84 (m, 8 H, ArH), 7.81 (dd, 2 H, J 4 =6.6, 1.7 Hz, ArH) ; ,3C NMR (50 MHz, CDC13) δ 23.7, 96.4, 124.2, 125.0, 125.7, 128.1, 129.8,133.0, 136.5, 137.9, 151.8, 167.0 ; IR (KBr) 3230 (brs, NH), 3061, 1681, 1595, 1560, 1505, 1496, 1468, 1367, 1267, 1072, 954, 763, 692 cnT1 ; MS m/z(相對強度)277 (M+, 14),235 (24),207 (6),180 (2),131 (5),102 (23), 77 (45),65 (5),51 (34),43 (100). Cl7Hl5N30 分析計算值:C: 73.63; H: 17 1373468 5.45; N: 15.15 ’ 貫際值· C: 73.52; Η: 5.64; N: 15.49。 [實施例3]以醋酸酐作為胺基醯化試劑 於氮氣系統下’將實施例1所製得之5_胺基_丨,3_二苯基吼。坐(化 合物5 )溶解於無水四氫呋喃,並直接添加乙酐加以混合,接著加 熱迴流,並利用薄層層析法監測。待反應完成後(約2小時),以 濃縮乾燥移除四氫咬喃,再加入二氣甲烷溶解反應混合物’以水 萃取’收集有機層,再以飽和食鹽水洗滌後,經過濾及濃縮有機 層,最後進行層析純化’即可製得產率為83%的二苯基_1//-吡唑-5-基)乙醯胺(化合物12)產物,如表丨所示。 [實施例4]以乙酸乙酯作為胺基醯化試劑 於氮氣系統下’將實施例1所製得之5_胺基_丨,3_二苯基吡唑(化 合物5)溶解於無水四氫呋喃,再直接添加乙酸乙酯加以混合,加 熱迴流12小時後’利用薄層層析法監測。於反應終止後,以濃縮 乾燥移除四氫呋喃,再加入二氣曱烷溶解反應混合物,以水萃取, 收集有機層後,以飽和食鹽水洗滌,經過濾及濃縮有機層,最後 進行層析純化’即可製得產率為小於1〇%的#_(1,3_二苯基_17/_吡 °坐-5-基)乙酿胺(化合物12)產物,如表1所示。 於上述實施例2至4之胺基醯化反應中,5-胺基-1,3-二苯基吡 。坐(化合物5 )分別與醯氯類、酸酐類 '酯類三種酿化試劑進行反 應’其反應流程係如下圖所示。由於酸針類和酯類衍生物必須在 南皿迴流之條件下始能進行反應’故於製程中較耗能’相對於此, 醯氣類試劑則可在〇至l〇〇c之反應條件下進行。 1373468® Analytical data: 7V-(1,3-diphenyl-1//-pyrazol-5-yl)acetamide (Compound I2): melting point (purified by ruthenium column chromatography, yellow solid) 148 to 150 °C; WNMROCDCbJOOMHzM 2.06 (s, 3 H, Me), 6.95 (s, 1 Hs Py-H), 7.32-7.84 (m, 8 H, ArH), 7.81 (dd, 2 H, J 4 =6.6, 1.7 Hz, ArH) ; , 3C NMR (50 MHz, CDC13) δ 23.7, 96.4, 124.2, 125.0, 125.7, 128.1, 129.8, 133.0, 136.5, 137.9, 151.8, 167.0 ; IR (KBr) 3230 (brs, NH), 3061, 1681, 1595, 1560, 1505, 1496, 1468, 1367, 1267, 1072, 954, 763, 692 cnT1 ; MS m/z (relative intensity) 277 (M+, 14), 235 (24), 207 (6 ), 180 (2), 131 (5), 102 (23), 77 (45), 65 (5), 51 (34), 43 (100). Cl7Hl5N30 Analytical calculated value: C: 73.63; H: 17 1373468 5.45; N: 15.15 'Period value · C: 73.52; Η: 5.64; N: 15.49. [Example 3] 5-amino-indole, 3-diphenylphosphonium obtained in Example 1 was prepared under the nitrogen system using acetic anhydride as an amine sulfonating reagent. The solution (Compound 5) was dissolved in anhydrous tetrahydrofuran and directly mixed with acetic anhydride, followed by heating under reflux and monitoring by thin layer chromatography. After the reaction is completed (about 2 hours), the tetrahydrogenate is removed by concentration and drying, and then the dioxane is added to dissolve the reaction mixture, and the organic layer is collected by water extraction, and then washed with saturated brine, filtered and concentrated. The layer was finally subjected to chromatographic purification to obtain a product of 83% yield of diphenyl_1//-pyrazol-5-yl)acetamide (Compound 12) as shown in Table 。. [Example 4] 5-Amino-indole, 3-diphenylpyrazole (Compound 5) obtained in Example 1 was dissolved in anhydrous tetrahydrofuran using ethyl acetate as an amine sulfonating reagent under a nitrogen gas system. Then, ethyl acetate was directly added and mixed, and after heating under reflux for 12 hours, it was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved in dioxane, and extracted with water. The organic layer is collected, washed with saturated brine, filtered and concentrated, and then purified. The product of #_(1,3-diphenyl-17/ppyridin-5-yl)ethinamine (Compound 12) having a yield of less than 1% by weight can be obtained as shown in Table 1. In the amine oximation reaction of the above Examples 2 to 4, 5-amino-1,3-diphenylpyridinium. The reaction (supplement 5) is reacted with three kinds of glycerin and acid anhydride esters, respectively, and the reaction scheme is as shown in the following figure. Since acid needles and ester derivatives must be able to react under the conditions of recirculation of the south dish, it is relatively energy-consuming in the process, and the helium-based reagent can be reacted in the reaction conditions of 〇 to l〇〇c. Go on. 1373468
表1、5-胺基-1,3-二苯基吡唑(化合物5)進行各種親核反應 製得#-(1,3-二苯基-1//-吡唑-5-基)乙醯胺。 醯化試劑 ΑΜ,3-二苯基-I//-»比吐-5-基乙隨胺 產率(%) 氣化乙醯 12 85 醋酸酐 12 83 乙酸乙酯 12 <10Table 1, 5-amino-1,3-diphenylpyrazole (Compound 5) was subjected to various nucleophilic reactions to obtain #-(1,3-diphenyl-1//-pyrazole-5-yl)B. Guanamine. Deuterated reagent ΑΜ,3-diphenyl-I//-»Bis-5-yl-ethyl amide yield (%) gasified acetonitrile 12 85 acetic anhydride 12 83 ethyl acetate 12 <10
[實施例5至21] 實施例5至21係結合縮合環化反應及胺基醯化反應,利用一鋼 合成法製備一系列斤~( 1,3 -二苯基-1 //-11比α坐-5 -基)笨甲醢胺衍生 • 物,其反應流程係如下圖所示。 19 1373468[Examples 5 to 21] Examples 5 to 21 were combined with a condensation cyclization reaction and an amine oximation reaction to prepare a series of jin~( 1,3 -diphenyl-1 //-11 ratio by a steel synthesis method. The α-spin-5-yl) amidocarboxamide derivative is shown in the following figure. 19 1373468
ΟkA^CNΟkA^CN
PhNHNH 2 迴流小時:94%PhNHNH 2 reflux hour: 94%
NH, Ph-NNH, Ph-N
55
X A W ClX A W Cl
W NH 11 CH2CI2 or THF W=甲基、笨曱 基、或經或未 經取代之苯基W NH 11 CH2CI2 or THF W = methyl, alum, or unsubstituted phenyl
Ph-NPh-N
12-28 12. W = Me, 77%, 13. W = CH2Ph, 90% 14. W = Ar, R1, R2, R3 = H, 78% 15. W = Ar, R1, R2 = F, R3 = H, 77% 16. W = Ar, R1, R2 = H, R3 = F, 70%12-28 12. W = Me, 77%, 13. W = CH2Ph, 90% 14. W = Ar, R1, R2, R3 = H, 78% 15. W = Ar, R1, R2 = F, R3 = H, 77% 16. W = Ar, R1, R2 = H, R3 = F, 70%
17. W = Ar, R1 = Cl, R2, R3 = H: 85% 18. W= Ar, R1, R3 = H. R2 = Cl, 71% 19. W = Ar, R1 = Me, R2, R3 = H, 84% 20. W = Ar, R1, R2 = H, R3 = Me, 76% 21. W = Ar, R1, R2 = H, R3 = CF3, 78% 22. W = Ar, R1 = OMe, R2, R3 = H, 90% 23. W = Ar, R1, R3 = H, R2 = OMe, 72% 24. W = Ar, R1, R3 = F, R2 = H, 88% 25. W = Ar, R1, R3 = H R2 = CN, 90% 26. W = Ar, R1, R2 = H R3 = CN, 78% 27. W = Ar, R1 = N02, R2, R3 = H, 76% 28. W = Ar, R1, R2 = H R3 = N02, 89% [實施例5]合成3-二笨基-1//-吡唑-5-基)乙醯胺 於氮氣系統下,取苯曱醯乙氰(化合物11)與等當量的苯肼,在 無溶劑條件(neat)下進行反應2小時後,於冰浴下降溫並攪拌反 應混合.物,再緩慢逐滴加入氣化乙醯,待氣化乙醯添加完成後, 撤除冰浴,回溫至室溫,再攪拌約2小時,利用薄層層析法監測 反應進行。當反應終止後,以濃縮乾燥移除四氫咬。南,再加入二 氣曱烷溶解反應混合物,經水萃取洗滌,收集有機層,再以飽和 食鹽水洗滌,經過濾和濃縮後,最後進行層析純化,即可製得產 率為77%的7V-(1,3-二苯基-1//-吡唑-5-基)乙醯胺(化合物12)。 [實施例6]合成2-苯基二苯基-1//-吡唑-5-基)乙醯胺 於氮氣系統下,取苯甲醯乙氰(化合物11)與等當量的苯肼,在 無落劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, 20 1373468 再緩慢逐滴加入苯乙醯氣,待苯乙醯氣添加完成後,撤除冰浴, 回溫至室溫’再攪拌約2小時’以薄層層析法監測反應進行。當 反應終止後,以乾燥濃縮四氫呋喃’再加入二氯曱烷溶解反應混 合物’經水萃取洗滌’收集有機層,再以飽和食鹽水洗滌,經過 據和濃縮後’最後進行層析純化,即可製得產率為90%的2-苯基 -#-(1,3-二笨基比。坐_5_基)乙醯胺(化合物丨3 )。 分析數據:2-苯基#(1,;3-二苯基-1/^吡唑_5-基)乙醯胺(化合物13):(經 石夕膠管柱層析純化,黃色固體)132至134°C; iHNMRfDCl^OOMHzy 3 69 (s, 2 H, CH2), 7.05 (s, 1 H, Py-H), 7.09-7.43 (m, 13 H, ArH), 7.83 (d, 2 H, 6.6 Hz, ArH) ; ,3C NMR (50 MHz, CDC13) δ 29.7, 94.9, 123.66 (2 χ CH), 124.2, 125.7 (2 x CH), 128.1 (2 x CH), 128.6, 129.5 (4 x CH), 129.6, 129.8 (2 x CH), 132.9, 133.5, 136.5, 137.4, 151.8, 167.3 ; IR (KBr) 3268 (brs, NH), 3064, 2924, 1700, 1559, I486, 1458, 1368, 1158, 1073,954 cm^MSm/z(相對強度) 353 (M+, 8), 269 (1), 235 (18), 207 (3), 180 (1), 167 (1), 131 (3), 102 (17), 91 (100),77 (40),65 (29),51 (18). C23H19N30 分析計算值:C: 78.16; H: 5.42; N: 11.89 ;實際值:C:78.01;H:5.34;N: 11.69。 [實施例7]合成AT-(l,3-二苯基-1//-吡唑-5-基)苯醯胺 於氮氣系統下,取苯甲醯乙氰(化合物11)與等當量的笨肼,於 無溶劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, 再緩慢逐滴加入氣化苯曱醯,待氯化苯曱酿添加完成後,撤除冰 浴,回溫至室溫,再攪拌約2小時,以薄層層析法監測反應進行。 當反應終止後,以濃縮乾燥移除四氫呋喃,再加入二氣曱烷溶解 反應混合物,經水萃取洗滌,收集有機層,再以飽和食鹽水洗滌, 經過濾和濃縮後,最後進行層析純化,即可製得產率為78%的 21 1373468 二苯基-I//-。比嗤-5-基)苯醒胺(化合物14),如表2所示。 分析數據:7V-(1,3-二笨基-1//-吡唑-5-基)苯醯胺(化合物14):熔點(經矽膠 管柱層析純化,白色固體)171至173°C; iHNMR^CDCbJOOMHzMTJO (s, 1 Η, Py-H), 7.30-7.64 (m, 9 H, ArH), 7.88 (dd, 2 H, J= 6.6, 1.6 Hz, ArH), 7.87 (dd, 2 H, 7= 6.6, 1.6 Hz, ArH), 8.06 (dd, 2 H, /= 6.6, 1.6 Hz, ArH) ; l3C NMR (50 MHz, CDC13) δ 95.9, 124.9 (2 χ CH), 125.8 (2 χ CH), 127.1 (2 χ CH), 128.2, 128.5 (2 χ CH), 129.0 (2 x CH), 129.3, 130.1 (2 x CH), 130.2, 132.5, 133.0, 133.7, 136.7, 137.9, 171.1 ; IR (KBr) 3275 (brs} NH), 3062, 1645, 1558, 1365, 1258, 1072,954,763,711,698 〇11-1 ; MSm/z (相對強度)339(M+,74), 234 (2), 206 (2), 105 (100), 77 (45),51 (5). C22Hl7N30 分析計算值:C: 77.86; H: 5.05; N: 12.38 ;實際值:C: 77.56; H: 5.24; N: 12.47。 [實施例8]合成3-氟-7V-(1,3-二苯基-1//-吡唑-5-基)笨醯胺 於氮氣系統下,取笨曱醯乙氰(化合物11)與等當量的苯肼,在 無溶劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, 再緩慢逐滴加入間氟笨曱醯氣,待間氟苯曱醯氣添加完成後,撤 除冰浴,回溫至室溫,再攪拌約2小時,以薄層層析法監測反應 進行。當反應終止後’以濃縮乾燥移除四氫呋喃,再加入二氣甲 院溶解反應混合物’經水萃取洗滌,收集有機層,再以飽和食鹽 水洗滌’經過濾和濃縮後,最後進行層析純化,即製得產率為77% 的3-氟-;V-(1,3-二苯基吡唑_5_基)笨醯胺(化合物15)產物,如 表2所示。 分析數據:3-H(l,3-二苯基·丨//_吡唑_5_基)苯醯胺(化合物15):熔點(自 CH2Cl2/MeOH 中再結晶,白色固體)175 至 177 〇c; iH nmr (CDq3, 2〇〇 MHz) 1373468 δ 7.18 (s, 1 Η, Py-H), 7.31-7.41 (m, 8 Η, ArH), 7.57 (dd, 4 H, J = 4.2, 1.4 Hz, • ArH), 7.88 (dd, 2 H, J= 6.6, 1.4 Hz, ArH), 8.21 (b, 1 Η, NH) ; ,3C NMR (50 • MHz, CDC13)8 96.4, 114.5, 114.9, 119.4, 119.8, 122.4 (2 χ CH), 124.7 (2 x CH), 125.8, 128.6, 128.7(2 x CH), 130.1 (2 χ CH), 130.6, 130.8, 132.9, 135.3, 135.4, 136.3.137.8, 152.0, 160.4, 162.6, 165.3 ; IR (KBr) 3269 (brs, NH), 3064, 1684, 1589, 1458, 1365, 1290, 1072, 956,692 cm_l;MSm/z(相對強度)357 (ivf, 15), 356 (15), 206 (2),123 (100), 101 (18),95 (35),77 (17), 51 (10). C22Hl6FN30 分 析計算值:C: 73.94; H: 4.51; N: 11.76 ;實際值:C: 73.66; H:4.46;N: 11.41。 •[實施例9]合成4-氟-7V-(1,3-二苯基-1//-吡唑-5-基)苯醯胺 於氮氣系統下,取苯曱醯乙氰(化合物11)與等當量的苯肼,在 無溶劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, 再緩慢逐滴加入對氟苯曱醯氣,待對氟苯曱醯氣添加完成後,撤 除冰浴,回溫至室溫,再攪拌約2小時,以薄層層析法監測反應 進行。當反應終止後,以濃縮乾燥移除四氫呋喃,再加入二氣甲 烷溶解反應混合物,經水萃取洗滌,收集有機層,再以飽和食鹽 | 水洗滌,經過濾和濃縮後,最後進行層析純化,即製得產率為70% 的4-氟-ΛΜ,3-二苯基-177-吡唑-5-基苯醯胺(化合物16),如表2 所示。 分析數據:4-氟-iV-(l,3-二苯基-1//-吡唑-5-基)苯醯胺(化合物16):熔點 (自 CH2Cl2/MeOH 中再結晶,白色固體)187 至 189°C ; WNMRiCDCb, 200 MHz) δ 7.12 (t, 1 Η, J= 8.7 Hz, ArH), 7.18 (s, 1H, Py-H), 7.32-7.48 (m, 4 H, ArH), 7.55-7.58 (m, 4 H, ArH), 7.70-7.77 (m, 2 H, ArH), 7.88 (dd, 4 H, J = 7.9, 1.3 Hz, ArH), 8.12 (b, 1H,NH); l3C NMR (50 MHz, CDC13) δ 96.0, Π6.0, 116.4, 124.8 (2 x CH), 125.8 (2 χ CH), 128.2, 128.6 (2 x CH), 128.7, 129.4, 1373468 129_6, 130.1 (2 xCH),132.9, 136.5, 137.9, 146.2, 152.1,162.6 ; IR(KBr) 3217 (brs,NH), 3045, 1685, 1529, 1504, 1460, 1367, 1286, 1234, 1072, 918, 760, 694 cm—1; MS m/2(相對強度)357 (M+,15),234 (1 ),206 (1 ),123 (100), 102 (24), 95 (46),77 (24),51 (12). C22Hl6FN30 分析計算值:c: 73.94; H: 4.51; N: 11.76 ; 實際值:C: 73.87; H:4.67; N: 11.35。 [實施例10]合成2-氣-"-(1,3-二苯基-1//-吡唑-5-基)苯醯胺 於氮氣系統下,取苯曱醯乙氰(化合物11)與等當量的苯肼’ 在無溶劑條件下反應2小時後,於冰浴下降溫並搜拌反應混合物’ 再緩慢逐滴加入鄰氣曱醯氣,待鄰氣笨曱醯氣添加完成後,撤除 冰浴’回溫至室溫,再攪拌約2小時,以薄層層析法監測反應進 行。當反應終止後,以濃縮乾燥移除四氫呋喃,再加入二氣曱烷 溶解反應混合物經水萃取洗蘇,收集有機層,再以飽和食鹽水 洗滌’經過濾和濃縮後,最後進行層析純化,即製得產率為85% 的2-氣-AM,3-二苯基-1//-吡唑-5-基笨醯胺(化合物17),如表2所 示。 分析數據:2-氣-7V-(1,3-二苯基-1//-吡唑-5-基)苯醯胺(化合物17):,熔點(經 矽膠管柱層析純化,黃色固體)147至149°C ; WNMR^CDCb, 200ΜΗζ)δ 7.14 (s, 1 H, Py-H), 7.22-7.68 (m, 11 H, ArH), 7.70-7.94 (m, 3 H, ArH), 8.64 (b, 1 Η, NH) ; l3C NMR (50 MHz, CDC13) δ 96.2, 125.5 (2 χ CH), 125.8 (2 x CH), 127.5, 128.2, 128.6 (2 χ CH), 128.9, 129.5 (2 x CH), 130.5, 131.2, 132.0,132.5,132.9,136.6, 137.6, 151.9, 162.7, 168.9 ; IR (KBr) 3256 (brs, NH), 3066, 1666, 1566, 1502, 1460, 1369, 1263, 1117, 1051, 765, 696 cm"' ; MS m/z (相對強度)373 〇Vf,10),338(18),234(1),206 (2), 141 (44),139(100),111 (36),102 (34),77 (36),51 (16). C22H16C1N30 分析計算值:C: 70.68; H: 4.31; N: 24 Ϊ373468 1 1·24 ;實際值:c: 70.29; Η: 4.51; N:丨丨.丨4。 • [ κ她例1丨]合成3·氣-々-(1,3-二苯基_]//_吡唑_5_基)苯醯胺 於氮氣系統下,取笨曱醯乙氰(化合物丨丨)與等當量的苯肼,在 無溶劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, 再緩‘fe逐滴加入間氣曱醯氣,待間氣笨甲醯氣添加完成後’撤除 冰洽,回溫至室溫,再攪拌約2小時,以薄層層析法監測反應進 行。當反應終止後,濃縮乾燥移除四氫呋喃,再加入二氣曱烷溶 解反應混合物,經水萃取洗滌,收集有機層,再以飽和食鹽水洗 ® 蘇’經過濾和濃縮後,最後進行層析純化,即製得產率為71%的 3-氣-#-1,3-二苯基_1//_吡唑_5_基笨醯胺(化合物18),如表2所示。 分析數據:3-氣-AL(i,3_二苯基吡唑_5_基)苯醯胺(化合物丨8):熔點(經 石夕膠管柱層析純化,黃色固體)168至17〇 〇c ; iHNMR(CDC13, 200 ΜΗζ)δ 7.14 (s, 1 Η, Py-H), 7.22-7.61 (m, 10 H, ArH), 7.65-7.94 (m, 3 H, ArH), 8.04 (b, 1 H, NH); l3CNMR(50MHz, CDC13)8 96.4, 124.8(2 x CH), 124.9, 125.8(2 x CH), 127.7, 128.2, 128.6 (2 x CH), 128.8, 130.1 (2 x CH), 130.3, 132.6, 133.7, φ 134.9, 136.2, 137.8, 152.1, 162.6, 169.6; IR (KBr) 3248 (brs, NH), 3052, 1675, 1573, 1498, 1455, 1431,1358, 1292, 1252, 1061,758, 692 cm-1 ; MS m/z (相對 強度)373 (M+, 15),343 (1),234 (2),206(3), 141 (33),139(100), 111 (46),l〇2 (32), 77 (33), 75 (27), 51 (19). C22HI6C1N30 分析計算值:C: 70.68; HM.31; • N: 11.24 ;實際值:C: 70.29; H: 4.51; N: 11.14。 [實施例12]合成2-曱基3-二苯基-1//-吡唑-5-基)苯醯胺 於氮氣系統下,取苯曱醯乙氰(化合物11)與等當量的苯肼,在 無溶劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, 再緩慢逐滴添加鄰甲基苯甲醯氣,待間鄰甲基笨曱醯氯添加完成 25 1373468 後,撤除冰浴,回溫至室溫,再攪拌約2小時,以薄層層析法監 測反應進行。當反應終止後,以濃縮乾燥移除四氫呋喃,再加入 二氣曱烷溶解反應混合物,經水萃取洗滌,收集有機層,再以飽 和食鹽水洗蘇,經過渡和濃縮後,最後進行層析純化,即製得產 率為84%的2-曱基-W-(l,3-二苯基-1//-吡唑-5-基)苯醯胺(化合物 19 ),如表2所示。 分析數據:2-甲基-AK1,3-二苯基-1//-吡唑-5-基)苯醯胺(化合物19):熔點 (自CH2C12/己烷中再結晶,白色固體)187至lSVC^HNMR^CDCbJOO MHz) δ 2.17 (s, 3 H, CH3), 6.82 (s, 1 H, Py-H), 6.91-7.56 (m, 12 H, ArH), 7.86 (dd,2H, J=7.1, 1.0 Hz, ArH) ; l3C NMR (50 MHz, CDC13) δ 19.7, 102.8, 125.2, 125.7, 125.9, 127.3, 128.2, 128.6, 129.1, 129.4, 131.3 (5 χ CH), 132.8, 134.3 (2 x C), 137.6, 138.3 (2 χ C), 151.8, 172.1 ; IR (KBr) 3064 (brs, NH), 1718, 1683, 1599, 1549, 1501, 1458, 1383, 1319, 1233, 1140, 1108, 1078, 953, 901, 841 cm-1 ; MS m々(相對強度)354 (M+,14), 336 (13), 307 (11),289 (11),262 (8), 235 (9), 219 (12), 178 (9), 154 (68), 136 (65), 119 (100), 107 (36), 91 (79), 77 (50),69(43), 55 (50). C23Hl9N30 分析計算值:C: 78.16; Η: 5.42; N: 11.89 ;實 際值:78.19; Η: 5.47; N: 11.69。 [實施例13]合成4-曱基-A41,3-二苯基-1//-吡唑-5-基)苯醯胺 於氮氣系統下,取苯曱醯乙氰(化合物11)與等當量的苯肼,在 無溶劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, 再緩慢逐滴添加鄰曱基苯甲醯氯,待間鄰甲基苯曱醯氣添加完成 後,撤除冰浴,回溫至室溫,再攪拌約2小時,以薄層層析法監 測反應進行。當反應終止後,以乾燥濃縮移除四氫吱喃,再加入 二氣甲烷溶解反應混合物,經水萃取洗滌,收集有機層,再ύ飽 1373468 和食鹽水洗滌,經過濾和濃縮後,最後進行層析純化,即製得產 率為76%的4-甲基-;V-(1,3-二苯基-1//-吡唑-5-基)苯醯胺(化合物 20),如表2所示。 分析數據:4-曱基二苯基-1//-吡唑-5-基)苯醯胺(化合物20):熔點 (自CH2C12/己烷中再結晶,白色固體)181至183°C; 'HNMR^CDCbJOO MHz) δ 2.39 (s, 3 H, CH3), 7.19 (s, 1 H, Py-H), 7.24-7.65 (m, 12 H, ArH), 7.89 (dd,2 H, 7.3, 1.4 Hz, ArH),8.12 (b,1 H,NH); 13C NMR (50 MHz, CDC13) δ 21.5, 95.7, 124.8 (2 x CH), 125.8 (2 x CH),127.1 (2 x CH), 128.1,128.6 (2 x CH), 129.6, 129.7 (2 χ CH), 130.0 (2 χ CH), 130.3, 133.0, 136.8, 137.9, 143.3, 152.0, 163.6 ; IR (KBr) 3277 (brs, NH), 1654, 1558, 1505, 1459, 1387, 1282, 1074, 1018, 953, 915, 834 cm_1 ; MS m/z (相對強度)354 (M+, 6),233 (2), 205 (2), 177 (1), 167(1), 130 (3), 119(100), 102 (19),91 (56), 77(19), 65 (8),51 (5). C23H19N30 分析計算值:C: 78.16; H: 5.42; N: 11.89;實際值:C: 78.05; H: 5.34; N: 11.71。 [實施例14]合成3-三It甲基-A/~(l,3-二苯基比。坐_5_基)苯酿胺 於氮氣系統下,取苯甲醯乙氰(化合物11)與等當量的苯肼,在 無溶劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, 再緩慢逐滴添加對三氟曱基苯曱醯氣,待對三氟甲基苯甲醯氣添 加完成後,撤除冰浴,回溫至室溫,再攪拌約2小時,以薄層層 析法監測反應進行。當反應終止後,以濃縮乾燥移除四氫咬喃, 再加入二氯甲烧溶解反應混合物,經水萃取洗務,收集有機層, 再以德和食鹽水洗務,經過滤和濃縮後,最後進行層析純化,即 製得產率為78%的3-三氟甲基-iV-(l,3-二苯基基)苯酸 胺(化合物21),如表2所示。 27 1373468 •$7析數據.3-二氣甲基-/V-(l,3-一本基-1//-α比〇坐-5-基)苯酿胺(化合物2 I ): 熔點(自CH2C12/己烷中再結晶’黃色固體)I%至198°C ; iHNMR (CDC13, 200 MHz) δ 7.19 (s, 1 H, Py-H), 7.29-7.49 (m, 4 H, ArH), 7.56-7.58 (m, 4 H, ArH), 7.71 (d, 2W,J= 8.7 Hz, ArH), 7.82-7.91 (m, 4 H, ArH), 8.21 (b, 1 H, NH) ; l3C NMR (50 _z,CDC13) δ 96.4, 124.0, 124.7 (2 x CH),125.8 (2 x CH), 126.1,127.6 (2 x CH),128.3, 128.6 (2 x CH),128.6, 128.8, 129.4, 130.1 (2 x CH), 130.5, 131.1, 133.8, 136.1, 1 137.8, 152.1, 162.6 ; IR (KBr) 3205 (brs, NH), 3051, 1658, 1593, 1556, 1537, 1498, 1460, 1367, 1303, 1168. 1066, 854, 758, 688 cm-1;MS m/z(相對強度)407 (M+,30),377 (2), 234 (4),206 (4),173 (100), 145 (54),131 (6), 102 (38), 77 (38),51 (15). C23H16F3N30 分析計算值:C: 67.81; H: 3.96; N: 10.31 ;實際值:C: 68.12; H: 4.10; N: 10.21。 [實施例15]合成2-曱氧基-7V-(1,3-二笨基-1//-吡唑_5_基)苯醯胺 於氮氣系統下,取苯甲醯乙氰(化合物11)與等當量的苯肼,在 無溶劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, 再緩慢逐滴添加鄰甲氧基苯曱醯氣,待鄰甲氧基苯曱醯氣添加完 成後’撤除冰浴’回溫至室溫,再攪拌約2小時,以薄層層析法 監測反應進行。當反應終止後’濃縮乾燥移除四氫咬喃,再加入 一氮甲坑溶解反應混合物,經水萃取洗蘇,收集有機層,再以飽 和食鹽水洗滌,經過濾和濃縮後,最後進行層析純化,即製得產 率為90%的2-曱氧基善(1,3-二苯基-1//-。比唑_5·基)苯醯胺(化合物 22),如表2所示。 分析數據:2-甲氧基-AKU-二笨基-丨从吡唑_5_基)笨醯胺(化合物22):熔 點(經矽膠管柱層析純化,白色固體)196至198。(:; 4νΜΚ(ΟΧ:13,200 MHz) δ 3i2 (s, 3 H, Me), 6.91 (d, 1 H, J= 6.9 Hz, ArH), 7.10 (t, 1 H, J = 4.6 137346817. W = Ar, R1 = Cl, R2, R3 = H: 85% 18. W= Ar, R1, R3 = H. R2 = Cl, 71% 19. W = Ar, R1 = Me, R2, R3 = H, 84% 20. W = Ar, R1, R2 = H, R3 = Me, 76% 21. W = Ar, R1, R2 = H, R3 = CF3, 78% 22. W = Ar, R1 = OMe, R2, R3 = H, 90% 23. W = Ar, R1, R3 = H, R2 = OMe, 72% 24. W = Ar, R1, R3 = F, R2 = H, 88% 25. W = Ar, R1, R3 = H R2 = CN, 90% 26. W = Ar, R1, R2 = H R3 = CN, 78% 27. W = Ar, R1 = N02, R2, R3 = H, 76% 28. W = Ar, R1, R2 = H R3 = N02, 89% [Example 5] Synthesis of 3-diphenyl-1//-pyrazol-5-yl) acetamidine under nitrous oxide system (Compound 11) and an equivalent amount of phenylhydrazine, reacted under solvent-free conditions (neat) for 2 hours, then cooled in an ice bath and stirred to react the mixture, and slowly added dropwise vaporized acetamidine to be gasified. After the addition of acetamidine was completed, the ice bath was removed, warmed to room temperature, stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. When the reaction was terminated, the tetrahydrogen bite was removed by concentration and drying. In the south, the reaction mixture is dissolved in dioxane, washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally purified by chromatography to obtain a yield of 77%. 7V-(1,3-Diphenyl-1//-pyrazol-5-yl)acetamide (Compound 12). [Example 6] Synthesis of 2-phenyldiphenyl-1//-pyrazol-5-yl)acetamidine Under a nitrogen system, benzamidine cyanide (compound 11) and an equivalent amount of phenylhydrazine were obtained. After reacting for 2 hours under the conditions of the unreacting agent, the temperature was lowered in an ice bath and the reaction mixture was stirred, and 20 1373468 was slowly added dropwise to the phenylacetonitrile gas. After the addition of the phenethyl hydrazine gas was completed, the ice bath was removed, and the temperature was returned to the room. The temperature was further stirred for about 2 hours to monitor the progress by thin layer chromatography. After the reaction is terminated, the concentrated tetrahydrofuran is added to dryness, and the reaction mixture is further dissolved by washing with water. The organic layer is collected, washed with saturated brine, and concentrated and finally purified by chromatography. A yield of 90% 2-phenyl-#-(1,3-diphenylidene.sodium-5-yl)acetamide (compound 丨3) was obtained. Analytical data: 2-phenyl#(1,;3-diphenyl-1/^pyrazole-5-yl)acetamide (Compound 13): (purified by Shixi gum column chromatography, yellow solid) 132 To 134 ° C; iHNMRfDCl^OOMHzy 3 69 (s, 2 H, CH2), 7.05 (s, 1 H, Py-H), 7.09-7.43 (m, 13 H, ArH), 7.83 (d, 2 H, 6.6 Hz, ArH) ; , 3C NMR (50 MHz, CDC13) δ 29.7, 94.9, 123.66 (2 χ CH), 124.2, 125.7 (2 x CH), 128.1 (2 x CH), 128.6, 129.5 (4 x CH ), 129.6, 129.8 (2 x CH), 132.9, 133.5, 136.5, 137.4, 151.8, 167.3; IR (KBr) 3268 (brs, NH), 3064, 2924, 1700, 1559, I486, 1458, 1368, 1158, 1073,954 cm^MSm/z (relative intensity) 353 (M+, 8), 269 (1), 235 (18), 207 (3), 180 (1), 167 (1), 131 (3), 102 (17), 91 (100), 77 (40), 65 (29), 51 (18). C23H19N30 Analytical calculated value: C: 78.16; H: 5.42; N: 11.89; Actual value: C: 78.01; H: 5.34; N: 11.69. [Example 7] Synthesis of AT-(l,3-diphenyl-1//-pyrazol-5-yl)benzamide under the nitrogen system, taking benzamidine cyanide (compound 11) and an equivalent amount Awkward, after reacting for 2 hours under solvent-free conditions, the temperature is lowered in an ice bath and the reaction mixture is stirred, and then the gasified phenylhydrazine is slowly added dropwise. After the chlorinated phenylhydrazine is added, the ice bath is removed and the temperature is returned. After stirring to room temperature for about 2 hours, the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved in dioxane, washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally purified by chromatography. A yield of 78% of 21 1373468 diphenyl-I//- was obtained. More than 嗤-5-yl) phenylamine (Compound 14), as shown in Table 2. Analytical data: 7V-(1,3-diphenyl-1//-pyrazol-5-yl)phenylguanamine (Compound 14): melting point (purified by hydrazine column chromatography, white solid) 171 to 173° C; iHNMR^CDCbJOOMHzMTJO (s, 1 Η, Py-H), 7.30-7.64 (m, 9 H, ArH), 7.88 (dd, 2 H, J= 6.6, 1.6 Hz, ArH), 7.87 (dd, 2 H, 7= 6.6, 1.6 Hz, ArH), 8.06 (dd, 2 H, /= 6.6, 1.6 Hz, ArH) ; l3C NMR (50 MHz, CDC13) δ 95.9, 124.9 (2 χ CH), 125.8 (2 χ CH), 127.1 (2 χ CH), 128.2, 128.5 (2 χ CH), 129.0 (2 x CH), 129.3, 130.1 (2 x CH), 130.2, 132.5, 133.0, 133.7, 136.7, 137.9, 171.1; IR (KBr) 3275 (brs} NH), 3062, 1645, 1558, 1365, 1258, 1072,954,763,711,698 〇 11-1 ; MSm/z (relative intensity) 339 (M+,74), 234 (2), 206 ( 2), 105 (100), 77 (45), 51 (5). C22Hl7N30 Analytical calculated value: C: 77.86; H: 5.05; N: 12.38; actual value: C: 77.56; H: 5.24; N: 12.47. [Example 8] Synthesis of 3-fluoro-7V-(1,3-diphenyl-1//-pyrazol-5-yl) acesulfame under nitrogen system, abbreviated acetonitrile (Compound 11) After reacting with an equivalent amount of benzoquinone in a solvent-free condition for 2 hours, the temperature is lowered in an ice bath and the reaction mixture is stirred, and then the inter-fluorinated alum gas is slowly added dropwise, after the addition of the fluorophenyl hydrazine gas is completed. The ice bath was removed, warmed to room temperature, stirred for additional 2 hours, and the reaction was monitored by thin layer chromatography. When the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and then the reaction mixture is dissolved by water extraction. The organic layer is collected and washed with saturated brine. After filtration and concentration, the chromatographic purification is carried out. That is, a product of 3-fluoro-; V-(1,3-diphenylpyrazole-5-yl)benzamide (Compound 15) having a yield of 77% was obtained, as shown in Table 2. Analytical data: 3-H(l,3-diphenyl-indene//-pyrazole-5-phenyl)benzamide (Compound 15): melting point (recrystallized from CH2Cl2 / MeOH, white solid) 175 to 177 〇c; iH nmr (CDq3, 2〇〇MHz) 1373468 δ 7.18 (s, 1 Η, Py-H), 7.31-7.41 (m, 8 Η, ArH), 7.57 (dd, 4 H, J = 4.2, 1.4 Hz, • ArH), 7.88 (dd, 2 H, J= 6.6, 1.4 Hz, ArH), 8.21 (b, 1 Η, NH) ; , 3C NMR (50 • MHz, CDC13) 8 96.4, 114.5, 114.9 , 119.4, 119.8, 122.4 (2 χ CH), 124.7 (2 x CH), 125.8, 128.6, 128.7 (2 x CH), 130.1 (2 χ CH), 130.6, 130.8, 132.9, 135.3, 135.4, 136.3.137.8 , 152.0, 160.4, 162.6, 165.3; IR (KBr) 3269 (brs, NH), 3064, 1684, 1589, 1458, 1365, 1290, 1072, 956,692 cm_l; MSm/z (relative intensity) 357 (ivf, 15) , 356 (15), 206 (2), 123 (100), 101 (18), 95 (35), 77 (17), 51 (10). C22Hl6FN30 Analytical calculated value: C: 73.94; H: 4.51; N : 11.76 ; Actual values: C: 73.66; H: 4.46; N: 11.41. • [Example 9] Synthesis of 4-fluoro-7V-(1,3-diphenyl-1//-pyrazol-5-yl)benzamide as a benzoic acid cyanide under a nitrogen system (Compound 11) After reacting with an equivalent amount of benzoquinone in a solvent-free condition for 2 hours, the temperature is lowered in an ice bath and the reaction mixture is stirred, and then p-fluorobenzoquinone gas is slowly added dropwise, after the addition of the fluorobenzoquinone gas is completed. The ice bath was removed, warmed to room temperature, stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved by adding methane. After washing with water, the organic layer is collected, washed with saturated brine, water, filtered and concentrated, and finally purified by chromatography. That is, 4-fluoro-indole, 3-diphenyl-177-pyrazol-5-ylbenzoguanamine (Compound 16) having a yield of 70% was obtained, as shown in Table 2. Analytical data: 4-Fluoro-iV-(l,3-diphenyl-1//-pyrazol-5-yl)benzamide (Compound 16): m.p. (yield from CH2Cl2/MeOH, white solid) 187 to 189 ° C; WNMRiCDCb, 200 MHz) δ 7.12 (t, 1 Η, J = 8.7 Hz, ArH), 7.18 (s, 1H, Py-H), 7.32-7.48 (m, 4 H, ArH), 7.55-7.58 (m, 4 H, ArH), 7.70-7.77 (m, 2 H, ArH), 7.88 (dd, 4 H, J = 7.9, 1.3 Hz, ArH), 8.12 (b, 1H, NH); l3C NMR (50 MHz, CDC13) δ 96.0, Π6.0, 116.4, 124.8 (2 x CH), 125.8 (2 χ CH), 128.2, 128.6 (2 x CH), 128.7, 129.4, 1373468 129_6, 130.1 (2 xCH), 132.9, 136.5, 137.9, 146.2, 152.1, 162.6; IR(KBr) 3217 (brs, NH), 3045, 1685, 1529, 1504, 1460, 1367, 1286, 1234, 1072, 918, 760, 694 cm —1; MS m/2 (relative intensity) 357 (M+, 15), 234 (1), 206 (1), 123 (100), 102 (24), 95 (46), 77 (24), 51 ( 12). Calculated for C22Hl6FN30: c: 73.94; H: 4.51; N: 11.76; Actual: C: 73.87; H: 4.67; N: 11.35. [Example 10] Synthesis of 2-gas-"-(1,3-diphenyl-1//-pyrazol-5-yl)benzamide as a benzoic acid cyanide under a nitrogen system (Compound 11) After reacting with an equivalent amount of benzoquinone in a solvent-free condition for 2 hours, the temperature is lowered in an ice bath and the reaction mixture is mixed. Then, the adjacent gas is slowly added dropwise, and the addition of the adjacent gas is completed. The ice bath was removed and warmed to room temperature, stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved in dioxane, and the mixture is extracted with water. The organic layer is collected and washed with saturated brine. After filtration and concentration, the chromatographic purification is carried out. That is, 2-gas-AM,3-diphenyl-1//-pyrazole-5-yl acinoxalide (Compound 17) was obtained in a yield of 85%, as shown in Table 2. Analytical data: 2-gas-7V-(1,3-diphenyl-1//-pyrazol-5-yl)phenylguanamine (Compound 17): melting point (purified by hydrazine column chromatography, yellow solid 147 to 149 ° C; WNMR^CDCb, 200 ΜΗζ) δ 7.14 (s, 1 H, Py-H), 7.22-7.68 (m, 11 H, ArH), 7.70-7.94 (m, 3 H, ArH), 8.64 (b, 1 Η, NH) ; l3C NMR (50 MHz, CDC13) δ 96.2, 125.5 (2 χ CH), 125.8 (2 x CH), 127.5, 128.2, 128.6 (2 χ CH), 128.9, 129.5 ( 2 x CH), 130.5, 131.2, 132.0, 132.5, 132.9, 136.6, 137.6, 151.9, 162.7, 168.9; IR (KBr) 3256 (brs, NH), 3066, 1666, 1566, 1502, 1460, 1369, 1263, 1117, 1051, 765, 696 cm"' ; MS m/z (relative intensity) 373 〇Vf,10),338(18),234(1),206 (2), 141 (44),139(100) , 111 (36), 102 (34), 77 (36), 51 (16). C22H16C1N30 Analytical calculated value: C: 70.68; H: 4.31; N: 24 Ϊ 373468 1 1·24 ; Actual value: c: 70.29; Η: 4.51; N: 丨丨.丨4. • [ κ she example 1 合成] synthesis of 3 · gas - 々 - (1,3-diphenyl _] / / _ pyrazole _5 yl) benzoguanamine under a nitrogen system, take a clunk acetonitrile ( The compound 丨丨) is reacted with an equivalent amount of phenylhydrazine in a solvent-free condition for 2 hours, then the temperature is lowered in an ice bath and the reaction mixture is stirred, and then the mixture is added dropwise to the gas, and the gas is added to the gas. After the gas addition was completed, the ice was removed, and the mixture was warmed to room temperature, stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved by dioxane, washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally purified by chromatography. That is, 3-gas-#-1,3-diphenyl_1//-pyrazole-5-yl azelaamine (Compound 18) having a yield of 71% was obtained, as shown in Table 2. Analytical data: 3-gas-AL(i,3_diphenylpyrazole-5-phenyl)benzamide (Compound 丨8): melting point (purified by Shixi rubber column chromatography, yellow solid) 168 to 17 〇 〇c ; iHNMR(CDC13, 200 ΜΗζ) δ 7.14 (s, 1 Η, Py-H), 7.22-7.61 (m, 10 H, ArH), 7.65-7.94 (m, 3 H, ArH), 8.04 (b , 1 H, NH); l3CNMR (50MHz, CDC13) 8 96.4, 124.8 (2 x CH), 124.9, 125.8 (2 x CH), 127.7, 128.2, 128.6 (2 x CH), 128.8, 130.1 (2 x CH ), 130.3, 132.6, 133.7, φ 134.9, 136.2, 137.8, 152.1, 162.6, 169.6; IR (KBr) 3248 (brs, NH), 3052, 1675, 1573, 1498, 1455, 1431, 1358, 1292, 1252, 1061,758, 692 cm-1 ; MS m/z (relative intensity) 373 (M+, 15), 343 (1), 234 (2), 206(3), 141 (33), 139(100), 111 (46), l〇2 (32), 77 (33), 75 (27), 51 (19). C22HI6C1N30 Analytical calculations: C: 70.68; HM.31; • N: 11.24; Actual: C: 70.29 ; H: 4.51; N: 11.14. [Example 12] Synthesis of 2-mercapto 3-diphenyl-1//-pyrazol-5-yl)benzamide Under a nitrogen system, benzoquinone (Compound 11) and equivalent benzene were taken.肼, after reacting for 2 hours without solvent, the temperature was lowered in an ice bath and the reaction mixture was stirred, and then o-methylbenzonitrile was slowly added dropwise, after the addition of m-o-methyl sulphonium was completed 25 1373468. The ice bath was removed, warmed to room temperature, stirred for additional 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved by adding dioxane, washed with water, and the organic layer is collected, washed with saturated brine, and then subjected to chromatography and purification. That is, 2-mercapto-W-(l,3-diphenyl-1//-pyrazol-5-yl)benzamide (Compound 19) was obtained in a yield of 84%, as shown in Table 2. Analytical data: 2-methyl-AK1,3-diphenyl-1//-pyrazol-5-ylphenylamine (Compound 19): melting point (recrystallized from CH2C12 / hexanes, white solid) 187 To lSVC^HNMR^CDCbJOO MHz) δ 2.17 (s, 3 H, CH3), 6.82 (s, 1 H, Py-H), 6.91-7.56 (m, 12 H, ArH), 7.86 (dd, 2H, J =7.1, 1.0 Hz, ArH) ; l3C NMR (50 MHz, CDC13) δ 19.7, 102.8, 125.2, 125.7, 125.9, 127.3, 128.2, 128.6, 129.1, 129.4, 131.3 (5 χ CH), 132.8, 134.3 (2 x C), 137.6, 138.3 (2 χ C), 151.8, 172.1 ; IR (KBr) 3064 (brs, NH), 1718, 1683, 1599, 1549, 1501, 1458, 1383, 1319, 1233, 1140, 1108, 1078, 953, 901, 841 cm-1 ; MS m々 (relative intensity) 354 (M+, 14), 336 (13), 307 (11), 289 (11), 262 (8), 235 (9), 219 (12), 178 (9), 154 (68), 136 (65), 119 (100), 107 (36), 91 (79), 77 (50), 69 (43), 55 (50). Analysis calculated for C23Hl9N30: C: 78.16; Η: 5.42; N: 11.89; actual value: 78.19; Η: 5.47; N: 11.69. [Example 13] Synthesis of 4-mercapto-A41,3-diphenyl-1//-pyrazol-5-yl)benzamide under a nitrogen system, taking benzoquinone (Compound 11) and the like Equivalent phenylhydrazine, after reacting for 2 hours without solvent, the temperature is lowered in an ice bath and the reaction mixture is stirred, and then o-mercaptobenzyl hydrazine chloride is slowly added dropwise, after the addition of m-toluene gas is completed. The ice bath was removed, warmed to room temperature, stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration in a dry state, and the reaction mixture is dissolved by adding methane, washed with water, and the organic layer is collected, washed with 1373468 and brine, filtered and concentrated, and finally layered. Purification and purification, that is, the yield of 76% 4-methyl-; V-(1,3-diphenyl-1//-pyrazol-5-yl)benzamide (Compound 20), as shown in the table 2 is shown. Analytical data: 4-mercaptodiphenyl-1//-pyrazol-5-yl)benzamide (Compound 20): m.p. (recrystallized from CH2C12/hexanes, white solid) 181 to 183 °C; 'HNMR^CDCbJOO MHz) δ 2.39 (s, 3 H, CH3), 7.19 (s, 1 H, Py-H), 7.24-7.65 (m, 12 H, ArH), 7.89 (dd, 2 H, 7.3, 1.4 Hz, ArH), 8.12 (b, 1 H, NH); 13C NMR (50 MHz, CDC13) δ 21.5, 95.7, 124.8 (2 x CH), 125.8 (2 x CH), 127.1 (2 x CH), 128.1,128.6 (2 x CH), 129.6, 129.7 (2 χ CH), 130.0 (2 χ CH), 130.3, 133.0, 136.8, 137.9, 143.3, 152.0, 163.6 ; IR (KBr) 3277 (brs, NH), 1654, 1558, 1505, 1459, 1387, 1282, 1074, 1018, 953, 915, 834 cm_1 ; MS m/z (relative intensity) 354 (M+, 6), 233 (2), 205 (2), 177 ( 1), 167(1), 130 (3), 119(100), 102 (19), 91 (56), 77(19), 65 (8), 51 (5). C23H19N30 Analytical calculation: C: 78.16; H: 5.42; N: 11.89; actual values: C: 78.05; H: 5.34; N: 11.71. [Example 14] Synthesis of 3-tri-It-methyl-A/~ (l,3-diphenyl ratio. Sodium _5-yl) phenyl-ternamine was taken under a nitrogen system to obtain benzamidine cyanide (Compound 11) After reacting with an equivalent amount of benzoquinone in the absence of solvent for 2 hours, the temperature was lowered in an ice bath and the reaction mixture was stirred, and then p-trifluorodecyl phenyl hydrazine was slowly added dropwise to the trifluoromethyl benzophenone. After the addition of helium gas was completed, the ice bath was removed, warmed to room temperature, and stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. When the reaction is terminated, the tetrahydrogenate is removed by concentration and drying, and then the reaction mixture is dissolved by adding methylene chloride, and the organic layer is collected by water extraction, and then washed with de and brine, filtered and concentrated, and finally Chromatographic purification gave a yield of 78% of 3-trifluoromethyl-iV-(l,3-diphenyl)benzoic acid amine (Compound 21) as shown in Table 2. 27 1373468 • $7 analysis data. 3-Dimethylmethyl-/V-(l,3-one-based-1//-α ratio 〇--5-yl) phenylamine (Compound 2 I): melting point ( Recrystallization of 'yellow solids' from CH2C12/hexanes I% to 198 °C; iHNMR (CDC13, 200 MHz) δ 7.19 (s, 1 H, Py-H), 7.29-7.49 (m, 4 H, ArH) , 7.56-7.58 (m, 4 H, ArH), 7.71 (d, 2W, J = 8.7 Hz, ArH), 7.82-7.91 (m, 4 H, ArH), 8.21 (b, 1 H, NH) ; l3C NMR (50 _z, CDC13) δ 96.4, 124.0, 124.7 (2 x CH), 125.8 (2 x CH), 126.1, 127.6 (2 x CH), 128.3, 128.6 (2 x CH), 128.6, 128.8, 129.4, 130.1 (2 x CH), 130.5, 131.1, 133.8, 136.1, 1 137.8, 152.1, 162.6 ; IR (KBr) 3205 (brs, NH), 3051, 1658, 1593, 1556, 1537, 1498, 1460, 1367, 1303 , 1168. 1066, 854, 758, 688 cm-1; MS m/z (relative intensity) 407 (M+, 30), 377 (2), 234 (4), 206 (4), 173 (100), 145 (54), 131 (6), 102 (38), 77 (38), 51 (15). C23H16F3N30 Analytical calculated value: C: 67.81; H: 3.96; N: 10.31 ; Actual value: C: 68.12; H: 4.10; N: 10.21. [Example 15] Synthesis of 2-decyloxy-7V-(1,3-diphenyl-1//-pyrazole-5-yl)benzamide Under the nitrogen system, benzamidine cyanide (compound) 11) After reacting with an equivalent amount of benzoquinone in the absence of solvent for 2 hours, the temperature is lowered in an ice bath and the reaction mixture is stirred, and then o-methoxybenzoquinone gas is slowly added dropwise to the o-methoxybenzoquinone. After the completion of the addition of helium, the 'ice bath was removed' and the temperature was warmed to room temperature, and the mixture was further stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. When the reaction is terminated, the mixture is concentrated and dried to remove the tetrahydrogenate. Then, the reaction mixture is dissolved by adding a nitrogen nitrite. The extract is washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally layered. Purification and purification, that is, the yield of 90% of 2-nonyloxy good (1,3-diphenyl-1 / / -. azole 3-5 group) benzoguanamine (Compound 22), as shown in Table 2 Shown. Analytical data: 2-methoxy-AKU-diphenyl-purine from pyrazole-5-yl) acesulfame (Compound 22): melting point (purified by hydrazine column chromatography, white solid) 196 to 198. (:; 4νΜΚ(ΟΧ:13,200 MHz) δ 3i2 (s, 3 H, Me), 6.91 (d, 1 H, J= 6.9 Hz, ArH), 7.10 (t, 1 H, J = 4.6 1373468
Hz, ArH), 7.13 (s, 1 H, Py-H), 7.33-7.89 (m, 8 H, ArH), 7.91 (dd, 2 H, 7= 6.7, • 1.3 Hz, ArH), 8.43 (dd, 1 H, J = 6.7, 1.3 Hz, ArH) ; ,3C NMR (50 MHz, CDC13) δ 55.6, 94.6, 111.4, 120.1, 121.8, 125.8 (2 χ CH), 125.9 (2 x CH), 128.0, 129.8 (2 x CH), 132.7 (2 χ CH), 133.1, 133.9, 135.1, 136.7, 138.1, 152.1, 157.2, 161.2; IR (KBr) 3306 (brs, NH), 3062, 2924, 1674, 1598, 1570, 1496, 1483, 1371, 1296, 1244, 1163. 1018, 759, 694 cm_l;MS w/z(相對強度)369 (M+, 2), 206 (1), 135 (100),120 (3), 102 (15),92 (25), 77 (49),63 (7),51 (11). C23Hl9N30 分析 計算值:C: 74.78; H: 5.18; N: 11.37 ;實際值:C: 74_98; H: 5.43; N: 11_48。 ® [實施例16]合成3-甲氧基-7V-(1,3-二苯基-1//-吡唑-5-基)苯醯胺 於氮氣系統下,取苯曱醯乙氰(化合物11)與等當量的苯肼,在 無溶劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, 再緩慢逐滴添加間曱氧基苯甲醯氣,待間甲氧基苯甲醯氣添加完 成後,撤除冰浴,回溫至室溫,再攪拌約2小時,以薄層層析法 監測反應進行。當反應終止後,以濃縮乾燥移除四氫呋喃,再加 入二氣甲烷溶解反應混合物,經水萃取洗滌,收集有機層,再以 φ 飽和食鹽水洗滌,經過濾和濃縮後,最後進行層析純化,即可製 得產率為72%的3-曱氧基-7V-(1,3-二苯基-1//-吡唑-5-基)苯醯胺(化 合物23)’如表2所示。 分析數據:3-曱氧基-AKU-二苯基-1//-吡唑-5-基)苯醯胺(化合物23):熔 點(經矽膠管柱層析純化,黃色固體)175至177°C ; WNMI^CDCl^OO MHz) δ 3.84 (s, 3 Η, Me), 7.19 (s, 1 H, Py-H), 7.28-7.72 (m, 12 H, ArH), 7.88 (d, 2 H, J= 8.0 Hz, ArH), 8.21 (b, 1 H, NH); ,3C NMR (50 MHz, CDC13) δ 55.5, 96.1, 112.6, 118.6, 118.7, 124.4 (2 χ CH), 124.8, 125.9 (2.x CH), 128.2, 128.6 (2 x CH), 129.6, 130.0 (2 x CH), 133.0, 134.6, 136.6, 137.9, 152.0, 160.1, 29 1373468 163.7 ; IR (KBr) 3257 (brs, NH), 3066, 2843, 1667, 1597, 1560, 1502, 1460, 1369, 1284, 1230, 1041,769,702 cm_l;MSm/Z(相對強度)369 (M+, 1),234 (2), 206 (2), 135 (100),107 (27),92 (25),77 (52),64 (13),51 (12). C23H丨9N30 分析 計算值:C: 74.78; Η: 5.18; N: 11.37 ;實際值:C: 74.55; Η: 5.64; N: 11.72。 [實施例17]合成2,4-二氟基3-二苯基-1//-吡唑-5-基)苯醯胺 於氮氣系統下,取苯甲醯乙氰(化合物11)與等當量的笨肼,在 無溶劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, 再緩慢逐滴添加鄰對二氟基苯曱醯氣,待鄰對二氟基苯曱醯氣添 加完成後,撤除冰浴,回溫至室溫,再攪拌約2小時,以薄層層 析法監測反應進行。當反應終止後,以濃縮乾燥移除四氫呋喃, 再加入二氣甲烷溶解反應混合物,經水萃取洗滌,收集有機層, 再以飽和食鹽水洗蘇,經過濾、和濃縮後,最後進行層析純化,即 製得產率為88%的2,4-二氟基-7V-(1,3-二苯基-1//-吡唑-5-基)苯醯 胺(化合物24),如表2所示。 分析數據:2,4-二氟基-尽(1,3-二苯基-1//-吡唑-5-基)苯醯胺(化合物24): 熔點(自CH2C12/己烷中再結晶,黃色固體)162至164 °C ; W NMR (CDC13, 200 MHz) δ 6.74-6.89 (m, 1 Η, ArH), 7.92-7.10 (m, 1 H, ArH), 7.26 (s, 1 H, Py-H), 7.31-7.51 (m, 4 H, ArH), 7.55-7.59 (m, 4 H, ArH), 7.88 (dd, 2 H, J = 6.7, 1.4 Hz, ArH), 8.14-8.39 (m, 1 H, ArH), 8.74 (b, 1 Η, NH) ; ,3C NMR (50 MHz, CDC13) δ 95.5, 104.0, 104.5, 105.0, 112.9, 113.3, 116.7, 116.9, 117.0, 125.1 (2 x CH), 125.8 (2 χ CH), 128.2, 128.6 (2 χ CH), 128.8, 130.0 (2 χ CH), 132.9, 134.2, 134.4, 136.7, 152.0, 158.2, 164.3 ; IR (KBr) 3423 (brs,NH), 3061, 1693, 1614, 1570, 1494, 1289, 1111,970, 766, 694 cm—1 ; MS w/z (相對強度) 376 (W,100),358 (3),336 (3),304 (3),282 (5),262 (3),234 ⑹,219 (4)::207 30 1373468 ‘ (5),154 (5),141 (98),113 ⑺,92 ⑷,77 (12),57 (4)· C22H|5f2N3〇 分析計算 • 值:C: 70.39; H: 4.03; N: 11.19 ;實際值:C: 70·81; H: 4.19; N: 11.54。 •[實施例18]合成3-氰基-#-(l,3-二苯基·丨//·吡唑_5_基)苯醯胺 於氮氣系統下’取苯曱醯乙氰(化合物11 )與等當量的苯肼,在 無浴劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, 再緩慢逐滴添加鄰氰基苯曱醯氯’待鄰氰基苯甲醯氣添加完成 後,撤除冰浴,回溫至室溫,再搜拌約2小時,以薄層層析法監 測反應進行。當反應終止後,以濃縮乾燥移除四氫呋喃,再加入 一氮甲院〉谷解反應混合物’經水萃取洗務,收集有機層,再以飽 和食鹽水洗滌,經過濾和濃縮後,最後進行層析純化,即製得產 率為90%的3-氰基-ΑΚ1,3-二苯基-1//-吼唑_5_基)苯醯胺(化合物 25),如表2所示。 分析數據氰基善(1,3-二苯基-1//-。比唑_5·基)苯酿胺(化合物25):炫點 (經石夕膠管柱層析純化,褐色固體)207至208 4 NMR €CDC1:3, 200 δ 6.90 (s, 1 Η, Py-H), 7.26-7.45 (m, 11 H, ArH), 7.79-7.92 (m, 3 H, ArH) ; l3C φ NMR (50 MHz, CDC13) δ 100.5, 112.7, 117.1, 124.3 (2 χ CH), 125.3 (2 χ CH), 128.3 (2 x CH), 128.7, 129.5 (2 χ CH), 129.6, 131.2, 131.8, 134.4, 135.3, 135.7, 138.6, 151.7, 164.3 ; IR (KBr) 3309 (brs, NH), 3068, 2922, 2852, 2232, 1689, 1654, 1560, 1498, 1458, 1363, 1292, 1190, 1072,916cnTi;MSm/z(相對強度) , 364 (M+,59), 234 (11),207 (6),147 (8),130 (100),102 (49),91 (2),77 (15),64 ⑴,51 ⑻· C23H16N40 分析計算值:C: 75.81; H: 4.43; N: 15.38 ;實際值:C: 75.49; H: 4.65; N: 15.18。 [實施例19]合成4-氰基-ΛΓ-(1,3-二苯基-1//-吡唑-5-基)苯醯胺 於氮氣系統下,取苯甲醯乙氰(化备物11)與等當量的苯肼’在 31 1373468 無溶劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, 再緩慢逐滴添加對氰基苯曱醯氣,待對氰基苯甲醯氯添加完成 後’撤除冰浴’回溫至室溫,再攪拌約2小時,以薄層層析法監 測反應進行。當反應終止後,以濃縮乾燥移除四氫呋喃,再加入 二氣甲烷溶解反應混合物,經水萃取洗滌,收集有機層,再以飽 和食鹽水洗滌’經過濾和濃縮後,最後進行層析純化,即製得產 率為78%的4-氰基-7V-(1,3-二苯基-1//-吡唑-5-基)苯醯胺(化合物 26) ’如表2所示。 分析數據:4-氰基r7V-(i,3-二苯基-1//-吡唑-5-基)笨醯胺(化合物26):熔點 (經矽膠管柱層析純化,黃色固體)2〇7至209 °C;它NMR (CDC13, 200 MHz) δ 7_02 (s, 1 H, Py-H),7.35-7.49 (m, 6 H,ArH),7.66-7.72 (m,3 H,ArH), 7.90-7.95 (m, 3 H, ArH), 8.12-8.20 (m, 2 H, ArH), 8.27 (b, 1 Η, NH) ; ,3C NMR (50 MHz, CDC13) δ 99.7, 112.7, 117.7, 124.0 (2 χ CH), 125.3 (2 χ CH), 127.7, 127.9, 128.6 (2 χ CH), 129.9 (2 χ CH), 129.9, 131.3,132.1, 133.4, 134.9, 135.3, 136.8, 139.2, 150.7, 163.8 ; IR (KBr) 3250 (brs, NH), 3087, 1686, 1578, 1501, 1296, 769, 699 cm_l ; MS m/z (相對強度)364 (M+, 100),335 (6),262 (3),234 (12),206 (7),130 (98),102 (44),77 (16),51 (5). C23H|6N40 分析計算值:C: 75.81; Η: 4·43; N: 15.38 ;實際值:C: 76.12; Η: 4·42; N: 15.14。 ' [實施例20]合成2-硝基-iV-(l,3-二苯基-1//-°比唑-5-基)苯醯胺 於氮氣系統下,取苯甲醯乙氰(化合物11)與等當量的苯肼’在 無溶劑條件下反應2小時後’於冰各下降溫並撥掉反應混合物’ 再緩慢逐滴添加鄰硝基苯甲醯氣,待鄰硝基苯曱酿氣添加完成 後,撤除冰浴’回溫至室溫’再攪拌約2小時,以薄層層析法監 測反應進行。當反應終止後,以濃縮乾燥移除四氫呋喃,再加入 -1373468 二氯曱烷溶解反應混合物,經水萃取洗滌,收集有機層,再以飽 和食鹽水洗滌,經過濾和濃縮後,最後進行層析純化,即製得產 率為76%的2-硝基3-二苯基-1//-吡唑-5-基)苯醯胺(化合物 27) ,如表2所示。 分析數據:2-硝基-#-(1,3-二苯基-1//-吡唑-5-基)苯醯胺(化合物27):熔點 (自CH2C12/己烷中再結晶,白色固體)229至231°C; iHNMR^CDCbJOO MHz) δ 7.00 (s, 1 Η, Py-H), 7.36-7.89 (m, 12 H, ArH), 8.08-8.26 (m, 3 H, ArH + NH) ; ,3C NMR (50 MHz, CDC13) δ 100.1, 124.4(2 x CH), 124.8, 125.7 (2 x CH), 128.3, 128.6, 129.2 (2 χ CH), 129.7, 130.2 (2 χ CH), 132.0, 133.1, 134.6, 135.6, 137.0, 138.9,144.4, 147.0, 150.8, 167.8 ; IR(KBr)3261 (brs, NH), 3061, 1718, 1533, 1502, 1354,1249, 7574, 690 cm-1;MS m/z(相對強度)385 (M+, 66), 370 (27), 339 (22), 323 (10), 307 (45), 289 (39), 285 (18), 262 (15), 234 (32), 206 (22), 178 (31), 165 (48),154 (100). C22H,6N403 分析計算值:C: 68.74; H: 4.20; N: 14.58 ;實際值:C: 68.81; H: 4.15; N: 14.81。 [實施例21]合成4-硝基-ΛΚ1,3-二苯基-1//-吡唑-5-基)笨醯胺 於氮氣系統下’取苯曱醯乙氰(化合物11)與等當量的苯肼,在 無溶劑條件下反應2小時後’於冰浴下降溫並攪拌反應混合物, 再緩慢逐滴添加對硝基苯曱醯氣,待對硝基苯曱醯氣添加完成 後,撤除冰浴,回溫至室溫,再攪拌約2小時,以薄層層析法監 測反應進行。當反應終止後,以濃縮乾燥移除四氫呋喃,再加入 二氣f烷溶解反應混合物’經水萃取洗滌,收集有機層,再以飽 和食鹽水洗滌,經過濾和濃縮後,最後進行層析純化,即製得產 率為89%的4-頌基-iV-(l,3-二苯基-1//-。比σ坐-5。基)笨醯胺(化合物 28) ,如表2所示。 33 1373468 分析數據:4-硝基-W-(l,3-二笨基-1//-吡唑-5-基)笨醯胺(化合物28):熔點 (自CH2C12/己烷令再結晶,黃色固體)221至223 °C ; iHNMRfDCbJOO MHz) δ 7.23 (s, 1 Η, Py-H), 7.37 (t, 1 Η), 7.43 (t, 1 Η), 7.51 (q, 1 Η), 7.60 (d, 2 H, J= 4.5 Hz, ArH), 7.36-7.89 (m, 12 H, ArH), 8.08-8.26 (m, 3 H, ArH + NH), 7.92 (m, 4H), 8.09 (b, 1 Η, NH), 8.32 (d, 2 H, 8.7 Hz, ArH) ; l3C NMR (50 MHz, CDC13) δ 100.1, 122.9 (2 x CH), 123.0 (2 χ CH), 124.7 (2 χ CH), 126.9, 127.5, 128.1 (2 x CH), 128.6 (2 χ CH), 128.8 (2 χ CH), 132.3, 136.1, 138.3,Hz, ArH), 7.13 (s, 1 H, Py-H), 7.33-7.89 (m, 8 H, ArH), 7.91 (dd, 2 H, 7= 6.7, • 1.3 Hz, ArH), 8.43 (dd , 1 H, J = 6.7, 1.3 Hz, ArH) ; , 3C NMR (50 MHz, CDC13) δ 55.6, 94.6, 111.4, 120.1, 121.8, 125.8 (2 χ CH), 125.9 (2 x CH), 128.0, 129.8 (2 x CH), 132.7 (2 χ CH), 133.1, 133.9, 135.1, 136.7, 138.1, 152.1, 157.2, 161.2; IR (KBr) 3306 (brs, NH), 3062, 2924, 1674, 1598, 1570 , 1496, 1483, 1371, 1296, 1244, 1163. 1018, 759, 694 cm_l; MS w/z (relative strength) 369 (M+, 2), 206 (1), 135 (100), 120 (3), 102 (15),92 (25), 77 (49),63 (7),51 (11). C23Hl9N30 Analytical calculated value: C: 74.78; H: 5.18; N: 11.37 ; Actual value: C: 74_98; H : 5.43; N: 11_48. ® [Example 16] Synthesis of 3-methoxy-7V-(1,3-diphenyl-1//-pyrazol-5-yl)benzamide under nitrous acid system Compound 11) is reacted with an equivalent amount of phenylhydrazine in a solvent-free condition for 2 hours, then the temperature is lowered in an ice bath and the reaction mixture is stirred, and then m-decyloxybenzonitrile is slowly added dropwise, to be m-methoxybenzene. After the addition of formazan gas was completed, the ice bath was removed, warmed to room temperature, and stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and then the reaction mixture is dissolved by adding methane, washed with water, and the organic layer is collected, washed with φ saturated brine, filtered and concentrated, and finally purified by chromatography. A yield of 72% of 3-decyloxy-7V-(1,3-diphenyl-1//-pyrazol-5-yl)benzamide (Compound 23) can be obtained as shown in Table 2. Show. Analytical data: 3-decyloxy-AKU-diphenyl-1//-pyrazol-5-yl)benzamide (Compound 23): melting point (purified by hydrazine column chromatography, yellow solid) 175 to 177 °C; WNMI^CDCl^OO MHz) δ 3.84 (s, 3 Η, Me), 7.19 (s, 1 H, Py-H), 7.28-7.72 (m, 12 H, ArH), 7.88 (d, 2 H, J = 8.0 Hz, ArH), 8.21 (b, 1 H, NH); , 3C NMR (50 MHz, CDC13) δ 55.5, 96.1, 112.6, 118.6, 118.7, 124.4 (2 χ CH), 124.8, 125.9 (2.x CH), 128.2, 128.6 (2 x CH), 129.6, 130.0 (2 x CH), 133.0, 134.6, 136.6, 137.9, 152.0, 160.1, 29 1373468 163.7 ; IR (KBr) 3257 (brs, NH ), 3066, 2843, 1667, 1597, 1560, 1502, 1460, 1369, 1284, 1230, 1041, 769, 702 cm_l; MSm/Z (relative strength) 369 (M+, 1), 234 (2), 206 (2) , 135 (100), 107 (27), 92 (25), 77 (52), 64 (13), 51 (12). C23H丨9N30 Analytical calculated value: C: 74.78; Η: 5.18; N: 11.37; Actual value: C: 74.55; Η: 5.64; N: 11.72. [Example 17] Synthesis of 2,4-difluoro 3-diphenyl-1//-pyrazol-5-yl)benzamine under the nitrogen system, taking benzamidine cyanide (compound 11) and the like The equivalent of awkward, after reacting for 2 hours without solvent, the temperature is lowered in an ice bath and the reaction mixture is stirred, and o-p-difluorobenzoquinone gas is slowly added dropwise, to the adjacent p-difluorobenzophenone gas. After the addition was completed, the ice bath was removed, warmed to room temperature, and stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved by adding methane, washed with water, and the organic layer is collected, washed with saturated brine, filtered, concentrated, and finally purified by chromatography. That is, a yield of 88% of 2,4-difluoro-7V-(1,3-diphenyl-1//-pyrazol-5-yl)benzamide (Compound 24) was obtained, as shown in Table 2 Shown. Analytical data: 2,4-difluoro-ethyl (1,3-diphenyl-1//-pyrazol-5-yl)benzamide (Compound 24): melting point (recrystallized from CH2C12/hexane) , yellow solid) 162 to 164 °C; W NMR (CDC13, 200 MHz) δ 6.74-6.89 (m, 1 Η, ArH), 7.92-7.10 (m, 1 H, ArH), 7.26 (s, 1 H, Py-H), 7.31-7.51 (m, 4 H, ArH), 7.55-7.59 (m, 4 H, ArH), 7.88 (dd, 2 H, J = 6.7, 1.4 Hz, ArH), 8.14-8.39 ( m, 1 H, ArH), 8.74 (b, 1 Η, NH) ; , 3C NMR (50 MHz, CDC13) δ 95.5, 104.0, 104.5, 105.0, 112.9, 113.3, 116.7, 116.9, 117.0, 125.1 (2 x CH), 125.8 (2 χ CH), 128.2, 128.6 (2 χ CH), 128.8, 130.0 (2 χ CH), 132.9, 134.2, 134.4, 136.7, 152.0, 158.2, 164.3 ; IR (KBr) 3423 (brs, NH), 3061, 1693, 1614, 1570, 1494, 1289, 1111,970, 766, 694 cm-1; MS w/z (relative strength) 376 (W,100),358 (3),336 (3) ,304 (3),282 (5),262 (3),234 (6),219 (4)::207 30 1373468 ' (5),154 (5),141 (98),113 (7),92 (4),77 (12), 57 (4)· C22H|5f2N3〇 Analytical calculation • Value: C: 70.39; H: 4.03; N: 11.19 ; Actual value: C: 70·81; H: 4.19 ; N: 11.54. • [Example 18] Synthesis of 3-cyano-#-(l,3-diphenyl·indol//·pyrazole-5-yl)benzamide as a benzoic acid cyanide (nitrogen compound) 11) After reacting with an equivalent amount of benzoquinone in a bathless condition for 2 hours, the temperature is lowered in an ice bath and the reaction mixture is stirred, and then o-cyanobenzoquinone chloride 'o-cyanobenzamide is slowly added dropwise. After the gas addition was completed, the ice bath was removed, warmed to room temperature, and further mixed for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and then the mixture is extracted by water extraction, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally layered. The purification was carried out to obtain 3-cyano-indole 1,3-diphenyl-1//-carbazole-5-phenyl)benzamide (Compound 25) in a yield of 90%, as shown in Table 2. Analytical data: Cyanamide (1,3-diphenyl-1//-.biazole-5) phenylamine (Compound 25): Hyun point (purified by Shixi rubber column chromatography, brown solid) 207 To 208 4 NMR €CDC1:3, 200 δ 6.90 (s, 1 Η, Py-H), 7.26-7.45 (m, 11 H, ArH), 7.79-7.92 (m, 3 H, ArH) ; l3C φ NMR (50 MHz, CDC13) δ 100.5, 112.7, 117.1, 124.3 (2 χ CH), 125.3 (2 χ CH), 128.3 (2 x CH), 128.7, 129.5 (2 χ CH), 129.6, 131.2, 131.8, 134.4 , 135.3, 135.7, 138.6, 151.7, 164.3; IR (KBr) 3309 (brs, NH), 3068, 2922, 2852, 2232, 1689, 1654, 1560, 1498, 1458, 1363, 1292, 1190, 1072, 916cnTi; MSm/z (relative intensity), 364 (M+, 59), 234 (11), 207 (6), 147 (8), 130 (100), 102 (49), 91 (2), 77 (15), Anal. Calcd.: C: 75.81; [Example 19] Synthesis of 4-cyano-indenyl-(1,3-diphenyl-1//-pyrazol-5-yl)benzoguanamine under a nitrogen system, and taking benzamidine cyanide 11) reacted with an equivalent amount of benzoquinone at 31 1373468 under solvent-free conditions for 2 hours, then cooled in an ice bath and stirred the reaction mixture, and slowly added p-cyanobenzoquinone gas slowly, to p-cyanobenzene After the addition of formazan chlorine was completed, the temperature was removed to room temperature and stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved by adding methane, washed with water, and the organic layer is collected and washed with saturated brine. After filtration and concentration, the chromatographic purification is carried out. A yield of 78% of 4-cyano-7V-(1,3-diphenyl-1//-pyrazol-5-yl)benzamide (Compound 26) was obtained as shown in Table 2. Analytical data: 4-cyano-r7V-(i,3-diphenyl-1//-pyrazol-5-yl) acesulfame (Compound 26): m.p. (m.p. 2〇7 to 209 °C; it NMR (CDC13, 200 MHz) δ 7_02 (s, 1 H, Py-H), 7.35-7.49 (m, 6 H, ArH), 7.66-7.72 (m, 3 H, ArH), 7.90-7.95 (m, 3 H, ArH), 8.12-8.20 (m, 2 H, ArH), 8.27 (b, 1 Η, NH) ; , 3C NMR (50 MHz, CDC13) δ 99.7, 112.7 , 117.7, 124.0 (2 χ CH), 125.3 (2 χ CH), 127.7, 127.9, 128.6 (2 χ CH), 129.9 (2 χ CH), 129.9, 131.3, 132.1, 133.4, 134.9, 135.3, 136.8, 139.2 , 150.7, 163.8 ; IR (KBr) 3250 (brs, NH), 3087, 1686, 1578, 1501, 1296, 769, 699 cm_l ; MS m/z (relative intensity) 364 (M+, 100), 335 (6) ,262 (3),234 (12),206 (7),130 (98),102 (44),77 (16),51 (5). C23H|6N40 Analytical calculated value: C: 75.81; Η: 4 · 43; N: 15.38 ; Actual value: C: 76.12; Η: 4·42; N: 15.14. [Example 20] Synthesis of 2-nitro-iV-(l,3-diphenyl-1//-~bazol-5-yl)benzamide Under the nitrogen system, benzoic acid acetonitrile was taken ( Compound 11) is reacted with an equivalent amount of phenylhydrazine in a solvent-free condition for 2 hours, then 'decreasing the temperature in ice and dialing off the reaction mixture'. Then slowly adding o-nitrobenzidine to the o-nitrobenzoquinone After the addition of the brewing gas was completed, the ice bath was removed and returned to room temperature for further 2 hours, and the reaction was monitored by thin layer chromatography. When the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and then the reaction mixture is dissolved in -1373468 dichloromethane, washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally chromatographed. Purification, i.e., yield of 76% 2-nitro-3-diphenyl-1//-pyrazol-5-yl)benzamide (Compound 27), as shown in Table 2. Analytical data: 2-nitro-#-(1,3-diphenyl-1//-pyrazol-5-yl)phenylguanamine (Compound 27): melting point (recrystallized from CH2C12/hexanes, white Solid) 229 to 231 ° C; iHNMR^CDCbJOO MHz) δ 7.00 (s, 1 Η, Py-H), 7.36-7.89 (m, 12 H, ArH), 8.08-8.26 (m, 3 H, ArH + NH ; ; 3C NMR (50 MHz, CDC13) δ 100.1, 124.4 (2 x CH), 124.8, 125.7 (2 x CH), 128.3, 128.6, 129.2 (2 χ CH), 129.7, 130.2 (2 χ CH), 132.0, 133.1, 134.6, 135.6, 137.0, 138.9, 144.4, 147.0, 150.8, 167.8; IR (KBr) 3261 (brs, NH), 3061, 1718, 1533, 1502, 1354, 1249, 7574, 690 cm-1; MS m/z (relative intensity) 385 (M+, 66), 370 (27), 339 (22), 323 (10), 307 (45), 289 (39), 285 (18), 262 (15), 234 (32), 206 (22), 178 (31), 165 (48), 154 (100). C22H, 6N403 Analytical calculated values: C: 68.74; H: 4.20; N: 14.58 ; Actual value: C: 68.81 ; H: 4.15; N: 14.81. [Example 21] Synthesis of 4-nitro-indole 1,3-diphenyl-1//-pyrazol-5-yl) acesulfame under nitrogen system 'take benzoquinone cyanide (compound 11) and the like Equivalent phenylhydrazine, after reacting for 2 hours without solvent, 'cool down in an ice bath and stir the reaction mixture, then slowly add p-nitrophenyl hydrazine gas after the addition of p-nitrophenyl hydrazine gas is completed. The ice bath was removed, warmed to room temperature, stirred for additional 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved by adding dioxane. The organic layer is collected, washed with saturated brine, filtered and concentrated, and finally purified by chromatography. That is, a yield of 89% of 4-mercapto-iV-(l,3-diphenyl-1//-. than σ--5-yl) abbreviated amine (compound 28) was obtained, as shown in Table 2. Show. 33 1373468 Analytical data: 4-nitro-W-(l,3-diphenyl-1//-pyrazol-5-yl) acesulfame (Compound 28): melting point (recrystallization from CH2C12/hexane) , yellow solid) 221 to 223 °C; iHNMRfDCbJOO MHz) δ 7.23 (s, 1 Η, Py-H), 7.37 (t, 1 Η), 7.43 (t, 1 Η), 7.51 (q, 1 Η), 7.60 (d, 2 H, J = 4.5 Hz, ArH), 7.36-7.89 (m, 12 H, ArH), 8.08-8.26 (m, 3 H, ArH + NH), 7.92 (m, 4H), 8.09 ( b, 1 Η, NH), 8.32 (d, 2 H, 8.7 Hz, ArH) ; l3C NMR (50 MHz, CDC13) δ 100.1, 122.9 (2 x CH), 123.0 (2 χ CH), 124.7 (2 χ CH), 126.9, 127.5, 128.1 (2 x CH), 128.6 (2 χ CH), 128.8 (2 χ CH), 132.3, 136.1, 138.3,
138.5, 150.8, 162.0, 163.5 ; IR (KBr) 3250 (brs, NH), 3087, 1686, 1578, 1501, 1296, 769, 699 cnT1 ; MS (相對強度)364 (IVT,100),335 (6),262 (3), 234 (12),206 (7),130 (98), 102 (44),77 (16),51 (5). C23Hl6N4〇 分析計算值:c: 75.81; H: 4.43; N: 15.38 ;實際值:C: 76.12; H: 4.42; N: 15.14。138.5, 150.8, 162.0, 163.5 ; IR (KBr) 3250 (brs, NH), 3087, 1686, 1578, 1501, 1296, 769, 699 cnT1 ; MS (relative intensity) 364 (IVT, 100), 335 (6) , 262 (3), 234 (12), 206 (7), 130 (98), 102 (44), 77 (16), 51 (5). C23Hl6N4 〇 analytical calculated value: c: 75.81; H: 4.43; N: 15.38 ; Actual value: C: 76.12; H: 4.42; N: 15.14.
表2、利用一鍋合成法製備#-(1,3-二苯基-1//-°比°坐-5-基)苯甲酿胺衍生物 產物 產率 (%) 貫施例 R1 R2 R3 7V-(1,3-二苯基-1//-吡唑-5-基)笨γ" 醯胺衍生物 7 Η Η Η 14 78 8 Η F Η 15 77 9 Η Η F 16 70 10 Cl Η Η 17 85 11 Η C1 Η 18 71 12 Me Η Η 19 84 13 Η Η Me 20 76 14 Η Η cf3 21 78 15 OMe Η Η 22 90 16 Η OMe Η 23 72 17 F Η F 24 88 18 Η CN Η 25 90 19 Η Η CN 26 78 20 Ν〇2 Η Η 27 76 21 Η Η Ν〇2 28 89 34 1373468 [實施例22至27] 實施例22至27係利用一鍋合成法製備一系列含雜環取代基之 W-(l,3-二苯基-1-//-吡唑-5-基)醯胺類衍生物,其反應流程係如下圖 戶斤示0 11Table 2. Preparation of #-(1,3-diphenyl-1//-°°-s--5-yl)benzamide derivatives by one-pot synthesis Product yield (%) Example R1 R2 R3 7V-(1,3-Diphenyl-1//-pyrazol-5-yl) stupid γ" decylamine derivative 7 Η Η Η 14 78 8 Η F Η 15 77 9 Η Η F 16 70 10 Cl Η Η 17 85 11 Η C1 Η 18 71 12 Me Η Η 19 84 13 Η Η Me 20 76 14 Η Η cf3 21 78 15 OMe Η Η 22 90 16 Η OMe Η 23 72 17 F Η F 24 88 18 Η CN Η 25 90 19 Η Η CN 26 78 20 Ν〇2 Η Η 27 76 21 Η Η Ν〇 2 28 89 34 1373468 [Examples 22 to 27] Examples 22 to 27 were prepared by one-pot synthesis using a series of heterocyclic substitutions. The reaction process of the W-(l,3-diphenyl-1-//-pyrazol-5-yl) decylamine derivative is as follows:
PhNHNH2 迴紐3小呜,94%PhNHNH2 back to 3 hours, 94%
NH, Ph-NNH, Ph-N
Ο '人ClΟ 'People Cl
CH2Cl2orTHFCH2Cl2orTHF
29-34 W=雜芳基或經雜芳 基取代之磺酲基29-34 W=heteroaryl or heteroaryl substituted sulfonyl
,73% ,84% ,90% [實施例22]合成iV-2-呋喃-1,3-二苯基-5-胺基-1//-吡唑 於氮氣系統下,取苯曱醯乙氰(化合物11)與等當量的苯肼,在 無溶劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, 再缓慢逐滴添加2-呋喃曱醯氣,待2-呋喃曱醯氣添加完成後,撤 除冰浴,回溫至室溫,再攪拌約2小時,以薄層層析法監測反應 進行。當反應終止後,以濃縮乾燥移除四氫呋喃,再加入二氣曱 院溶解反應混合物,經水萃取洗蘇,收集有機層,再以飽和食鹽 水洗滌,經過濾和濃縮後,最後進行層析純化,即製得產率為70% 的#-2-呋喃-1,3-二苯基-5-胺基-1//-吡唑(化合物29),如表3所示。 35 1373468 分析數據:Λ,-2-呋喃-1,3-二苯基-5-胺基-1//-吡唑(化合物29):熔點(經矽 膠管柱層析純化,褐色固體)143至1450C; iHNMRiCDCbJOOMHzMe.SA (dd,1 H,《/= 3.6, 1.7 Hz,呋喃-H),7.18 (s,1 H,Py-H),7.25 (d,1 H,J= 3.6 Hz, 呋喃-H),7.32-7.51 (m,6 H),7.56-7.60 (m,3 Η), 7·89 (dd,2 H,《/= 8.0, 1.3 Hz, ArH), 8.34 (b5 1 Η, NH) ; ,3C NMR (50 MHz, CDC13) δ 95.4, 112.8, 116.4, 124.7 (2 x CH), 125.8 (2 χ CH), 128.1, 128.6 (3 χ CH), 130.0 (2 χ CH), 133.0, 136.0, 137.9, 144.8, 146.8, 152.0, 154.2 ; IR (KBr) 3400 (brs, NH), 3277, 3138, 3061, 1672, 1587, 1556, 1537, 1500, 1471, 1415, 1365, 1288, 1228, 1157, 1074, 1012, 954, 883, 763, 692 cnT1 ; MS w/z (相對強度)330 (M+, 100),315 (9), 262 (11), 236 (14), 221 (16), 207 (12), 154 (28), 121 (42), 119 (58), 95 (95), 79 (57), 69 (100),55(99). C2〇H|5N302HRMS 計算值:329.1164 ;實際值:329.1241。 [實施例23]合成W-2-噻吩碳醯基-1,3-二苯基-5-胺基-1//-吡唑 於氮氣系統下’取苯甲醯乙氰(化合物11)與等當量的苯肼,在 無溶劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, 再緩慢逐滴添加2-噻吩甲醯氣,待2-»塞吩甲醯氯添加完成後,撤 除冰浴’回溫至室溫’再攪拌約2小時,以薄層層析法監測反應 進行。當反應終止後’以濃縮乾燥移除四氫呋喃,再加入二氣甲 烷溶解反應混合物,經水萃取洗滌,收集有機層,再以飽和食鹽 水洗滌’經過濾和濃縮後’最後進行層析純化,即製得產率為77% 的嗔吩被酿基-1,3-·一本基-5-胺基-1。坐(化合物30),如表 3所示。, 73%, 84%, 90% [Example 22] Synthesis of iV-2-furan-1,3-diphenyl-5-amino-1//-pyrazole under a nitrogen system, taking benzoquinone B Cyanide (Compound 11) and an equivalent amount of phenylhydrazine, reacted for 2 hours without solvent, then cooled in an ice bath and stirred the reaction mixture, and then slowly added 2-furanium to 2-furan After the gas addition was completed, the ice bath was removed, warmed to room temperature, stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. When the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and then the reaction mixture is dissolved in a gas mixture, and the mixture is washed with water, and the organic layer is collected, washed with saturated brine, filtered, concentrated, and finally purified by chromatography. That is, #-2-furan-1,3-diphenyl-5-amino-1//-pyrazole (Compound 29) having a yield of 70% was obtained, as shown in Table 3. 35 1373468 Analytical data: Λ,-2-furan-1,3-diphenyl-5-amino-1//-pyrazole (Compound 29): melting point (purified by hexane column chromatography, brown solid) 143 To 1450C; iHNMRiCDCbJOOMHzMe.SA (dd, 1 H, "/= 3.6, 1.7 Hz, furan-H), 7.18 (s, 1 H, Py-H), 7.25 (d, 1 H, J = 3.6 Hz, furan -H), 7.32 - 7.51 (m, 6 H), 7.56-7.60 (m, 3 Η), 7·89 (dd, 2 H, "/= 8.0, 1.3 Hz, ArH), 8.34 (b5 1 Η, NH) ; , 3C NMR (50 MHz, CDC13) δ 95.4, 112.8, 116.4, 124.7 (2 x CH), 125.8 (2 χ CH), 128.1, 128.6 (3 χ CH), 130.0 (2 χ CH), 133.0 , 136.0, 137.9, 144.8, 146.8, 152.0, 154.2; IR (KBr) 3400 (brs, NH), 3277, 3138, 3061, 1672, 1587, 1556, 1537, 1500, 1471, 1415, 1365, 1288, 1228, 1157, 1074, 1012, 954, 883, 763, 692 cnT1 ; MS w/z (relative intensity) 330 (M+, 100), 315 (9), 262 (11), 236 (14), 221 (16), 207 (12), 154 (28), 121 (42), 119 (58), 95 (95), 79 (57), 69 (100), 55 (99). C2〇H|5N302HRMS Calculated value: 329.1164; Actual value: 329.1241. [Example 23] Synthesis of W-2-thiophenecarbenyl-1,3-diphenyl-5-amino-1//-pyrazole in the presence of a nitrogen system to extract benzamidine cyanide (compound 11) and Equivalent phenylhydrazine, after reacting for 2 hours without solvent, the temperature was lowered in an ice bath and the reaction mixture was stirred, and then 2-thiophenemethyl hydrazine was slowly added dropwise, after the addition of 2-» s. The ice bath was removed and returned to room temperature for a further 2 hours, and the reaction was monitored by thin layer chromatography. When the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and then the reaction mixture is dissolved by adding methane, washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally purified by chromatography. A porphin-yttrium-1,3-hexyl-5-amino-1 was obtained in a yield of 77%. Sit (Compound 30) as shown in Table 3.
分析數據:#-2-噻吩碳醯基-1,3-二苯基-5-胺基-1//-吡唑(化合物30):橘 紅色膠體;1H NMR(CDC13): 7.04 (dd,1 11,/=4.9, 3.8 出屬吩奶,7.13 (s,1 H,Py-H),7.36-7.66 (m,10 H,ArH),7.86-7.90 (m, 2 H,噻吩-Η), 7.90 (b,1H 1373468 NH) ; ,3C NMR (CDC13): 96.0, 124.7 (2 χ CH), 125.8 (2 χ CH), 128.1, 128.2, • 128.6 (2 χ CH + CH),129.2, 1.30.1 (2 χ CH), 131.8, 132.9, 136.2, 137.4, 137.8, m , 152.0, 158.1 ; IR (KBr) 3061 (brs, NH), 2922, 2851, 1654, 1554, 1537, 1504, 1365, 1283, 1214, 1171, 1065, 1038, 888 cnT'MSw/z(相對強度)345 (M+, 42), 236 (4), 207 (3), 111 (100), 102 (11), 83 (2), 77 (10), 51 (3). C2〇H,5N3OS HRMS 計算值:345.0936 ;實際值:345.0939。 [實施例24]合成iV-異噁唑-5-碳醯基-1,3-二苯基-5-胺基-1//-吡唑 於氮氣系統下,取苯曱醯乙氰(化合物11)與等當量的苯肼,在 • 無溶劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, 再緩慢逐滴添加異噁唑-5-氯化碳醯氣,待異噁唑-5-氣化碳醯氯添 加完成後,撤除冰浴,回溫至室溫,再攪拌約2小時,以薄層層 析法監測反應進行。當反應終止後,以濃縮乾燥移除四氫。夫喃, 再加入二氣甲烷溶解反應混合物,經水萃取洗滌,收集有機層, 再以飽和食鹽水洗滌,經過濾和濃縮後,最後進行層析純化,即 製得產率為71%的異噁唑-5-碳醯基-1,3-二苯基-5-胺基-1//-吡 ^ 。坐(化合物3 1 ),如表3所示。 分析數據:尽異噁唑-5-碳醯基-1,3-二苯基-5-胺基-1//-吡唑(化合物31): 熔點(經矽膠管柱層析純化,橘色固體)153至155°C; 4 NMR (CDC13): 7.04 • (d,1 H,*/= 1.8 Hz,異噁唑-H),7.19 (s, 1 H,Py-H),7,35—7.58 (m,8 H,ArH), 7.87 (dd, 2 H,/=6.6, 1.4 Hz, ArH), 8.35 (d, 1 H,/= 1.8 8.51 (b5 1HNH); I3CNMR(CDC13): 96.2, 107.9, 124.7(2 χ CH), 125.8 (2 χ CH), 128.3, 128.6 (2 x CH), 128.9, 130.2 (2 χ CH), 132.7, 135.0, 137.5, 151.4, 151.7, 152.0, 161.5 ; IR (KBr) 3399 (brs, NH), 3306, 3151, 3085, 1700, 1559, 1498, 1457, 1418, 1364, 1330, 1270,1204, 1162, 1073, 1018, 825 cm-1; MS m/z(相對強度) 37 1373468 331 (M+,62),262 (15),236 (11),203 (11), 169 (12),154 (22), 121 (21),119 (41),95 (74),79 (53),69 (96),55 (100). Cl9Hl4N402 HRMS 計算值: 330.1117 ;實際值:330.1187 ; Ci9Hi4N402 分析計算值:C: 69.68; H: 4.27; N: 16.96 ;實際值:c: 69.91; H: 4.54; N: 17.21。 [實施例25]合成#-2-苯呋喃碳醯基-1,3-二苯基-5-胺基-1//-吡唑 於氮氣系統下,取苯曱醯乙氰(化合物11)與等當量的苯肼,在 無溶劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, 再緩慢逐滴添加2-苯呋喃曱醯氣,待2-苯呋喃甲醯氣添加完成 後,撤除冰浴,回溫至室溫,再攪拌約2小時,以薄層層析法監 測反應進行。當反應終止後,以濃縮乾燥移除四氫呋喃,再加入 二氣甲烷溶解反應混合物,經水萃取洗滌,收集有機層,再以飽 和食鹽水洗滌,經過濾和濃縮後,最後進行層析純化,即製得產 率為73%的7V-2-苯呋喃碳醯基-1,3-二苯基-5-胺基-1//-吡唑(化合 物3 2)’如表3所示。Analytical data: #-2-thiophenecarbenyl-1,3-diphenyl-5-amino-1//-pyrazole (Compound 30): orange-red colloid; 1H NMR (CDC13): 7.04 (dd, 1 11, /= 4.9, 3.8 out of the order, 7.13 (s, 1 H, Py-H), 7.36-7.66 (m, 10 H, ArH), 7.86-7.90 (m, 2 H, thiophene-Η) , 7.90 (b, 1H 1373468 NH) ; , 3C NMR (CDC13): 96.0, 124.7 (2 χ CH), 125.8 (2 χ CH), 128.1, 128.2, • 128.6 (2 χ CH + CH), 129.2, 1.30 .1 (2 χ CH), 131.8, 132.9, 136.2, 137.4, 137.8, m , 152.0, 158.1 ; IR (KBr) 3061 (brs, NH), 2922, 2851, 1654, 1554, 1537, 1504, 1365, 1283 , 1214, 1171, 1065, 1038, 888 cnT'MSw/z (relative intensity) 345 (M+, 42), 236 (4), 207 (3), 111 (100), 102 (11), 83 (2) , 77 (10), 51 (3). C2〇H, 5N3OS HRMS calcd.: 345.0936; actual value: 345.0939. [EXAMPLE 24] Synthesis of iV-isoxazole-5-carbon fluorenyl-1,3-di Phenyl-5-amino-1//-pyrazole in a nitrogen system, taking phenylhydrazine cyanide (compound 11) and an equivalent of phenylhydrazine, reacting in a solvent-free condition for 2 hours, in an ice bath Decrease the temperature and stir the reaction mixture, then add the isoxazole slowly and dropwise. -5-carbonate helium gas, after the addition of isoxazole-5-gasified carbonium chloride, remove the ice bath, warm to room temperature, stir for about 2 hours, and monitor the reaction by thin layer chromatography. After the reaction is terminated, the tetrahydrogen is removed by concentration and drying, and the reaction mixture is dissolved in dioxane, washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally. Purification by chromatography, i.e., 71% yield of isoxazol-5-carbenyl-1,3-diphenyl-5-amino-1//-pyridin. Sit (Compound 3 1 ), As shown in Table 3. Analytical data: dioxazole-5-carbonindolyl-1,3-diphenyl-5-amino-1//-pyrazole (Compound 31): melting point Purification by chromatography, orange solid) 153 to 155 ° C; 4 NMR (CDC13): 7.04 • (d, 1 H,*/= 1.8 Hz, isoxazole-H), 7.19 (s, 1 H, Py- H), 7, 35 - 7.58 (m, 8 H, ArH), 7.87 (dd, 2 H, /= 6.6, 1.4 Hz, ArH), 8.35 (d, 1 H, / = 1.8 8.51 (b5 1HNH); I3CNMR (CDC13): 96.2, 107.9, 124.7 (2 χ CH), 125.8 (2 χ CH), 128.3, 128.6 (2 x CH), 128.9, 130.2 (2 χ CH), 132.7, 135.0, 137.5, 151.4, 151.7, 152.0, 161.5; IR (KBr) 3399 (brs, NH), 3306, 3151, 3085, 1700, 1559, 1498, 1457, 1418, 1364, 1330, 1270, 1204, 1162, 1073, 1018, 825 cm- 1; MS m/z (relative intensity) 37 1373468 331 (M+, 62), 262 (15), 236 (11), 203 (11), 169 (12), 154 (22), 121 (21), 119 (41), 95 (74), 79 (53), 69 (96), 55 (100). Cl9Hl4N402 HRMS calc.: 330.1117; calc.::::::::::::::::::::::::::::::::::::: : 16.96 ; Actual value: c: 69.91; H: 4.54; N: 17.21. [Example 25] Synthesis of #-2-benzenefurancarbenyl-1,3-diphenyl-5-amino-1//-pyrazole under a nitrogen system, taking phenylhydrazine cyanide (Compound 11) After reacting with an equivalent amount of benzoquinone in a solvent-free condition for 2 hours, the temperature was lowered in an ice bath and the reaction mixture was stirred, and 2-benzofuranium oxime was slowly added dropwise, and the addition of 2-benzaldehyde methyl hydrazine was completed. Thereafter, the ice bath was removed, warmed to room temperature, and stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved by adding methane, washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally purified by chromatography. 7V-2-benzofurancarbenyl-1,3-diphenyl-5-amino-1//-pyrazole (compound 3 2) having a yield of 73% was obtained as shown in Table 3.
分析數據:TV-2-苯呋喃碳醯基-l,3-二苯基-5-胺基-1//-吡唑(化合物32):熔 點(經矽膠管柱層析純化,深紅色固體)164至166°C ;NMR (CDC13): 7.24-7.72 (m, 14 H, ArH), 7.90 (dd, 2 U, J = 8.1, 1.6 Hz, ArH), 8.62 (b, 1HAnalytical data: TV-2-phenylfurancarbenyl-l,3-diphenyl-5-amino-1//-pyrazole (Compound 32): melting point (purified by hydrazine column chromatography, dark red solid 164 to 166 ° C; NMR (CDC13): 7.24-7.72 (m, 14 H, ArH), 7.90 (dd, 2 U, J = 8.1, 1.6 Hz, ArH), 8.62 (b, 1H)
I NH) ; l3C NMR (CDC13): 95.8, 111.9, 112.5, 123.0, 124.2, 124.7 (2 χ CH), 125.8 (2 x CH), 127.3, 127.5, 127.7 (2 x CH + CH), 128.2, 128.6 (2 χ CH), 130.1, 132.9, 135.8, 137.8, 147.2, 152.1, 154.8 ; IR (KBr) 3061 (brs, NH), 2922, 2850, 1554, 1504, 1365, 1282, 1170, 1142 crtT1 ;MSm/z(相對強度)379 (1^,47),351 (16), 246 (4), 233 (2), 206 (3), 180 (1), 145 (100), 131 (4), 102 (15), 89 (33), 77 (14),63 (5),51 (4). C24Hl7N302 HRMS 計算值:379.1321 ;實際值:379.1315。 ,· [實施例26]合成#-5-偏苯三甲醯基-1,3-二苯基-5-胺基-1//-吡唑! 38 1373468 於氮氣系統下,取苯甲醯乙氰(化合物11)與等當量的苯肼,在 ' 無溶劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, • 再緩慢逐滴添加偏苯三曱醯氣,待偏苯三甲醯氣添加完成後,撤 除冰浴,回溫至室溫,再攪拌約2小時,以薄層層析法監測反應 進行。當反應終止後,濃縮乾燥四氫呋喃,再加入二氯甲烷溶解 反應混合物,經水萃取洗滌,收集有機層,再以飽和食鹽水洗滌, 經過濾和濃縮後,最後進行層析純化,即製得產率為84%的ΑΓ-5-偏苯三甲醯基-1,3-二苯基-5-胺基-1//-吡唑(化合物33),如表3所 • 示。 分析數據:W-5-偏苯三甲醯基-1,3-二苯基-5-胺基-1//-吡唑(化合物33):黃 色膠體;111抓411〇:0(:丨3):6.78(3,1氏?乂-印,6.95(5,11^,異苯并呋喃-1^(異 苯并呋喃-Η),7.27-7.50 (m,8 Η,ArH),7.72-7.89 (m,3 H, ArH),8.06 (d,1 Η, «/= 6.4 Hz,異苯并呋喃-H),8.5 (b, 1H NH) ; l3C NMR (CDC13): 97.6, 104.1, 122.7, 124.4 (2 χ CH), 124.8, 125.7 (2 χ CH), 128.5, 128.7, 129.4 (2 χ CH + CH), 129.8, 130.0, 131.8, 132.4, 133.9, 135.7, 137.9, 139.4, 151.9, 152.1 φ 165.0 ; IR (KBr) 3062 (brs, NH), 2924, 1735, 1674, 1558, 1497, 1458, 1367, 1087 cnT1 ;MS m/z(相對強度)409 (M+, 4), 364 (100),336 (5),313 (6), 262 (4), 234 (12), 206 (12), 180 (5), 131 (4), 103 (10), 91 (9), 77 (27), 55 (6). • C24H15N304 分析計算值;C: 70.41; Η: 3·ό9; N: 10.26;實際值:C: 70.27; Η: 3.78; N: 11.22。 [貫施例27]合成TV·喧琳-8-確酿基-1,3-二苯基-5-胺基-1//-°比。坐 於氮氣系統下,取苯曱醯乙氰(化合物11)與等當量的苯肼,在 無溶劑條件下反應2小時後,於冰浴下降溫並攪拌反應混合物, 再緩慢逐滴添加查啦-8 -續酿氣’待喧说-8 -績酿氯添加完成後,撤 39 1373468 除冰浴,回溫至室溫,再攪拌約2小時,以薄層層析法監測反應 進行。當反應終止後,以濃縮造移除四氫呋喃,再加入二氣曱烷 溶解反應混合物,經水萃取洗滌,收集有機層,再以飽和食鹽水 洗滌,經過濾和濃縮後,最後進行層析純化,即製得產率為90% 的7V-喹啉-8-磺醯基-1,3-二笨基-5-胺基-1//-吡唑(化合物34),如表 3所示° 分析數據:喹啉-8-磺醯基-1,3-二苯基-5-胺基-1//-吡唑(化合物34):深 紅色膠體;1H NMR (CDC13, 200 ΜΗζ) δ 6.38 (s,1 H,Py-H),7.25—7.68 (m,12 H,ArH+喹啉-H),8_01 (dd, 1 H,«/二 8.4, 1.4 Hz,喹啉-H), 8.20(dd,1 H,《/二 8·4,1·7Ηζ,啥琳-H), 8.35(dd,lH,J=7.3,1.4Hz,啥啦-H),8.47(dd,lH,J = 4.3, 1.7 Hz,啥。林-H);I3C NMR (50 MHz, CDC13) δ 96.4, 122.3, 123.7, 125.2 (2 x CH), 125.5 (2 χ CH), 125.7, 127.4, 128.1, 128.3, 128.5 (2 χ CH), 129.3 (2 x CH), 131.5, 132.6, 134.0, 135.0, 136.4, 137.1, 137.8, 151.0, 151.4 ; IR (KBr) 3450 (brs, NH), 3061, 1597, 1544, 1502, 1460, 1379, 1173, 1146, 766, 696 cm—1 ; MS m/z (相對強度)427 (IVT, 86),395 (59),337 (13),289 (13), 281 (20), 235 (59), 221 (23), 207 (28), 194 (15), 185 (46), 176 (38), 165 (32), 154 (80), 109 (86),83 (100), 71 (100),57 (100). C24H18N402S HRMS 計算值: 427.1150 ;實際值:427.1123 ; C24H|8N402S 分析計算值;C: 67.59; H: 4.25; N: 13.14 ;實際值:C: 67_25; Η: 4_56; N: 12.97。 1373468 表3、1用-锅合成法製備含雜環取代基之#_(1,3二苯基小凡 基)醯胺類衍‘生物 坐-5- —---~~_ 醯化試劑 s雜環取代基之二苯基 ----吡唑-5-基)醯胺類衍生物產率(%) 29 30 31 70 77 71 2-呋喃甲醯氣 2-噻吩甲醯氣 異。惡°坐-5 -氣化·ε炭醒 氣I NH) ; l3C NMR (CDC13): 95.8, 111.9, 112.5, 123.0, 124.2, 124.7 (2 χ CH), 125.8 (2 x CH), 127.3, 127.5, 127.7 (2 x CH + CH), 128.2, 128.6 (2 χ CH), 130.1, 132.9, 135.8, 137.8, 147.2, 152.1, 154.8; IR (KBr) 3061 (brs, NH), 2922, 2850, 1554, 1504, 1365, 1282, 1170, 1142 crtT1 ;MSm/ z (relative intensity) 379 (1^,47),351 (16), 246 (4), 233 (2), 206 (3), 180 (1), 145 (100), 131 (4), 102 ( 15), 89 (33), 77 (14), 63 (5), 51 (4). C24Hl7N302 HRMS calculated: 379.1321; actual value: 379.1315. [Example 26] Synthesis #-5-p-trimellimidyl-1,3-diphenyl-5-amino-1//-pyrazole! 38 1373468 Under the nitrogen system, take the benzamidine B Cyanide (Compound 11) and an equivalent of phenylhydrazine, reacted for 2 hours under solvent-free conditions, then cool the reaction mixture in an ice bath and stir the reaction mixture. • Slowly add benzotriazole gas dropwise, to be trimellitic. After the addition of helium gas was completed, the ice bath was removed, warmed to room temperature, and stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is concentrated and dried, and the reaction mixture is dissolved in dichloromethane, washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and then purified by chromatography to yield. The rate of 84% ΑΓ-5-p-trimellimidyl-1,3-diphenyl-5-amino-1//-pyrazole (Compound 33) is shown in Table 3. Analytical data: W-5-p-trimethylene-yl-1,3-diphenyl-5-amino-1//-pyrazole (compound 33): yellow colloid; 111 grab 411 〇: 0 (: 丨 3 ): 6.78 (3,1 乂?乂-印, 6.95 (5,11^, isobenzofuran-1^(isobenzofuran-oxime), 7.27-7.50 (m,8 Η,ArH),7.72- 7.89 (m,3 H, ArH), 8.06 (d,1 Η, «/= 6.4 Hz, isobenzofuran-H), 8.5 (b, 1H NH) ; l3C NMR (CDC13): 97.6, 104.1, 122.7 , 124.4 (2 χ CH), 124.8, 125.7 (2 χ CH), 128.5, 128.7, 129.4 (2 χ CH + CH), 129.8, 130.0, 131.8, 132.4, 133.9, 135.7, 137.9, 139.4, 151.9, 152.1 φ 165.0 ; IR (KBr) 3062 (brs, NH), 2924, 1735, 1674, 1558, 1497, 1458, 1367, 1087 cnT1 ; MS m/z (relative intensity) 409 (M+, 4), 364 (100), 336 (5), 313 (6), 262 (4), 234 (12), 206 (12), 180 (5), 131 (4), 103 (10), 91 (9), 77 (27), 55 (6). • C24H15N304 Analytical calculated value; C: 70.41; Η: 3·ό9; N: 10.26; Actual value: C: 70.27; Η: 3.78; N: 11.22. [Comprehensive Example 27] Synthesis of TV·喧琳-8-Exactly kiln-1,3-diphenyl-5-amino-1//- ratio. Sitting under a nitrogen system, taking benzoquinone cyanide 11) and an equivalent of phenylhydrazine, reacted in the absence of solvent for 2 hours, then cooled in an ice bath and stirred the reaction mixture, and slowly added a drop of lag-8 - continued brewing gas 'waiting to say -8 - After the completion of the addition of chlorine, the ice bath was removed from 39 1373468, warmed to room temperature, stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. When the reaction was terminated, the tetrahydrofuran was removed by concentration and then added. The reaction mixture is dissolved in dioxane, washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and then purified by chromatography to give a yield of 90% of 7V-quinoline- 8-sulfonyl-1,3-diphenyl-5-amino-1//-pyrazole (Compound 34), as shown in Table 3, Analytical data: quinoline-8-sulfonyl-1, 3-diphenyl-5-amino-1//-pyrazole (Compound 34): dark red colloid; 1H NMR (CDC13, 200 ΜΗζ) δ 6.38 (s, 1 H, Py-H), 7.25-7.68 (m, 12 H, ArH + quinoline-H), 8_01 (dd, 1 H, «/ 8.4, 1.4 Hz, quinoline-H), 8.20 (dd, 1 H, "/2:8,4,1· 7Ηζ,啥琳-H), 8.35(dd,lH,J=7.3,1.4Hz, 啥啦-H), 8.47(dd,lH,J = 4 .3, 1.7 Hz, 啥. Lin-H); I3C NMR (50 MHz, CDC13) δ 96.4, 122.3, 123.7, 125.2 (2 x CH), 125.5 (2 χ CH), 125.7, 127.4, 128.1, 128.3, 128.5 (2 χ CH), 129.3 (2 x CH), 131.5, 132.6, 134.0, 135.0, 136.4, 137.1, 137.8, 151.0, 151.4; IR (KBr) 3450 (brs, NH), 3061, 1597, 1544, 1502, 1460, 1379, 1173, 1146 , 766, 696 cm -1 ; MS m/z (relative intensity) 427 (IVT, 86), 395 (59), 337 (13), 289 (13), 281 (20), 235 (59), 221 ( 23), 207 (28), 194 (15), 185 (46), 176 (38), 165 (32), 154 (80), 109 (86), 83 (100), 71 (100), 57 ( 100). Calculated for C24H18N402S HRMS: 427.1150; actual value: 427.1123; C24H|8N402S analytical value; C: 67.59; H: 4.25; N: 13.14; actual value: C: 67_25; Η: 4_56; N: 12.97. 1373468 Table 3, 1 Preparation of a heterocyclic substituent-containing #_(1,3 diphenyl phenanthrene) decylamine derivative 'Biological sitting-5-----~~_ 醯化试剂Yield of diphenyl----pyrazol-5-yl)guanamine derivatives of s heterocyclic substituents (%) 29 30 31 70 77 71 2-furanyl fluorene 2-thiophene oxime.恶°坐-5 - gasification · ε charcoal
由以.上實施例可知,本發明之方法可提供一簡易方便之製程以 製備尚產率之酿胺基。比。坐衍生物。 2_笨呋喃甲醯氣 偏笨三甲醯氣 上述實施例僅係用以例示說明本發明之原理及功效,而非用於 限制本發明。任何熟於此項技藝之人士均可在不違背本發明之技 術原理及精神的情況下,對上述實施例進行修改及變化。因此, 本發明之權利保護範圍應如後述之申請專利範圍所列者。As can be seen from the above examples, the process of the present invention provides a simple and convenient process for preparing a desired amine group. ratio. Sitting on the derivative. 2_ 呋 呋 醯 偏 偏 偏 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述Modifications and variations of the above-described embodiments can be made by those skilled in the art without departing from the spirit and scope of the invention. Therefore, the scope of protection of the present invention should be as set forth in the appended claims.
【圖式簡單說明】 .fe. 〇 【主要元件符號說明】 無0 41[Simple description of the diagram] .fe. 〇 [Main component symbol description] None 0 41
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