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CN1761653A - Process for preparing N-heteroaryl-N-arylamines and analogous processes by reacting N-aryl carbamates with halogenated heteroaryl groups - Google Patents

Process for preparing N-heteroaryl-N-arylamines and analogous processes by reacting N-aryl carbamates with halogenated heteroaryl groups Download PDF

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CN1761653A
CN1761653A CN 200480007137 CN200480007137A CN1761653A CN 1761653 A CN1761653 A CN 1761653A CN 200480007137 CN200480007137 CN 200480007137 CN 200480007137 A CN200480007137 A CN 200480007137A CN 1761653 A CN1761653 A CN 1761653A
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CN100579965C (en
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J·R·史努尼安
P-A·奥利弗-沙菲尔
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Abstract

The present invention relates to a process for the production of a diarylamine compound of formula or a salt thereof, comprising the step of coupling a compound of formula (II) with an amine of formula (III) in the presence of an alkali metal salt or a transition metal catalyst, wherein: ar (Ar)1And Ar2Independently is Q; wherein each Q is an aryl or heteroaryl ring system, optionally fused to a saturated or unsaturated 5-8 membered ring having 0-4 heteroatoms; wherein Q is optionally substituted as defined in claim 1, wherein: x is a leaving group; y is-C -O-Z; z is selected from C1－C6Aliphatic radical, benzyl, Fmoc, -SO2R' and Q, provided that Q is not substituted by X or alkyne; wherein R' is as defined in claim 1.

Description

通过使N-芳基氨基甲酸酯与卤代杂芳基反应 制备N-杂芳基-N-芳基胺的方法和类似方法Process for preparing N-heteroaryl-N-arylamines by reacting N-aryl carbamates with halogenated heteroaryl groups and analogous processes

技术领域technical field

本发明涉及二芳基胺及其类似物的简易合成方法。本发明的方法生产二芳基胺的收率和纯度高。本发明还涉及可用于本发明方法的中间体。本发明还涉及由本发明方法所生产的二芳基胺。The present invention relates to the simple synthesis method of diarylamine and its analog. The yield and purity of diarylamine produced by the method of the invention are high. The invention also relates to intermediates useful in the process of the invention. The invention also relates to the diarylamines produced by the process of the invention.

背景技术Background technique

蛋白激酶参与各种对细胞外信号的细胞应答。最近，已经发现了有丝分裂原-活化蛋白激酶(MAPK)家族。这一家族成员是Ser/Thr激酶，通过磷酸化作用活化它们的底物[B.Stein等人，Ann.Rep.Med.Chem.，31，pp.289-98(1996)]。MAPK本身被多种信号活化，包括生长因子、细胞因子、UV辐射和应激反应诱导剂。Protein kinases are involved in a variety of cellular responses to extracellular signals. Recently, the mitogen-activated protein kinase (MAPK) family has been discovered. Members of this family are Ser/Thr kinases, which activate their substrates by phosphorylation [B. Stein et al., Ann. Rep. Med. Chem., 31, pp. 289-98 (1996)]. MAPKs themselves are activated by a variety of signals, including growth factors, cytokines, UV radiation, and stress-response inducers.

一种特别引人注意的MAPK是p38。p38也称细胞因子抑制性抗炎药结合蛋白(CSBP)和RK，是从被脂多糖(LPS)受体CD14转染并且被LPS诱导的鼠前B细胞中分离的。p38自此已被分离和测序，在人和小鼠中都具有编码它的cDNA。在受应激反应和细胞因子刺激的细胞中已经观察到p38的活化，前者例如脂多糖(LPS)、UV、茴香霉素或渗透压休克的处理，后者例如IL-1和TNF。One MAPK of particular interest is p38. p38, also known as cytokine suppressive anti-inflammatory drug binding protein (CSBP) and RK, was isolated from murine pre-B cells transfected with the lipopolysaccharide (LPS) receptor CD14 and induced by LPS. p38 has since been isolated and sequenced, and there are cDNAs encoding it in both humans and mice. Activation of p38 has been observed in cells stimulated by stress responses such as lipopolysaccharide (LPS), UV, anisomycin or treatment with osmotic shock, and cytokines such as IL-1 and TNF.

p38激酶的抑制引起IL-1和TNF产生的阻断。IL-1和TNF刺激其他促炎性细胞因子的产生，例如IL-6和IL-8，在急性与慢性炎性疾病和绝经后骨质疏松中都有牵连[R.B.Kimble等人，Endocrinol.，136，pp.3054-61(1995)]。Inhibition of p38 kinase results in blockade of IL-1 and TNF production. IL-1 and TNF stimulate the production of other proinflammatory cytokines, such as IL-6 and IL-8, implicated in both acute and chronic inflammatory diseases and postmenopausal osteoporosis [R.B. Kimble et al., Endocrinol., 136, pp. 3054-61 (1995)].

基于这一发现，相信p38以及其他MAPK在介导对炎性刺激物的细胞应答中起作用，例如白细胞蓄积、巨噬细胞/单核细胞活化、组织吸收、发热、急性期应答和中性白血病增多。另外，MAPK、例如p38已在癌症、凝血酶诱导的血小板聚集、免疫缺陷障碍、自体免疫疾病、细胞死亡、变态反应、骨质疏松和神经变性疾病中有牵连。p38抑制剂也已在疼痛控制领域中有牵连，它抑制前列腺素内过氧化物合成酶-2的诱导作用。其他与IL-1、IL-6、IL-8或TNF过度产生有关的疾病如WO 96/21654所述。Based on this finding, it is believed that p38, as well as other MAPKs, play a role in mediating cellular responses to inflammatory stimuli, such as leukocyte accumulation, macrophage/monocyte activation, tissue resorption, fever, acute phase response, and neutrophils increase. Additionally, MAPKs, such as p38, have been implicated in cancer, thrombin-induced platelet aggregation, immunodeficiency disorders, autoimmune diseases, cell death, allergy, osteoporosis, and neurodegenerative diseases. p38 inhibitors have also been implicated in the field of pain control by inhibiting the induction of prostaglandin endoperoxide synthase-2. Other diseases associated with overproduction of IL-1, IL-6, IL-8 or TNF are described in WO 96/21654.

很多在医药上具备重要的对抗各种靶、包括MAPK的性质的分子包含二芳基胺。一个实例是一类被鉴别为有力的p38 MAP激酶抑制剂的分子(例如参见WO 99/58502和WO 00/17175)。不过，尽管它们作为药物是有效的，不过很少有制备含有芳基胺的分子而无大量副产物的方式。钯催化的芳基胺与芳基卤偶联已经成为传统的生产包含二芳基胺的分子的策略。不过，当采用一元芳基胺时，向胺过量加入芳基卤配偶体的问题已在传统上导致低收率和杂质的问题。为此，一元胺并不是为这种转化所普遍采用的底物，这限制了钯催化的偶联反应的范围。Many molecules that possess pharmaceutically important properties against various targets, including MAPK, contain diarylamines. An example is a class of molecules identified as potent p38 MAP kinase inhibitors (see eg WO 99/58502 and WO 00/17175). However, despite their effectiveness as pharmaceuticals, there are few ways of preparing arylamine-containing molecules without substantial by-products. Palladium-catalyzed coupling of arylamines to aryl halides has been a traditional strategy for the production of diarylamine-containing molecules. However, when monoaryl amines are employed, the problem of excess addition of the aryl halide partner to the amine has traditionally resulted in low yields and impurity problems. For this reason, monoamines are not commonly used substrates for this transformation, which limits the scope of palladium-catalyzed coupling reactions.

因此，需要二芳基胺及其类似物的简易合成方法，它避免过度芳基化的问题，以高收率和纯度得到二芳基胺。也需要由这样一种方法生产的中间体。Therefore, there is a need for facile synthesis of diarylamines and their analogs which avoid the problem of overarylation and provide diarylamines in high yield and purity. There is also a need for intermediates produced by such a process.

发明内容Contents of the invention

按照一种实施方式，本发明提供二芳基胺的简易合成方法，它避免过度芳基化的问题，适用于大规模制备，提供高收率。本发明也避免有害试剂的使用，例如锡化合物。具体而言，本发明提供这样一种方法，其中通过向氮加成适合的保护基团，一元芳基胺被暂时赋予“二元性”。一旦生成，这种被保护的苯胺衍生物与芳基离去基团经历受碱金属盐促进的或过渡金属催化的交叉偶联，生成中间体，在去保护后生成二芳基胺底物。生成产物的收率可以很高，副产物很少。According to one embodiment, the present invention provides a facile synthesis of diarylamines, which avoids the problem of excessive arylation, is suitable for large-scale preparations, and provides high yields. The present invention also avoids the use of hazardous reagents, such as tin compounds. In particular, the present invention provides a method wherein monoaryl amines are temporarily rendered "dual" by the addition of a suitable protecting group to the nitrogen. Once formed, this protected aniline derivative undergoes an alkali metal salt-promoted or transition metal-catalyzed cross-coupling with an aryl leaving group to generate an intermediate that, after deprotection, yields a diarylamine substrate. The yield of the product can be very high, and the by-products are few.

本发明提供生产式(I)化合物或其盐的方法：The present invention provides a method for producing a compound of formula (I) or a salt thereof:

Figure A20048000713700131
Figure A20048000713700131

其中：in:

Ar1和Ar2是如下所定义的。Ar 1 and Ar 2 are defined below.

本发明的方法包括在碱金属盐或过渡金属催化剂的存在下使式(II)化合物与式(III)胺偶联得到式(I)二芳基胺的步骤：The method of the present invention comprises the step of coupling the compound of formula (II) with the amine of formula (III) to obtain the diarylamine of formula (I) in the presence of an alkali metal salt or a transition metal catalyst:

              Ar1-X          Ar2-NH-YAr 1 -X Ar 2 -NH-Y

               (II)            (III)(II) (III)

其中：in:

Ar1、Ar2、X和Y是如下所定义的。Ar 1 , Ar 2 , X and Y are defined below.

本发明的方法具有允许从一元芳基胺衍生物制备式(I)化合物而无过度芳基化的问题的优点。本发明的方法具有进一步允许以高收率与纯度制备式(I)化合物的优点，另外反应条件简易，容易规模化供大规模制备。The process of the present invention has the advantage of allowing the preparation of compounds of formula (I) from monoarylamine derivatives without the problem of excessive arylation. The method of the present invention has the further advantage of allowing the compound of formula (I) to be prepared with high yield and purity, and the reaction conditions are simple and easy to scale up for large-scale preparation.

发明的详细说明Detailed Description of the Invention

本发明克服了现有技术的困难和缺点，提供生产式(I)化合物或其盐的方法：The present invention overcomes the difficulty and shortcoming of prior art, provides the method for producing formula (I) compound or its salt:

其中：in:

Ar1和Ar2独立地是Q；Ar 1 and Ar 2 are independently Q;

其中每个Q是芳基或杂芳基环系，可选地与具有0-4个杂原子的饱和或不饱和5-8元环稠合；wherein each Q is an aryl or heteroaryl ring system, optionally fused to a saturated or unsaturated 5-8 membered ring having 0-4 heteroatoms;

其中Q可选地在一个或多个环原子上被一个或多个取代基取代，所述取代基独立地选自卤素；C1-C6脂族基团，可选地被N(R′)2、OR′、CO2R′、C(O)N(R′)2、OC(O)N(R′)2、NR′CO2R′、NR′C(O)R′、SO2N(R′)2、N＝CH-N(R′)2或OPO3H2取代；C1-C6烷氧基，可选地被N(R′)2、OR′、CO2R′、C(O)N(R′)2、OC(O)N(R′)2、SO2N(R′)2、NR′CO2R′、NR′C(O)R′、N＝CH-N(R′)2或OPO3H2取代；Ar3；CF3；OCF3；OR′；SR′；SO2N(R′)2；OSO2R′；SCF3；NO2；CN；N(R′)2；CO2R′；0CO2N(R′)2；C(O)N(R′)2；NR′C(O)R′；NR′CO2R′；NR′C(O)C(O)R′；NR′SO2R′；OC(O)R′；NR′C(O)R2；NR′CO2R2；NR′C(O)C(O)R2；NR′C(O)N(R′)2；OC(O)N(R′)2；NR′SO2R2；NR′R2；N(R2)2；OC(O)R2；OPO3H2；和N＝CH-N(R′)2；wherein Q is optionally substituted on one or more ring atoms by one or more substituents independently selected from halogen; C 1 -C 6 aliphatic groups, optionally substituted by N(R' ) 2 , OR′, CO 2 R′, C(O)N(R′) 2 , OC(O)N(R′) 2 , NR′CO 2 R′, NR′C(O)R′, SO 2 N(R') 2 , N=CH-N(R') 2 or OPO 3 H 2 substituted; C 1 -C 6 alkoxy, optionally replaced by N(R') 2 , OR', CO 2 R', C(O)N(R') 2 , OC(O)N(R') 2 , SO 2 N(R') 2 , NR'CO 2 R', NR'C(O)R', N=CH-N(R') 2 or OPO 3 H 2 substitution; Ar 3 ; CF 3 ; OCF 3 ; OR';SR'; SO 2 N(R') 2 ; OSO 2 R'; SCF 3 ; NO 2 ; CN; N(R′) 2 ; CO 2 R′; 0CO 2 N(R′) 2 ; C(O)N(R′ ) 2 ; ';NR'C(O)C(O)R';NR'SO 2 R';OC(O)R';NR'C(O)R2;NR'CO 2 R 2 ; )C(O)R 2 ; NR′C(O)N(R′) 2 ; OC(O)N(R′) 2 ; NR′SO 2 R 2 ; NR′R 2 ; N(R 2 ) 2 ; OC(O)R 2 ; OPO 3 H 2 ; and N=CH—N(R′) 2 ;

R′选自氢；C1-C6脂族基团；或者5-6元碳环或杂环环系，可选地被1至3个取代基取代，所述取代基独立地选自卤素、C1-C6烷氧基、氰基、硝基、氨基、羟基和C1-C6脂族基团；R' is selected from hydrogen; C 1 -C 6 aliphatic groups; or 5-6 membered carbocyclic or heterocyclic ring systems, optionally substituted with 1 to 3 substituents independently selected from halogen , C 1 -C 6 alkoxy, cyano, nitro, amino, hydroxyl and C 1 -C 6 aliphatic groups;

R2是C1-C6脂族基团，可选地被N(R′)2、OR′、CO2R′、C(O)N(R′)2或SO2N(R′)2取代；或者碳环或杂环环系，可选地被N(R′)2、OR′、CO2R′、C(O)N(R′)2或SO2N(R′)2取代；R 2 is a C 1 -C 6 aliphatic group, optionally replaced by N(R′) 2 , OR′, CO 2 R′, C(O)N(R′) 2 or SO 2 N(R′) 2 substituted; or a carbocyclic or heterocyclic ring system, optionally by N(R') 2 , OR', CO 2 R', C(O)N(R') 2 or SO 2 N(R') 2 replace;

其中Ar3是芳基或杂芳基环系，可选地与具有0-4个杂原子的饱和或不饱和5-8元环稠合；wherein Ar is an aryl or heteroaryl ring system, optionally fused to a saturated or unsaturated 5-8 membered ring having 0-4 heteroatoms;

其中Ar3可选地在一个或多个环原子上被一个或多个取代基取代，所述取代基独立地选自卤素；C1-C6脂族基团，可选地被N(R′)2、OR′、CO2R′、C(O)N(R′)2、OC(O)N(R′)2、NR′CO2R′、NR′C(O)R′、SO2N(R′)2、N＝CH-N(R′)2或OPO3H2取代；C1-C6烷氧基，可选地被N(R′)2、OR′、CO2R′、C(O)N(R′)2、OC(O)N(R′)2、SO2N(R′)2、NR′CO2R′、NR′C(O)R′、N＝CH-N(R′)2或OPO3H2取代；CF3；OCF3；OR′；SR′；SO2N(R′)2；OSO2R′；SCF3；NO2；CN；N(R′)2；CO2R′；CO2N(R′)2；C(O)N(R′)2；NR′C(O)R′；NR′CO2R′；NR′C(O)C(O)R′；NR′SO2R′；OC(O)R′；NR′C(O)R2；NR′CO2R2；NR′C(O)C(O)R2；NR′C(O)N(R′)2；OC(O)N(R′)2；NR′SO2R2；NR′R2；N(R2)2；OC(O)R2；OPO3H2；和N＝CH-N(R′)2。wherein Ar 3 is optionally substituted on one or more ring atoms by one or more substituents independently selected from halogen; C 1 -C 6 aliphatic groups, optionally substituted by N(R ′) 2 , OR′, CO 2 R′, C(O)N(R′) 2 , OC(O)N(R′) 2 , NR′CO 2 R′, NR′C(O)R′, SO 2 N(R') 2 , N=CH-N(R') 2 or OPO 3 H 2 substituted; C 1 -C 6 alkoxy, optionally replaced by N(R') 2 , OR', CO 2 R′, C(O)N(R′) 2 , OC(O)N(R′) 2 , SO 2 N(R′) 2 , NR′CO 2 R′, NR′C(O)R′ , N=CH-N(R') 2 or OPO 3 H 2 substitution; CF 3 ; OCF 3 ; OR';SR'; SO 2 N(R') 2 ; OSO 2 R'; SCF 3 ; NO 2 ; CN; N(R′) 2 ; CO 2 R′; CO 2 N(R′) 2 ; C(O)N(R′) 2 ; NR′C(O)R′; NR′CO 2 R′; NR'C(O)C(O)R';NR'SO 2 R';OC(O)R';NR'C(O)R2;NR'CO 2 R 2 ; (O)R 2 ; NR′C(O)N(R′) 2 ; OC(O)N(R′) 2 ; NR′SO 2 R 2 ; NR′R 2 ; N(R 2 ) 2 ; (O) R2 ; OPO3H2 ; and N=CH-N(R') 2 .

在优选的实施方式中，Ar1和Ar2独立地选自可选被取代的苯基、萘基、苯并咪唑基、苯并噻吩基、苯并呋喃基、吲哚基、喹啉基、苯并噻唑基、苯并噁唑基、苯并咪唑基、异喹啉基、异吲哚基、吖啶基、苯并异噁唑基、吡啶基、嘧啶基、哒嗪基、四唑基、呋喃基、咪唑基、异噁唑基、噁二唑基、噁唑基、吡咯基、噻唑基、三唑基和噻吩基。在更优选的实施方式中，Ar1和Ar2独立地选自可选被取代的苯基和吡啶基。在进而更优选的实施方式中，Ar1是可选被取代的吡啶基，Ar2是可选被取代的苯基。In a preferred embodiment, Ar and Ar are independently selected from optionally substituted phenyl, naphthyl, benzimidazolyl, benzothienyl, benzofuryl, indolyl, quinolinyl, Benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolyl, isoindolyl, acridinyl, benzisoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, tetrazolyl , furyl, imidazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolyl, thiazolyl, triazolyl and thienyl. In a more preferred embodiment, Ar 1 and Ar 2 are independently selected from optionally substituted phenyl and pyridyl. In an even more preferred embodiment, Ar 1 is optionally substituted pyridyl and Ar 2 is optionally substituted phenyl.

本发明的方法包括在碱金属盐或过渡金属催化剂的存在下使式(II)化合物与式(III)胺偶联得到式(I)二芳基胺的步骤：The method of the present invention comprises the step of coupling the compound of formula (II) with the amine of formula (III) to obtain the diarylamine of formula (I) in the presence of an alkali metal salt or a transition metal catalyst:

              Ar1-X                 Ar2-NH-YAr 1 -X Ar 2 -NH-Y

               (II)                  (III)(II) (III)

其中：in:

X是离去基团；X is a leaving group;

Y是-C(O)-O-Z；Y is -C(O)-O-Z;

Z选自C1-C6脂族基团、苄基、Fmoc、-SO2R’和Q，其条件是Q不被X或炔烃取代；Z is selected from C 1 -C 6 aliphatic group, benzyl, Fmoc, -SO 2 R' and Q, with the proviso that Q is not substituted by X or alkyne;

Ar1、Ar2、Q和R’是如上所定义的。Ar 1 , Ar 2 , Q and R' are as defined above.

下列流程1描绘优选的本发明方法：The following scheme 1 depicts a preferred method of the invention:

流程1Process 1

Figure A20048000713700151
Figure A20048000713700151

其中Ar1、Ar2、X和Y是如上所定义的。上述步骤可以描述如下：wherein Ar 1 , Ar 2 , X and Y are as defined above. The above steps can be described as follows:

步骤1：使携带适合的离去基团X的式(II)化合物与携带Y-NH-部分的式(III)化合物反应。反应是在碱金属盐的存在下进行的，例如碳酸铯；或者作为替代选择在过渡金属催化剂的存在下，可选地在碱和一种或多种配体的存在下。Step 1: Reaction of a compound of formula (II) bearing a suitable leaving group X with a compound of formula (III) bearing a Y-NH- moiety. The reaction is carried out in the presence of an alkali metal salt, such as cesium carbonate; or alternatively in the presence of a transition metal catalyst, optionally in the presence of a base and one or more ligands.

在一种实施方式中，使用过渡金属催化剂。可以使用的示范性过渡金属催化剂包含过渡金属离子或原子和一种或多种适合的配体。优选地，过渡金属催化剂包含VIII族金属。更优选地，过渡金属催化剂包含钯。按照优选的实施方式，在步骤1中同时使用两种不同的配体。In one embodiment, a transition metal catalyst is used. Exemplary transition metal catalysts that can be used comprise transition metal ions or atoms and one or more suitable ligands. Preferably, the transition metal catalyst comprises a Group VIII metal. More preferably, the transition metal catalyst comprises palladium. According to a preferred embodiment, in step 1 two different ligands are used simultaneously.

按照优选的实施方式，在步骤1中联合使用过渡金属催化剂和一种碱。适合的碱包括KOtBu、NaOtBu、K3PO4、Na2CO3和Cs2CO3。更优选地，该碱是K3PO4。According to a preferred embodiment, in step 1 a transition metal catalyst and a base are used in combination. Suitable bases include KOtBu, NaOtBu , K3PO4 , Na2CO3 and Cs2CO3 . More preferably, the base is K 3 PO 4 .

在使用过渡金属催化剂时，步骤1所优选的溶剂包括甲苯和非极性质子惰性溶剂，例如MTBE、DME和己烷。Preferred solvents for Step 1 include toluene and non-polar aprotic solvents such as MTBE, DME and hexane when transition metal catalysts are used.

在另一种实施方式中，在步骤1中使用碱金属盐。优选地，碱金属盐是铯盐。In another embodiment, an alkali metal salt is used in step 1. Preferably, the alkali metal salt is a cesium salt.

在使用碱金属盐时，步骤1所优选的溶剂包括极性质子惰性溶剂，例如NMP。When alkali metal salts are used, preferred solvents for step 1 include polar aprotic solvents such as NMP.

步骤2：Step 2:

在步骤2中，除去(IV)的基团Y，生成式(I)二芳基胺。In step 2, the group Y of (IV) is removed to generate a diarylamine of formula (I).

按照优选的实施方式，在步骤2中使用一种酸，例如TFA、HCl、HBr或HI。更优选地，该酸是TFA。According to a preferred embodiment, an acid such as TFA, HCl, HBr or HI is used in step 2. More preferably, the acid is TFA.

步骤2所优选的溶剂包括氯化溶剂，例如CH2Cl2、1，2-二氯乙烷和氯苯。Preferred solvents for step 2 include chlorinated solvents such as CH2Cl2 , 1,2-dichloroethane and chlorobenzene.

本发明的方法具有允许从一元芳基胺衍生物制备式(I)化合物而无过度芳基化的问题的优点。本发明的方法具有进一步允许以高收率与纯度和大规模制备式(I)化合物的优点。The process of the present invention has the advantage of allowing the preparation of compounds of formula (I) from monoarylamine derivatives without the problem of excessive arylation. The process of the present invention has the further advantage of allowing the preparation of compounds of formula (I) in high yields and purity and on a large scale.

步骤1试剂：Step 1 Reagents:

适合于本发明的过渡金属催化剂包含过渡金属原子或离子和一种或多种配体。过渡金属可以存在任意适合的氧化状态，从零化合价到该过渡金属可达到的任意更高化合价。按照优选的实施方式，过渡金属催化剂包含VIII族金属。更优选地，过渡金属催化剂包含钯。催化剂配合物可以包括螯合配体，非限制地包括膦与二膦、亚胺、胂及其杂合物的烷基与芳基衍生物。Transition metal catalysts suitable for the present invention comprise transition metal atoms or ions and one or more ligands. A transition metal may exist in any suitable oxidation state, from zero valence to any higher valence attainable for the transition metal. According to a preferred embodiment, the transition metal catalyst comprises a Group VIII metal. More preferably, the transition metal catalyst comprises palladium. The catalyst complex may include chelating ligands including, without limitation, alkyl and aryl derivatives of phosphines and diphosphines, imines, arsines, and hybrids thereof.

更优选地，过渡金属催化剂是式PdLn钯催化剂，其中每个L独立地选自Cl、-OAc、-O-甲苯基、卤素、PPh3、dppe、dppf和BINAP；n是整数1-4。上述过渡金属催化剂可以利用本领域已知的方法制备。More preferably, the transition metal catalyst is a palladium catalyst of the formula PdL n , wherein each L is independently selected from Cl, -OAc, -O-tolyl, halogen, PPh3 , dppe, dppf, and BINAP; n is an integer of 1-4 . The above-mentioned transition metal catalysts can be prepared by methods known in the art.

多种配体转化可以发生在本发明的方法之中。配体可以在本发明的方法之中与过渡金属键合，或者在全部或部分方法期间，配体相对于过渡金属而言可以处于不稳定构型。因此，本文所用的术语“过渡金属催化剂”包括任意向反应容器中引入的过渡金属催化剂和/或催化剂前体，如果必要的话，就地转化为催化剂的活性形式，参与反应。A variety of ligand transformations can occur within the methods of the invention. The ligand may be bound to the transition metal during the process of the invention, or the ligand may be in an unstable configuration with respect to the transition metal during all or part of the process. Thus, the term "transition metal catalyst" as used herein includes any transition metal catalyst and/or catalyst precursor introduced into the reaction vessel, converted to the active form of the catalyst in situ, if necessary, to participate in the reaction.

用在本发明方法中的过渡金属催化剂的量是任意促进二芳基胺产物生成的量。按照优选的实施方式，该量是催化量，其中催化剂的用量小于相对于芳基组分而言的化学计算量。在另一种优选的实施方式中，催化剂的含量范围为约0.01至约20摩尔百分比，相对于非胺芳基组分而言，更优选约1至约10摩尔百分比，进而更优选约1至约5摩尔百分比。The amount of transition metal catalyst used in the process of this invention is any amount which promotes the formation of the diarylamine product. According to a preferred embodiment, the amount is a catalytic amount, wherein the amount of catalyst used is less than the stoichiometric amount relative to the aryl component. In another preferred embodiment, the content of the catalyst is in the range of about 0.01 to about 20 mole percent, more preferably about 1 to about 10 mole percent, and even more preferably about 1 to about 20 mole percent relative to the non-amine aryl component. about 5 mole percent.

本领域技术人员可以容易地选自适当的溶剂用在本发明的方法中。溶剂的含量可以是任意有利于所需方法所需要的量，不必是溶解底物和/或所需方法试剂的量。根据本发明的溶剂将不会干扰二芳基胺产物的生成。适合的溶剂的实例非限制地包括卤化溶剂、烃溶剂、醚溶剂、质子溶剂和质子惰性溶剂。溶剂的混合物也包括在本发明的范围内。使用过渡金属催化剂的本发明方法步骤1所优选的溶剂包括甲苯、苯或者非极性质子惰性溶剂，例如MTBE、DME或己烷。A person skilled in the art can easily select an appropriate solvent for use in the method of the present invention. The amount of solvent can be any amount necessary to facilitate the desired process, not necessarily an amount that dissolves the substrate and/or the desired process reagents. Solvents according to the invention will not interfere with the formation of diarylamine products. Examples of suitable solvents include, without limitation, halogenated solvents, hydrocarbon solvents, ether solvents, protic solvents, and aprotic solvents. Mixtures of solvents are also included within the scope of the present invention. Preferred solvents for step 1 of the process of the invention using transition metal catalysts include toluene, benzene or non-polar aprotic solvents such as MTBE, DME or hexane.

按照一种实施方式，使用过渡金属催化剂的偶联步骤(步骤1)发生在一种碱的存在下。适合的碱的实例非限制地包括碱金属氢氧化物、碱金属醇盐、金属碳酸盐、磷酸盐、碱金属芳基氧化物、碱金属氨基化物、三元胺、(烃基)氢氧化铵和二氮杂有机碱。碱的用量可以是任意允许二芳基胺产物生成的量。本发明所优选的碱包括KOtBu、NaOtBu、K3PO4、Na2CO3和Cs2CO3。According to one embodiment, the coupling step (step 1 ) using a transition metal catalyst takes place in the presence of a base. Examples of suitable bases include, without limitation, alkali metal hydroxides, alkali metal alkoxides, metal carbonates, phosphates, alkali metal aryl oxides, alkali metal amides, triamines, (hydrocarbyl)ammonium hydroxides and diaza organic bases. The amount of base used can be any amount that allows the formation of the diarylamine product. Preferred bases of the present invention include KOtBu, NaOtBu , K3PO4 , Na2CO3 and Cs2CO3 .

适合于本发明的碱金属盐包含钠、钾、铷或铯离子的盐。优选地，适合于本发明的碱金属盐包含钾或铯离子的盐。优选的碱金属盐包含碳酸盐、磷酸盐和醇盐。更优选的碱金属盐包括碳酸钾和碳酸铯。最优选地，碱金属盐是碳酸铯。Alkali metal salts suitable for the present invention comprise salts of sodium, potassium, rubidium or cesium ions. Preferably, alkali metal salts suitable for the present invention comprise salts of potassium or cesium ions. Preferred alkali metal salts include carbonates, phosphates and alkoxides. More preferred alkali metal salts include potassium carbonate and cesium carbonate. Most preferably, the alkali metal salt is cesium carbonate.

用在本发明方法中的过渡金属催化剂的量是任意促进二芳基胺产物生成的量。The amount of transition metal catalyst used in the process of this invention is any amount which promotes the formation of the diarylamine product.

使用碱金属盐的本发明方法步骤1所优选的溶剂包括极性质子惰性溶剂，例如NMP。Preferred solvents for step 1 of the process of the invention using alkali metal salts include polar aprotic solvents such as NMP.

步骤2试剂：Step 2 Reagents:

按照优选的实施方式，保护基团除去步骤(步骤2)发生在一种酸的存在下。适合的酸的实例非限制地包括HCl、HBr、HI和有机酸，包括甲酸、乙酸、丙酸、丁酸、甲磺酸、对-甲苯磺酸、苯磺酸和三氟乙酸。本发明所优选的酸包括HCl、HBr、HI和TFA。According to a preferred embodiment, the protecting group removal step (step 2) takes place in the presence of an acid. Examples of suitable acids include, without limitation, HCl, HBr, HI, and organic acids, including formic acid, acetic acid, propionic acid, butyric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and trifluoroacetic acid. Preferred acids of the invention include HCl, HBr, HI and TFA.

本发明方法步骤2所优选的溶剂包括氯化溶剂，例如CH2Cl2、1，2-二氯乙烷和氯苯。Preferred solvents for step 2 of the process of the present invention include chlorinated solvents such as CH2Cl2 , 1,2 -dichloroethane and chlorobenzene.

在本发明的一种实施方式中，X是离去基团。按照优选的实施方式，X选自由Cl、Br、I、F、OTf、OTs、碘鎓和重氮基组成的组。In one embodiment of the invention, X is a leaving group. According to a preferred embodiment, X is selected from the group consisting of Cl, Br, I, F, OTf, OTs, iodonium and diazo.

在本发明的一种实施方式中，Y是氨基甲酸酯类胺保护基团。按照优选的实施方式，Y是Boc。In one embodiment of the invention, Y is a carbamate amine protecting group. According to a preferred embodiment, Y is Boc.

正如本文所用的，应当适用下列定义，另有指示除外。而且，取代基的组合仅在这类组合导致稳定的化合物时才是可允许的。As used herein, the following definitions shall apply unless otherwise indicated. Also, combinations of substituents are permissible only if such combinations result in stable compounds.

一些用在说明书全文(包括化学式)中的缩写有：Some of the abbreviations used throughout the specification (including formulas) are:

Boc＝叔丁氧羰基Boc = tert-butoxycarbonyl

Fmoc＝芴基甲氧羰基Fmoc = fluorenylmethoxycarbonyl

Tf＝三氟甲磺酸酯Tf = Triflate

Ts＝对-甲苯磺酰Ts = p-toluenesulfonyl

Ms＝甲磺酰Ms = methylsulfonyl

TFA＝三氟乙酸TFA = trifluoroacetic acid

Ac＝乙酰Ac = acetyl

dba＝反式，反式-二亚苄基丙酮dba = trans, trans-dibenzylideneacetone

dppe＝1，2-双-(二苯膦基)乙烷dppe=1,2-bis-(diphenylphosphino)ethane

dppf＝1，1′-双-(二苯膦基)二茂铁dppf=1,1'-bis-(diphenylphosphino)ferrocene

dppp＝丙烷-1，3-二基双(二苯膦)dppp = propane-1,3-diylbis(diphenylphosphine)

BINAP＝2，2′-双(二苯膦基)-1，1′-联萘BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

MTBE＝甲基叔丁基醚MTBE = methyl tert-butyl ether

DME＝二甲氧基乙烷DME = dimethoxyethane

CDI＝1，1′-羰基二咪唑CDI=1,1'-carbonyldiimidazole

DCC＝N，N′-二环己基碳二亚胺DCC=N,N'-Dicyclohexylcarbodiimide

EDC＝1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐EDC = 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride

HOBt＝N-羟基苯并三唑HOBt=N-Hydroxybenzotriazole

NMP＝N-甲基吡咯烷酮NMP = N-methylpyrrolidone

DMF＝二甲基甲酰胺DMF = dimethylformamide

MCPBA＝间-氯过苯甲酸MCPBA = m-chloroperbenzoic acid

MMPP＝单过氧邻苯二甲酸镁六水合物MMPP = magnesium monoperoxyphthalate hexahydrate

DIBAL-H＝二异丁基氢化铝DIBAL-H = diisobutylaluminum hydride

LAH＝氢化铝锂LAH = lithium aluminum hydride

超氢化物＝三乙基硼氢化锂Superhydride = lithium triethylborohydride

L-selectride＝三仲丁基硼氢化锂L-selectride = lithium tri-sec-butyl borohydride

Red-Al＝双(甲氧基乙氧基)氢化铝钠Red-Al = sodium bis(methoxyethoxy)aluminum hydride

IPA＝异丙醇IPA = isopropyl alcohol

甘醇二甲醚＝二甲氧基乙烷Glyme = Dimethoxyethane

二甘醇二甲醚＝双(2-甲氧基乙基)醚Diethylene glycol dimethyl ether = bis(2-methoxyethyl) ether

正如本文所用的，应当适用下列定义，另有指示除外。措辞“可选被取代的”与措辞“取代或未取代的”是可互换使用的。而且，取代基的组合仅在这类组合导致化学上稳定的化合物时才是可允许的。另外，除非另有指示，官能团是独立地加以选择的。As used herein, the following definitions shall apply unless otherwise indicated. The phrase "optionally substituted" and the phrase "substituted or unsubstituted" are used interchangeably. Also, combinations of substituents are permissible only if such combinations result in chemically stable compounds. Also, unless otherwise indicated, functional groups are independently selected.

本文所用的术语“离去基团”具有本领域普通技术人员已知的定义(参见March，Advanced Organic Chemistry，4th Edition，JohnWiley & Sons，pp.352-357，1992，引用在此作为参考)。离去基团的实例非限制地包括卤素，例如F、Cl、Br和I；重氮基、芳基-与烷基-磺酰氧基和三氟甲磺酰氧基。The term "leaving group" as used herein has a definition known to those of ordinary skill in the art (see March, Advanced Organic Chemistry, 4th Edition, John Wiley & Sons, pp. 352-357, 1992, incorporated herein by reference). Examples of leaving groups include, without limitation, halogens such as F, Cl, Br, and I; diazo, aryl- and alkyl-sulfonyloxy, and trifluoromethanesulfonyloxy.

本文所用的术语“脂族基团”表示直链或支链C1-C12烃链，它是完全饱和的或者含有一个或多个不饱和单元。术语“脂族基团”还包括单环C3-C8烃或二环C8-C12烃，它是完全饱和的或者含有一个或多个不饱和单元，但是不是芳族的(所述环状烃链这里也被称为“碳环”或“环烷基”)，具有单一的与分子其余部分连接的点，其中所述二环环系中的任意一个环具有3-7个成员。例如，适合的脂族基团包括但不限于直链或支链烷基、烯基、炔基及其杂合物，例如(环烷基)烷基、(环烯基)烷基或(环烷基)烯基。The term "aliphatic group" as used herein denotes a straight or branched C1 - C12 hydrocarbon chain which is fully saturated or contains one or more units of unsaturation. The term "aliphatic group" also includes monocyclic C3 - C8 hydrocarbons or bicyclic C8 - C12 hydrocarbons which are fully saturated or contain one or more units of unsaturation, but which are not aromatic (the Cyclic hydrocarbon chains, also referred to herein as "carbocycles" or "cycloalkyls"), having a single point of attachment to the rest of the molecule, wherein any one ring in the bicyclic ring system has 3-7 members . For example, suitable aliphatic groups include, but are not limited to, straight or branched chain alkyl, alkenyl, alkynyl and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkenyl)alkyl or (cycloalkenyl)alkyl Alkyl)alkenyl.

单独或者作为较大部分的一部分使用的术语“烷基”、“烷氧基”、“羟基烷基”、“烷氧基烷基”和“烷氧基羰基”包括含有一至十二个碳原子的直链与支链。单独或者作为较大部分的一部分使用的术语“烯基”和“炔基”应当包括含有二至十二个碳原子的直链与支链，其中烯基包含至少一条双键，炔基包含至少一条三键。The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkyl" and "alkoxycarbonyl" used alone or as part of a larger moiety include straight and branched chains. The terms "alkenyl" and "alkynyl" used alone or as part of a larger moiety shall include straight and branched chains containing two to twelve carbon atoms, wherein alkenyl contains at least one double bond and alkynyl contains at least A triple key.

本文所用的术语“化学上稳定的”或“化学上可行的与稳定的”表示这样一种化合物结构，它赋予该化合物足以允许借助本领域已知方法制造和对哺乳动物给药的稳定性。通常，这类化合物在40℃或以下的温度下、在没有水分或其他化学反应性条件的存在下是稳定的，达至少一周。As used herein, the term "chemically stable" or "chemically feasible and stable" refers to a structure of a compound that imparts to the compound sufficient stability to permit manufacture and administration to mammals by methods known in the art. Typically, such compounds are stable at temperatures of 40°C or below for at least one week in the absence of moisture or other chemically reactive conditions.

术语“卤代烷基”、“卤代烯基”和“卤代烷氧基”表示被一个或多个卤原子取代的烷基、烯基或烷氧基，视情况而定。术语“卤素”表示F、Cl、Br或I。The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" represent an alkyl, alkenyl or alkoxy group, as the case may be, substituted with one or more halogen atoms. The term "halogen" means F, Cl, Br or I.

术语“杂原子”表示N、O或S，应当包括氮和硫的任意氧化形式，和任意碱性氮的季铵化形式。The term "heteroatom" means N, O or S, and shall include any oxidized forms of nitrogen and sulfur, and quaternized forms of any basic nitrogen.

单独或者作为较大部分一部分使用的术语“胺”或“氨基”表示三价氮，它可以是一元的或者可以被1-2个脂族基团取代。The term "amine" or "amino" used alone or as part of a larger moiety denotes a trivalent nitrogen which may be monovalent or may be substituted with 1-2 aliphatic groups.

单独或者作为较大部分“芳烷基”、“芳烷氧基”或“芳氧基烷基”的一部分使用的术语“芳基”表示具有总计五至十四个成员的单环、二环和三环碳环环系，其中该系统中至少一个环是芳族的，并且其中该系统中每个环含有3至8个环成员。术语“芳基”可以与术语“芳基环”互换使用。The term "aryl" used alone or as part of a larger moiety "aralkyl", "aralkoxy" or "aryloxyalkyl" denotes a monocyclic, bicyclic and tricyclic carbocyclic ring systems, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 8 ring members. The term "aryl" may be used interchangeably with the term "aryl ring".

本文所用的术语“杂环”、“杂环基”或“杂环的”表示具有五至十四个环成员的非芳族单环、二环或三环环系，其中一个或多个环成员是杂原子，其中该系统中每个环含有3至7个环成员。The term "heterocycle", "heterocyclyl" or "heterocyclic" as used herein means a non-aromatic monocyclic, bicyclic or tricyclic ring system having five to fourteen ring members, wherein one or more ring Members are heteroatoms, wherein each ring in the system contains 3 to 7 ring members.

本领域普通技术人员将认识到，稳定的、化学上可行的杂环或杂芳族环中的最大杂原子数取决于环的大小、不饱和的程度和杂原子的化合价。一般而言，杂环或杂芳族环可以具有一至四个杂原子，只要该杂环或杂芳族环是化学上可行的和稳定的。Those of ordinary skill in the art will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic or heteroaromatic ring depends on the size of the ring, the degree of unsaturation, and the valence of the heteroatoms. In general, a heterocyclic or heteroaromatic ring can have from one to four heteroatoms so long as the heterocyclic or heteroaromatic ring is chemically feasible and stable.

单独或者作为较大部分“杂芳烷基”或“杂芳基烷氧基”的一部分使用的术语“杂芳基”表示具有总计五至十四个环成员的单环、二环和三环环系，其中该系统中至少一个环是芳族的，该系统中至少一个环含有一个或多个杂原子，并且该系统中每个环含有3至7个环成员。术语“杂芳基”可以与术语“杂芳基环”或术语“杂芳族”互换使用。The term "heteroaryl" used alone or as part of a larger moiety "heteroaralkyl" or "heteroarylalkoxy" denotes monocyclic, bicyclic and tricyclic rings having a total of five to fourteen ring members. Ring systems, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and each ring in the system contains 3 to 7 ring members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

芳基(包括芳烷基、芳烷氧基、芳氧基烷基等)或杂芳基(包括杂芳烷基和杂芳烷氧基等)可以含有一个或多个取代基。芳基、杂芳基、芳烷基或杂芳烷基的不饱和碳原子上适合的取代基选自卤素、卤代烷基、-CF3、-R4、-OR4、-SR4、1，2-亚甲二氧基、1，2-亚乙二氧基、被保护的OH(例如酰氧基)、苯基(Ph)、被R4取代的Ph、-OPh、被R4取代的-OPh、-CH2Ph、被R4取代的-CH2Ph、-CH2CH2Ph、被R4取代的-CH2CH2Ph、-NO2、-CN、-N(R4)2、-NR4C(O)R4、-NR4C(O)N(R4)2、-NR4CO2R4、-NR4NRC(O)R4、-NR4C(O)N(R4)2、-NR4NR4C(O)R4、-NR4NR4C(O)N(R4)2、-NR4NR4CO2R4、-C(O)C(O)R4、-C(O)CH2C(O)R4、-CO2R4、-C(O)R4、-C(O)N(R4)2、-OC(O)N(R4)2、-SO2R4、-SO2N(R4)2、-S(O)R4、-NR4SO2N(R4)2、-NR4SO2R4、-C(＝S)N(R4)2、-C(＝NH)-N(R4)2、-(CH2)yNHC(O)R4、-(CH2)yR4、-(CH2)yNHC(O)NHR4、-(CH2)yNHC(O)OR4、-(CH2)yNHS(O)R4、-(CH2)yNHSO2R4或-(CH2)yNHC(O)CH(V-R4)R4，其中每个R4独立地选自氢、可选被取代的C1-6脂族基团、未取代的5-6元杂芳基或杂环、苯基(Ph)、-O-Ph、-CH2(Ph)；其中y是0-6；V是连接基团。当R4是C1-6脂族基团时，它可以被一个或多个取代基取代，所述取代基选自-NH2、-NH(C1-4脂族基团)、-N(C1-4脂族基团)2、-S(O)(C1-4脂族基团)、-SO2(C1-4脂族基团)、卤素、-(C1-4脂族基团)、-OH、-O-(C1-4脂族基团)、-NO2、-CN、-CO2H、-CO2(C1-4脂族基团)、-O-(卤代C1-4脂族基团)或-卤代(C1-4脂族基团)；其中每个C1-4脂族基团是未取代的。Aryl (including aralkyl, aralkoxy, aryloxyalkyl, etc.) or heteroaryl (including heteroaralkyl, heteroaralkoxy, etc.) groups may contain one or more substituents. Suitable substituents on unsaturated carbon atoms of aryl, heteroaryl, aralkyl or heteroaralkyl are selected from halogen, haloalkyl, -CF3 , -R4 , -OR4 , -SR4 , 1, 2-methylenedioxy, 1,2-ethylenedioxy, protected OH (e.g. acyloxy), phenyl (Ph), Ph substituted by R4 , -OPh, substituted by R4 -OPh, -CH 2 Ph, -CH 2 Ph substituted by R 4 , -CH 2 CH 2 Ph, -CH 2 CH 2 Ph substituted by R 4 , -NO 2 , -CN, -N(R 4 ) 2 , -NR 4 C(O)R 4 , -NR 4 C(O)N(R 4 ) 2 , -NR 4 CO 2 R 4 , -NR 4 NRC(O)R 4 , -NR 4 C(O )N(R 4 ) 2 , -NR 4 NR 4 C(O)R 4 , -NR 4 NR 4 C(O)N(R 4 ) 2 , -NR 4 NR 4 CO 2 R 4 , -C(O )C(O)R 4 , -C(O)CH 2 C(O)R 4 , -CO 2 R 4 , -C(O)R 4 , -C(O)N(R 4 ) 2 , -OC (O)N(R 4 ) 2 , -SO 2 R 4 , -SO 2 N(R 4 ) 2 , -S(O)R 4 , -NR 4 SO 2 N(R 4 ) 2 , -NR 4 SO 2 R 4 , -C(=S)N(R 4 ) 2 , -C(=NH)-N(R 4 ) 2 , -(CH 2 )yNHC(O)R 4 , -(CH 2 ) yR 4 , -(CH 2 ) y NHC(O)NHR 4 , -(CH 2 ) y NHC(O)OR 4 , -(CH 2 ) y NHS(O)R 4 , -(CH 2 ) y NHSO 2 R 4 or -(CH 2 ) y NHC(O)CH(VR 4 )R 4 , wherein each R 4 is independently selected from hydrogen, optionally substituted C 1-6 aliphatic groups, unsubstituted 5- 6-membered heteroaryl or heterocycle, phenyl (Ph), -O-Ph, -CH 2 (Ph); wherein y is 0-6; V is a linking group. When R 4 is a C 1-6 aliphatic group, it may be substituted by one or more substituents selected from -NH 2 , -NH (C 1-4 aliphatic group), -N (C 1-4 aliphatic group) 2 , -S(O)(C 1-4 aliphatic group), -SO 2 (C 1-4 aliphatic group), halogen, -(C 1-4 aliphatic group), -OH, -O-(C 1-4 aliphatic group), -NO 2 , -CN, -CO 2 H, -CO 2 (C 1-4 aliphatic group), - O-(halogenated C 1-4 aliphatic group) or -halo(C 1-4 aliphatic group); wherein each C 1-4 aliphatic group is unsubstituted.

术语“连接基团”或“连接剂”表示连接化合物两个部分的有机部分。连接剂由-O-、-S-、-NR*-、-C(R*)2-、-C(O)或亚烷基链构成。亚烷基链是饱和或不饱和的直链或支链C1-6碳链，它是可选被取代的，其中该链至多两个不相邻的饱和碳可选地被-C(O)-、-C(O)C(O)-、-C(O)NR*-、-C(O)NR*NR*-、NR*NR*-、-NR*C(O)-、-S-、-SO-、-SO2-、-NR*-、-SO2NR*-或-NR*SO2-代替；其中R*选自氢或脂族基团。亚烷基链上可选的取代基是如下关于脂族基团所述的。The term "linking group" or "linking agent" means an organic moiety that links two parts of a compound. Linkers consist of -O-, -S-, -NR*-, -C(R*) 2 -, -C(O) or alkylene chains. An alkylene chain is a saturated or unsaturated straight or branched C 1-6 carbon chain, which is optionally substituted, wherein up to two non-adjacent saturated carbons of the chain are optionally replaced by -C(O )-, -C(O)C(O)-, -C(O)NR*-, -C(O)NR*NR*-, NR*NR*-, -NR*C(O)-, - S-, -SO-, -SO 2 -, -NR*-, -SO 2 NR*- or -NR*SO 2 - instead; wherein R* is selected from hydrogen or an aliphatic group. Optional substituents on the alkylene chain are as described below for aliphatic groups.

脂族基团或非芳族杂环可以含有一个或多个取代基。脂族基团或非芳族杂环的饱和碳上适合的取代基选自如上关于芳基或杂芳基的不饱和碳所列举的那些和如下基团：＝O、＝S、＝NNHR5、＝NN(R5)2、＝NR5、-OR5、＝NNHC(O)R5、＝NNHCO2R5、＝NNHSO2R5或＝NR5，其中每个R5独立地选自氢或可选被取代的C1-6脂族基团。当R5是C1-6脂族基团时，它可以被一个或多个取代基取代，所述取代基选自-NH2、-NH(C1-4脂族基团)、-N(C1-4脂族基团)2、卤素、-OH、-O-(C1-4脂族基团)、-NO2、-CN、-CO2H、-CO2(C1-4脂族基团)、-O-(卤代C1-4脂族基团)或-(卤代C1-4脂族基团)；其中每个C1-4脂族基团是未取代的。An aliphatic group or a non-aromatic heterocycle may contain one or more substituents. Suitable substituents on saturated carbons of aliphatic groups or non-aromatic heterocyclic rings are selected from those listed above for unsaturated carbons of aryl or heteroaryl groups and the following groups: =O, =S, =NNHR 5 , =NN(R 5 ) 2 , =NR 5 , -OR 5 , =NNHC(O)R 5 , =NNHCO 2 R 5 , =NNHSO 2 R 5 or =NR 5 , wherein each R 5 is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic group. When R 5 is a C 1-6 aliphatic group, it may be substituted by one or more substituents selected from -NH 2 , -NH (C 1-4 aliphatic group), -N (C 1-4 aliphatic group) 2 , halogen, -OH, -O-(C 1-4 aliphatic group), -NO 2 , -CN, -CO 2 H, -CO 2 (C 1- 4 aliphatic group), -O-(halogenated C 1-4 aliphatic group) or -(halogenated C 1-4 aliphatic group); wherein each C 1-4 aliphatic group is not replaced.

非芳族杂环氮上的取代基选自-R6、-N(R6)2、-C(O)R6、-CO2R6、-C(O)C(O)R6、-C(O)CH2C(O)R6、-SO2R6、-SO2N(R6)2、-C(＝S)N(R6)2、-C(＝NH)-N(R6)2或-NRSO2R；其中每个R6独立地选自氢、可选被取代的C1-6脂族基团、可选被取代的苯基(Ph)、可选被取代的-O-Ph、可选被取代的-CH2(Ph)或者未取代的5-6元杂芳基或杂环。当R6是C1-6脂族基团或苯基环时，它可以被一个或多个取代基取代，所述取代基选自-NH2、-NH(C1-4脂族基团)、-N(C1-4脂族基团)2、卤素、-(C1-4脂族基团)、-OH、-O-(C1-4脂族基团)、-NO2、-CN、-CO2H、-CO2(C1-4脂族基团)、-O-卤代(C1-4脂族基团)或-(卤代C1-4脂族基团)；其中每个C1-4脂族基团是未取代的。The substituent on the non-aromatic heterocyclic nitrogen is selected from -R 6 , -N(R 6 ) 2 , -C(O)R 6 , -CO 2 R 6 , -C(O)C(O)R 6 , -C(O)CH 2 C(O)R 6 , -SO 2 R 6 , -SO 2 N(R 6 )2, -C(=S)N(R 6 ) 2 , -C(=NH)- N(R 6 ) 2 or -NRSO 2 R; wherein each R 6 is independently selected from hydrogen, optionally substituted C 1-6 aliphatic, optionally substituted phenyl (Ph), optionally Substituted -O-Ph, optionally substituted -CH2 (Ph), or unsubstituted 5-6 membered heteroaryl or heterocycle. When R 6 is a C 1-6 aliphatic group or a phenyl ring, it may be substituted by one or more substituents selected from -NH 2 , -NH(C 1-4 aliphatic group ), -N(C 1-4 aliphatic group) 2 , halogen, -(C 1-4 aliphatic group), -OH, -O-(C 1-4 aliphatic group), -NO 2 , -CN, -CO 2 H, -CO 2 (C 1-4 aliphatic group), -O-halogenated (C 1-4 aliphatic group) or -(halogenated C 1-4 aliphatic group group); wherein each C 1-4 aliphatic group is unsubstituted.

流程2-8阐述流程1方法应用于吡啶基芳基胺衍生物的合成。按照本发明合成的这些吡啶基二芳基胺可以进一步按照本领域技术人员已知的方法加以官能化，目的是生成有力的p38激酶抑制剂化合物。Schemes 2-8 illustrate the application of the method in Scheme 1 to the synthesis of pyridylarylamine derivatives. These pyridyldiarylamines synthesized according to the present invention can be further functionalized according to methods known to those skilled in the art in order to generate potent p38 kinase inhibitor compounds.

流程2Process 2

其中：in:

R3选自C1-C6脂族基团；芳基；和被C1-C6脂族基团、芳基、硝基、CN、CO2R′、CO2N(R′)2、OR′、NCO2R′、NR′C(O)N(R′)2或OC(O)N(R′)2取代的芳基；其条件是R3不是叔丁基；R 3 is selected from a C 1 -C 6 aliphatic group; an aryl group; and a C 1 -C 6 aliphatic group, an aryl group, a nitro group, CN, CO 2 R′, CO 2 N(R′) 2 , OR', NCO 2 R', NR'C(O)N(R') 2 or OC(O)N(R' ) substituted aryl; with the proviso that R 3 is not tert-butyl;

G1、G2、G3、G4和G5独立地选自氢、脂族基团、芳基、取代的芳基、硝基、CN、OR′、CO2R′、CO2N(R′)2、NR′CO2R′、NR′C(O)N(R′)2、CO(O)N(R′)2、F、Cl、Br、I、O-Ts、O-Ms、OSO2R′和OC(O)R′；G 1 , G 2 , G 3 , G 4 and G 5 are independently selected from hydrogen, aliphatic groups, aryl groups, substituted aryl groups, nitro groups, CN, OR', CO 2 R', CO 2 N( R′) 2 , NR′CO 2 R′, NR′C(O)N(R′) 2 , CO(O)N(R′) 2 , F, Cl, Br, I, O-Ts, O- Ms, OSO 2 R' and OC(O)R';

X是离去基团；X is a leaving group;

Y是-C(O)-O-Z；Y is -C(O)-O-Z;

Z选自C1-C6脂族基团、苄基、Fmoc、-SO2R′或Q，其条件是Q不被X或炔烃取代；Z is selected from a C 1 -C 6 aliphatic group, benzyl, Fmoc, -SO 2 R' or Q, with the proviso that Q is not substituted by X or an alkyne;

其中Q和R′是如上所定义的。wherein Q and R' are as defined above.

流程2所述各步可以描述如下：Each step in process 2 can be described as follows:

步骤1：原料21可以按照本领域已知工艺从2-氯烟酸合成得到(例如参见流程3)。使原料21与被保护的芳基胺22偶联(例如参见流程3)，反应条件为在碱金属盐的存在下，例如碳酸铯，在溶剂中，例如NMP；或者作为替代选择，在催化剂的存在下，例如乙酸钯，可选地在配体的存在下，例如BINAP或dppe，可选地在碱的存在下，例如磷酸钾，在相容性溶剂中，例如甲苯、MTBE、DME或己烷，得到式23被保护的偶联产物。Step 1: The starting material 21 can be synthesized from 2-chloronicotinic acid according to the known techniques in the art (see scheme 3 for example). The starting material 21 is coupled with a protected arylamine 22 (see, for example, Scheme 3) in the presence of an alkali metal salt, such as cesium carbonate, in a solvent such as NMP; or alternatively, in the presence of a catalyst in the presence of, for example, palladium acetate, optionally in the presence of a ligand, such as BINAP or dppe, optionally in the presence of a base, such as potassium phosphate, in a compatible solvent, such as toluene, MTBE, DME or hexyl alkane, the protected coupling product of formula 23 is obtained.

步骤2：在适合的溶剂中，例如二氯甲烷、1，2-二氯乙烷或氯苯，使被保护的偶联产物23与酸反应，例如TFA，得到式24化合物。Step 2: Reaction of the protected coupling product 23 with an acid, such as TFA, in a suitable solvent, such as dichloromethane, 1,2-dichloroethane or chlorobenzene, affords compounds of formula 24.

流程3a阐述原料21的合成，流程3b例证流程2的去保护的偶联产物24的进一步衍生化。Scheme 3a illustrates the synthesis of starting material 21 and Scheme 3b exemplifies the further derivatization of the deprotected coupling product 24 of Scheme 2.

                     流程3aProcess 3a

其中R3、G1、G2、G3、G4和G5是如上流程2所述的。Wherein R 3 , G 1 , G 2 , G 3 , G 4 and G 5 are as described in scheme 2 above.

流程3a和3b所述各步可以描述如下：The steps described in processes 3a and 3b can be described as follows:

步骤A：在HOBt和N-羟基琥珀酰亚胺的存在下，在极性质子惰性溶剂中，例如CH2Cl2、1，2-二氯乙烷、DMF或NMP，在加热下，使烟酸衍生物31与氯甲酸酯活化剂反应，例如SOCl2、氨甲酸苯基酯或氯甲酸对-硝基苯基酯，可以使31活化。然后加入式R3OH醇，生成化合物32。Step A: In the presence of HOBt and N-hydroxysuccinimide, in a polar aprotic solvent, such as CH2Cl2 , 1,2-dichloroethane, DMF or NMP, under heating, smoke 31 can be activated by reaction of the acid derivative 31 with a chloroformate activator, such as SOCl2 , phenyl carbamate, or p-nitrophenyl chloroformate. Then an alcohol of formula R 3 OH is added to generate compound 32.

步骤B：在催化剂和碱的存在下，前者例如乙酸钯，后者例如碳酸钠、碳酸钾、碳酸锂、碳酸铯、叔丁醇钾、叔丁醇钠或叔丁醇锂，在溶剂中，例如甲苯、MTBE、DME或己烷，使化合物32与硼酸偶联，例如33，得到34。Step B: in the presence of a catalyst and a base, the former such as palladium acetate, the latter such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide or lithium tert-butoxide, in a solvent, Coupling of compound 32 with a boronic acid, such as toluene, MTBE, DME or hexane, such as 33, affords 34.

步骤C：然后在一种试剂的存在下，例如MCPBA、过乙酸或MMPP，在氯化溶剂中，例如CH2Cl2或1，2-二氯乙烷，N-氧化偶联产物34，得到35。Step C: The product 34 is then N-oxidatively coupled in the presence of a reagent such as MCPBA, peracetic acid or MMPP in a chlorinated solvent such as CH2Cl2 or 1,2 -dichloroethane to give 35.

步骤D：在一种试剂的存在下，例如POCl3、POBr3、SOCl2、SO2Cl2或SOBr2，使N-氧化物35活化，得到21。Step D: Activation of N - oxide 35 to afford 21 in the presence of a reagent such as POCl3 , POBr3 , SOCl2 , SO2Cl2 or SOBr2 .

步骤1和2是如上流程2所述的。Steps 1 and 2 are as described in Flowchart 2 above.

步骤E：使游离胺24与活化羰基反应，例如X4C(O)X5，其中X4和X5各自独立地选自Cl、Br、I、咪唑、O-Ph、对-硝基苯氧基、取代的O-芳基或离去基团，衍生成对应的脲，然后在溶剂中，例如甲苯、DME或MTBE，使羰基与氢氧化铵反应，生成36。Step E: Reaction of free amine 24 with an activated carbonyl, such as X 4 C(O)X 5 , where X 4 and X 5 are each independently selected from Cl, Br, I, imidazole, O-Ph, p-nitrobenzene Oxygen, substituted O-aryl or leaving group, derivatization to the corresponding urea, followed by reaction of the carbonyl with ammonium hydroxide in a solvent such as toluene, DME or MTBE gives 36.

步骤F：在还原剂的存在下，例如DIBAL、LAH、超氢化物、L-Selectide、LiBH4、NaBH3(酰基苯胺)、Red-Al或NaBH4，在溶剂中，例如THF、DME、MTBE、MeOH、EtOH、IPA、t-BuOH、甘醇二甲醚或二甘醇二甲醚，将36的酯官能团还原为对应的醇，生成37。Step F: In the presence of a reducing agent, such as DIBAL, LAH, superhydride, L-Selectide, LiBH 4 , NaBH 3 (anilide), Red-Al or NaBH 4 , in a solvent such as THF, DME, MTBE , MeOH, EtOH, IPA, t-BuOH, glyme or diglyme, the ester function of 36 is reduced to the corresponding alcohol to generate 37.

步骤G：37的醇可以进一步官能化，例如用X4C(O)X5活化，其中X4和X5是如上步骤E所述的，然后使羰基与OH(CH2)2NH2反应，生成38。Step G: The alcohol of 37 can be further functionalized, e.g. activated with X4C (O) X5 , where X4 and X5 are as described above for Step E, and then the carbonyl is reacted with OH( CH2 ) 2NH2 , generating 38.

尽管流程4-7的方法是用具体试剂和原料加以阐述的，不过将为本领域技术人员所领会的是可以使用适合的类似反应剂和原料制备类似化合物。Although the methods of Schemes 4-7 are illustrated using specific reagents and starting materials, it will be appreciated by those skilled in the art that similar compounds can be prepared using appropriate similar reactants and starting materials.

流程4提供利用本发明方法生产二芳基胺的实例。Scheme 4 provides an example of the production of diarylamines using the process of the present invention.

流程4Process 4

Figure A20048000713700271
Figure A20048000713700271

流程4所述各步可以简要描述如下：Each step in process 4 can be briefly described as follows:

步骤1：6-氯-2-(4-氟苯基)-烟酸甲基酯41可以从2-氯烟酸合成得到(例如参见流程5)。使41与被保护的芳基胺偶联，例如Boc-2，6-二氟苯胺42(例如参见流程5)，反应条件为在碱金属盐的存在下，例如碳酸铯，在溶剂中，例如NMP；或者作为替代选择，在催化剂的存在下，例如乙酸钯，可选地在配体的存在下，例如BINAP，可选地在碱的存在下，例如磷酸钾，在相容性溶剂中，例如甲苯，得到式43被保护的偶联产物。Step 1: 6-Chloro-2-(4-fluorophenyl)-nicotinic acid methyl ester 41 can be synthesized from 2-chloronicotinic acid (eg see Scheme 5). Coupling of 41 with a protected arylamine, such as Boc-2,6-difluoroaniline 42 (see, for example, Scheme 5), in the presence of an alkali metal salt, such as cesium carbonate, in a solvent such as NMP; or alternatively, in the presence of a catalyst, such as palladium acetate, optionally in the presence of a ligand, such as BINAP, optionally in the presence of a base, such as potassium phosphate, in a compatible solvent, Such as toluene, the protected coupling product of formula 43 is obtained.

步骤2：在适合的溶剂中，例如二氯甲烷，使被保护的偶联产物43与酸反应，例如TFA，得到式44化合物。Step 2: Reaction of the protected coupling product 43 with an acid, such as TFA, in a suitable solvent, such as dichloromethane, affords compounds of formula 44.

更一般地，本领域技术人员将认识到式44化合物可以借助41a与42a的反应生成：More generally, those skilled in the art will recognize that compounds of formula 44 can be generated by the reaction of 41a and 42a:

Figure A20048000713700281
Figure A20048000713700281

其中X和Y是如上所述的。where X and Y are as described above.

流程5a阐述原料41的合成，流程5b阐述流程4的去保护的偶联产物44的进一步衍生化。Scheme 5a illustrates the synthesis of starting material 41 and Scheme 5b illustrates the further derivatization of the deprotected coupling product 44 of Scheme 4.

 流程5aProcess 5a

Figure A20048000713700291
Figure A20048000713700291

流程5bProcess 5b

Figure A20048000713700301
Figure A20048000713700301

流程5a和5b所述各步可以简要描述如下：Each step in processes 5a and 5b can be briefly described as follows:

步骤A：在HOBt和N-羟基琥珀酰亚胺的存在下，在极性质子惰性溶剂中，例如CH2Cl2、1，2-二氯乙烷、DMF或NMP，在加热下，使6-氯烟酸51与氯甲酸酯活化剂反应，例如SOCl2、氯甲酸苯基酯或氯甲酸对-硝基苯基酯，或者与碳二亚胺活化剂反应，例如CDI、DCC或EDC，使51活化。然后加入醇，例如甲醇，生成6-氯烟酸甲基酯52。Step A: In the presence of HOBt and N-hydroxysuccinimide, in a polar aprotic solvent, such as CH2Cl2 , 1,2 -dichloroethane, DMF or NMP, under heating, 6 - Reaction of chloronicotinic acid 51 with chloroformate activators such as SOCl2 , phenyl chloroformate or p-nitrophenyl chloroformate, or with carbodiimide activators such as CDI, DCC or EDC , to activate 51. Alcohol, such as methanol, is then added to generate methyl 6-chloronicotinate 52.

步骤B：在催化剂和碱的存在下，前者例如乙酸钯，后者例如碳酸钠、碳酸钾、碳酸锂、碳酸铯、叔丁醇钾、叔丁醇钠或叔丁醇锂，在溶剂中，例如甲苯、MTBE、DME或己烷，使化合物52与硼酸偶联，例如53，得到54。Step B: in the presence of a catalyst and a base, the former such as palladium acetate, the latter such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide or lithium tert-butoxide, in a solvent, Coupling of compound 52 with boronic acid, such as toluene, MTBE, DME or hexane, such as 53, affords 54.

步骤C：然后在一种试剂的存在下，例如MCPBA、过乙酸或MMPP，在氯化溶剂中，例如CH2Cl2或1，2-二氯乙烷，使偶联产物54N-氧化，得到55。Step C: The coupling product 54 is then N-oxidized in the presence of a reagent such as MCPBA, peracetic acid or MMPP in a chlorinated solvent such as CH2Cl2 or 1,2 -dichloroethane to give 55.

步骤D：在一种试剂的存在下，例如POCl3、POBr3、SOCl2、SO2Cl2或SOBr2，使活化N-氧化物55卤化，得到41。Step D: Halogenation of activated N-oxides 55 to afford 41 in the presence of a reagent such as POCl3 , POBr3 , SOCl2 , SO2Cl2 or SOBr2 .

步骤1和2是如上流程4所述的。Steps 1 and 2 are as described in Flowchart 4 above.

步骤E：使游离胺44与活化羰基反应，例如X4C(O)X5，其中X4和X5各自独立地选自Cl、Br、I、咪唑、O-Ph、对-硝基苯氧基、取代的O-芳基或离去基团，衍生成对应的脲，然后在溶剂中，例如甲苯、DME或MTBE，使羰基与氢氧化铵反应，生成56。Step E: Reaction of free amine 44 with an activated carbonyl, such as X 4 C(O)X 5 , where X 4 and X 5 are each independently selected from Cl, Br, I, imidazole, O-Ph, p-nitrobenzene Oxy, substituted O-aryl, or leaving group, derivatized to the corresponding urea, and reaction of the carbonyl with ammonium hydroxide in a solvent such as toluene, DME, or MTBE yields 56.

步骤F：在还原剂的存在下，例如DIBAL、LAH、超氢化物、L-Selectide、LiBH4、NaBH3(酰基苯胺)、Red-Al或NaBH4，在溶剂中，例如THF、DME、MTBE、MeOH、EtOH、IPA、t-BuOH、甘醇二甲醚或二甘醇二甲醚，将56的酯官能团还原为对应的醇，生成57。Step F: In the presence of a reducing agent, such as DIBAL, LAH, superhydride, L-Selectide, LiBH 4 , NaBH 3 (anilide), Red-Al or NaBH 4 , in a solvent such as THF, DME, MTBE , MeOH, EtOH, IPA, t-BuOH, glyme or diglyme, the ester function of 56 is reduced to the corresponding alcohol to generate 57.

步骤G：57的醇可以进一步官能化，例如与X4C(O)X5反应，其中X4和X5是如上步骤E所述的，然后使羰基与OH(CH2)2NH2反应，生成58。Step G: The alcohol of 57 can be further functionalized e.g. with X 4 C(O)X 5 where X 4 and X 5 are as described above for Step E, then reacting the carbonyl with OH(CH 2 ) 2 NH 2 , generating 58.

流程6提供利用本发明方法生产二芳基胺的实例。Scheme 6 provides an example of the production of diarylamines using the method of the present invention.

流程6Process 6

Figure A20048000713700311
Figure A20048000713700311

流程6所述各步可以简要描述如下：Each step in process 6 can be briefly described as follows:

步骤1：6-氯-2-(2，4-二氟苯基)-烟酸乙基酯61可以从2-氯烟酸合成得到(例如参见流程7)。使61与被保护的芳基胺偶联，例如Boc-2，6-二氟苯胺42(例如参见流程7)，反应条件为在碱金属盐的存在下，例如碳酸铯，在溶剂中，例如NMP；或者作为替代选择，在催化剂的存在下，例如乙酸钯，可选地在配体的存在下，例如BINAP，可选地在碱的存在下，例如磷酸钾，在相容性溶剂中，例如甲苯，得到式62被保护的偶联产物。Step 1: 6-Chloro-2-(2,4-difluorophenyl)-nicotinic acid ethyl ester 61 can be synthesized from 2-chloronicotinic acid (eg see Scheme 7). Coupling of 61 with a protected arylamine such as Boc-2,6-difluoroaniline 42 (see for example Scheme 7) in the presence of an alkali metal salt such as cesium carbonate in a solvent such as NMP; or alternatively, in the presence of a catalyst, such as palladium acetate, optionally in the presence of a ligand, such as BINAP, optionally in the presence of a base, such as potassium phosphate, in a compatible solvent, Such as toluene, the protected coupling product of formula 62 is obtained.

步骤2：在适合的溶剂中，例如二氯甲烷，使被保护的偶联产物62与酸反应，例如TFA，得到式63化合物。Step 2: Reaction of the protected coupling product 62 with an acid, such as TFA, in a suitable solvent, such as dichloromethane, to afford compounds of formula 63.

更一般地，本领域技术人员将认识到式63化合物可以借助61a与42a的反应生成：More generally, those skilled in the art will recognize that compounds of formula 63 can be generated by reaction of 61a with 42a:

Figure A20048000713700321
Figure A20048000713700321

其中X和Y是如上所定义的。wherein X and Y are as defined above.

流程7a阐述原料61的合成，流程7b阐述流程6的去保护的偶联产物63的进一步衍生化。Scheme 7a illustrates the synthesis of starting material 61 and Scheme 7b illustrates the further derivatization of the deprotected coupling product 63 of Scheme 6.

流程7aProcess 7a

Figure A20048000713700331
Figure A20048000713700331

流程7bProcess 7b

Figure A20048000713700341
Figure A20048000713700341

流程7a和7b所述各步可以简要描述如下：Each step in process 7a and 7b can be briefly described as follows:

步骤A：在HOBt和N-羟基琥珀酰亚胺的存在下，在极性质子惰性溶剂中，例如CH2Cl2、1，2-二氯乙烷、DMF或NMP，在加热下，使6-氯烟酸51与氯甲酸酯活化剂反应，例如SOCl2、氯甲酸苯基酯或氯甲酸对-硝基苯基酯，或者与碳二亚胺活化剂反应，例如CDI、DCC或EDC，使51活化。然后加入醇，例如乙醇，生成6-氯烟酸乙基酯71。Step A: In the presence of HOBt and N-hydroxysuccinimide, in a polar aprotic solvent, such as CH2Cl2 , 1,2 -dichloroethane, DMF or NMP, under heating, 6 - Reaction of chloronicotinic acid 51 with chloroformate activators such as SOCl2 , phenyl chloroformate or p-nitrophenyl chloroformate, or with carbodiimide activators such as CDI, DCC or EDC , to activate 51. Alcohol, such as ethanol, is then added to yield ethyl 6-chloronicotinate 71.

步骤B：在催化剂和碱的存在下，前者例如乙酸钯，后者例如碳酸钠、碳酸钾、碳酸锂、碳酸铯、叔丁醇钾、叔丁醇钠或叔丁醇锂，在溶剂中，例如甲苯、MTBE、DME或己烷，使化合物71与硼酸偶联，例如72，得到73。Step B: in the presence of a catalyst and a base, the former such as palladium acetate, the latter such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide or lithium tert-butoxide, in a solvent, Coupling of compound 71 with boronic acid, such as toluene, MTBE, DME or hexane, such as 72, affords 73.

步骤C：然后在一种试剂的存在下，例如MCPBA、过乙酸或MMPP，在氯化溶剂中，例如CH2Cl2或1，2-二氯乙烷，使偶联产物73N-氧化，得到74。Step C: The coupling product 73 is then N-oxidized in the presence of a reagent such as MCPBA, peracetic acid or MMPP in a chlorinated solvent such as CH2Cl2 or 1,2 -dichloroethane to give 74.

步骤D：在一种试剂的存在下，例如POCl3、POBr3、SOCl2、SO2Cl2或SOBr2，使活化N-氧化物74卤化，得到61。Step D: Halogenation of the activated N-oxide 74 to afford 61 in the presence of a reagent such as POCl3 , POBr3 , SOCl2 , SO2Cl2 or SOBr2 .

步骤1和2是如上流程6所述的。Steps 1 and 2 are as described in Flowchart 6 above.

步骤E：在碱的存在下，例如NaOH，在溶剂中，例如THF，使63的酯官能团皂化，然后在酸的存在下酸化，例如HCl，生成75。Step E: Saponification of the ester function of 63 in the presence of a base, such as NaOH, in a solvent, such as THF, followed by acidification in the presence of an acid, such as HCl, yields 75.

步骤F：然后使75与双光气、继之以NH4OH反应，生成酰胺-脲化合物76。Step F: 75 is then reacted with diphosgene followed by NH4OH to give amide-urea compound 76.

流程8Process 8

Figure A20048000713700351
Figure A20048000713700351

流程8所述各步可以简要描述如下：Each step in process 8 can be briefly described as follows:

步骤A：6-氯-2-(2，4-二氟苯基)-烟酸乙基酯61可以从2-氯烟酸合成得到。在碱金属盐的存在下，例如碳酸铯，在相容性溶剂中，例如NMP，使原料61与被保护的芳基胺偶联，例如Boc-2，6-二氟苯胺42，得到被保护的偶联产物。然后在适合的溶剂中，例如二氯甲烷，使被保护的偶联产物与酸反应，例如TFA，得到式63化合物。Step A: 6-Chloro-2-(2,4-difluorophenyl)-nicotinic acid ethyl ester 61 can be synthesized from 2-chloronicotinic acid. Coupling of starting material 61 with a protected arylamine, such as Boc-2,6-difluoroaniline 42, in the presence of an alkali metal salt, such as cesium carbonate, in a compatible solvent such as NMP affords a protected coupling products. The protected coupling product is then reacted with an acid, such as TFA, in a suitable solvent, such as dichloromethane, to provide compounds of formula 63.

步骤B：在碱的存在下，例如NaOH，在溶剂中，例如THF，使63的酯官能团皂化，然后在酸的存在下酸化，例如HCl，生成75。Step B: Saponification of the ester function of 63 in the presence of a base, such as NaOH, in a solvent, such as THF, followed by acidification in the presence of an acid, such as HCl, yields 75.

步骤C：然后使75与双光气、继之以NH4OH反应，生成酰胺-脲化合物76。Step C: 75 is then reacted with diphosgene followed by NH4OH to give amide-urea compound 76.

下列实施例以可以实施的方式阐述本发明，但是不应被解释为对本发明方法总体范围的限制。The following examples illustrate the invention in a manner in which it can be practiced, but should not be construed as limiting the general scope of the method of the invention.

酌情采用下列HPLC方法，另有指示除外：含0.1％TFA的水∶乙腈梯度(90∶10→10∶90→90∶10)在1ml/分钟和254nm下历经26分钟。该方法采用Zorbax SB Phenyl 4.6×25cm柱，5μm。术语“Tret”表示与化合物有关的保留时间，以分钟计。The following HPLC method was used as appropriate unless otherwise indicated: Gradient of water:acetonitrile with 0.1% TFA (90:10→10:90→90:10) at 1 ml/min and 254 nm over 26 min. The method employs a Zorbax SB Phenyl 4.6 x 25 cm column, 5 μm. The term "T ret " denotes the retention time, in minutes, associated with the compound.

按照另一种实施方式，本发明的方法提供式(A)或式(B)化合物：According to another embodiment, the method of the present invention provides a compound of formula (A) or formula (B):

Figure A20048000713700361
或
Figure A20048000713700362
Figure A20048000713700361
or
Figure A20048000713700362

其中：in:

每个X1、X2、X3和X4独立地选自氟或氯；each X 1 , X 2 , X 3 and X 4 is independently selected from fluorine or chlorine;

R是H或甲基。R is H or methyl.

式(A)和式(B)化合物可用作p38抑制剂。国际PCT公报WO99/58502(下称“’502公报”，其公开内容引用在此作为参考)公开了涵盖式(A)和式(B)化合物的一类化合物。本发明的方法可以容易地用于生产’502公报的化合物。Compounds of formula (A) and formula (B) are useful as p38 inhibitors. International PCT Publication WO99/58502 (hereinafter "'502 Publication", the disclosure of which is incorporated herein by reference) discloses a class of compounds encompassing compounds of formula (A) and formula (B). The method of the present invention can be readily used to produce the compounds of the '502 publication.

按照优选的式(A)实施方式，每个X1、X2、X3和X4是氟。按照另一种优选的式(A)实施方式，R是H。According to a preferred embodiment of formula (A), each of X 1 , X 2 , X 3 and X 4 is fluorine. According to another preferred embodiment of formula (A), R is H.

按照优选的式(B)实施方式，每个X1、X2和X4是氟。按照另一种优选的式(B)实施方式，R是H。According to a preferred embodiment of formula (B), each of X 1 , X 2 and X 4 is fluorine. According to another preferred embodiment of formula (B), R is H.

按照最优选的式(B)实施方式，本发明的方法生产下列化合物77：According to the most preferred embodiment of formula (B), the method of the present invention produces the following compound 77:

具体实施方式Detailed ways

实施例1Example 1

Figure A20048000713700371
Figure A20048000713700371

2-氯-烟酸甲基酯(52)：52是按照Synth.Comm.26(12)，2257-2272(1996)的方法制备的。向用氮净化过的烧瓶加入2-氯-烟酸(1000.0g，6.0mol，1.0当量)，继之以9L二氯甲烷。向其中加入亚硫酰氯(1.4L，19.7mol，3.2当量)，将反应物加热至40C，同时在氮下剧烈搅拌过夜。将酰氯溶液在冰浴中冷却，缓慢加入甲醇(3L，74mol，12当量)，同时保持温度在20℃。限速参数是大量HCl气体的剧烈放出。加入后，HPLC分析[Tret原料＝7.5分钟，Tret52＝11分钟]显示已有产物立即生成。在真空中除去挥发物，用EtOAc从10％Na2CO3中萃取残余物。合并有机层，干燥(MgSO4)，过滤，浓缩至淡黄色油。2-Chloro-nicotinic acid methyl ester (52): 52 was prepared according to the method of Synth.Comm.26(12), 2257-2272(1996). To the nitrogen purged flask was added 2-chloro-nicotinic acid (1000.0 g, 6.0 mol, 1.0 eq) followed by 9 L of dichloromethane. To this was added thionyl chloride (1.4 L, 19.7 mol, 3.2 eq) and the reaction was heated to 4OC with vigorous stirring under nitrogen overnight. The acid chloride solution was cooled in an ice bath, and methanol (3 L, 74 mol, 12 equiv) was slowly added while maintaining the temperature at 20°C. The rate-limiting parameter is the vigorous evolution of large amounts of HCl gas. After the addition, HPLC analysis [T ret starting material = 7.5 min, T ret 52 = 11 min] showed that product had formed immediately. The volatiles were removed in vacuo and the residue was extracted from 10% Na2CO3 with EtOAc. The organic layers were combined, dried ( MgSO4 ), filtered and concentrated to a light yellow oil.

实施例2Example 2

Figure A20048000713700372
Figure A20048000713700372

2-(4-氟-苯基)-烟酸甲基酯(54)：向用氮净化过的烧瓶加入Pd(Ph3)4(1.84g，1.6mmol，0.005当量)、碳酸钠(42.8g，404mmol，1.3当量)、52(55.5g，320.6mmol，1.0当量)、对-氟苯基硼酸(53.8g，384.7mmol，1.2当量)，继之以1.3L变性EtOH。将反应物加热至78℃，同时在N2下剧烈搅拌过夜。反应混合物的HPLC分析[Tret52＝10分钟，Tret54＝12分钟]显示原料已被完全消耗，生成后洗脱的峰。将反应物冷却至室温，在真空下除去溶剂。将残余物溶于EtOAc，洗涤，干燥(MgSO4)，通过硅藻土过滤，浓缩，得到淡黄色固体54。2-(4-Fluoro-phenyl)-nicotinic acid methyl ester (54): To a nitrogen purged flask was added Pd(Ph 3 ) 4 (1.84 g, 1.6 mmol, 0.005 equiv), sodium carbonate (42.8 g , 404 mmol, 1.3 equiv), 52 (55.5 g, 320.6 mmol, 1.0 equiv), p-fluorophenylboronic acid (53.8 g, 384.7 mmol, 1.2 equiv), followed by 1.3 L of denatured EtOH. The reaction was heated to 78 °C with vigorous stirring under N2 overnight. HPLC analysis of the reaction mixture [T ret 52 = 10 min, T ret 54 = 12 min] showed that the starting material was completely consumed, giving rise to a post-eluting peak. The reaction was cooled to room temperature and the solvent was removed under vacuum. The residue was dissolved in EtOAc, washed, dried ( MgSO4 ), filtered through celite and concentrated to afford 54 as a pale yellow solid.

实施例3Example 3

Figure A20048000713700381
Figure A20048000713700381

2-(4-氟-苯基)-1-氧基-烟酸甲基酯(55)：向用氮净化过的烧瓶加入脲过氧化氢(86.9g，924mmol，4.0当量)、二芳基吡啶54(53.4g，231mmol，1.0当量)和530mL乙酸。将浅黄色均匀溶液加热至70-75℃，同时在氮下剧烈搅拌，直至HPLC分析[Tret54＝12分钟，Tret55＝10分钟]显示＞97％完全。将反应物冷却至室温，将内容物缓慢倒在500g冰上。向剧烈搅拌的冰状混合物缓慢加入6N NaOH至pH7，同时维持温度为30℃。加入EtOAc和NaHCO3(固体)，直至达到8-9的水性pH，固体溶解。分离各层，水层用EtOAc反萃取。合并有机层，用5％NaHCO3洗涤，然后用过氧化物试纸测试氧化剂的存在。如果有机层为过酸阳性，那么重复碳酸氢盐洗涤，直至试验为阴性。一旦为过酸阴性，合并有机层，干燥(MgSO4)，过滤，浓缩至淡黄色固体55。2-(4-Fluoro-phenyl)-1-oxo-nicotinic acid methyl ester (55): To a nitrogen purged flask was added urea hydroperoxide (86.9 g, 924 mmol, 4.0 equiv), diaryl Pyridine 54 (53.4 g, 231 mmol, 1.0 equiv) and 530 mL of acetic acid. The pale yellow homogeneous solution was heated to 70-75°C while stirring vigorously under nitrogen until HPLC analysis [T ret 54 = 12 min, T ret 55 = 10 min] showed >97% complete. The reaction was cooled to room temperature and the contents were slowly poured onto 500 g of ice. To the vigorously stirred ice-like mixture was slowly added 6N NaOH to pH 7 while maintaining the temperature at 30 °C. EtOAc and NaHCO3 (solid) were added until an aqueous pH of 8-9 was reached and the solid dissolved. The layers were separated and the aqueous layer was back extracted with EtOAc. The organic layers were combined, washed with 5% NaHCO 3 , and tested for the presence of oxidizing agents with peroxide paper. If the organic layer is positive for peracid, repeat the bicarbonate wash until the test is negative. Once peracid negative, the organic layers were combined, dried ( MgSO4 ), filtered and concentrated to a light yellow solid 55.

实施例4Example 4

Figure A20048000713700382
Figure A20048000713700382

6-氯-2-(4-氟-苯基)-烟酸甲基酯(41)：向用氮净化过的烧瓶加入N-氧化物55(45g，182mmol，1.0当量)，继之以300mL二氯乙烷。一次性加入磷酰氯(101mL，1080mmol，6当量)，导致温度立即从17℃升至19℃，之后逐渐温热。将溶液在氮下加热至70-75℃，直至HPLC分析[Tret55＝10分钟，Tret41＝17分钟]显示＞94％完全。将反应物冷却至室温，在真空下浓缩内容物，以除去大多数POCl3。将残余物缓慢倒在450g冰上进行猝灭。使冰融化后，用二氯甲烷萃取产物。合并有机层，干燥(MgSO4)，通过硅藻土过滤，用二氯甲烷洗脱，浓缩至固体41。6-Chloro-2-(4-fluoro-phenyl)-nicotinic acid methyl ester (41): To a nitrogen-purged flask was added N-oxide 55 (45 g, 182 mmol, 1.0 equiv), followed by 300 mL Dichloroethane. Phosphorus oxychloride (101 mL, 1080 mmol, 6 equiv) was added in one portion, resulting in an immediate rise in temperature from 17°C to 19°C, followed by gradual warming. The solution was heated to 70-75°C under nitrogen until HPLC analysis [T ret 55 = 10 min, T ret 41 = 17 min] showed >94% complete. The reaction was cooled to room temperature and the contents were concentrated in vacuo to remove most of the POCl3 . The residue was quenched by pouring slowly onto 450 g of ice. After the ice was allowed to melt, the product was extracted with dichloromethane. The combined organic layers were dried ( MgSO4 ), filtered through celite eluting with dichloromethane and concentrated to solid 41.

实施例5Example 5

Figure A20048000713700391
Figure A20048000713700391

6-(2，6-二氟-苯基氨基)-2-(4-氟-苯基)-烟酸甲基酯(44)：向用氮净化过的烧瓶加入乙酸钯(13.2g，59mmol，0.04当量)、外消旋BINAP(36.6g，59mmol，0.04当量)，继之以1.9L甲苯。将不均匀浆液在氮下加热至50℃达2小时，冷却至30℃，然后一次性加入吡啶基氯41(386.4g，1.45mol，1.0当量)、Boc-2，6-二氟苯胺42(386.4g，1.69mol，1.2当量)和K3PO4(872g，4.1mol，2.8当量)，继之以1.9L甲苯冲洗。将不均匀反应混合物加热至100℃过夜，用HPLC监测。当HPLC显示反应完全转化为43时[Tret41＝17分钟，Tret43＝20.5分钟，Tret44＝17.6分钟，在229nm下监测](通常在18-20小时之间)，将反应物冷却至室温，内容物用1.94L EtOAc稀释。向其中加入1×1.94L 6N HCl，两层通过硅藻土过滤。将硅藻土的湿滤饼用2×1.9L EtOAc冲洗。分离各层，将有机层用1×1.9L盐水洗涤，干燥(MgSO4)，过滤，浓缩至褐色粘性的油。为了除去Boc保护基团，将油溶于1.94L二氯甲烷，加入388mL TFA。将反应物搅拌过夜，以利于Boc的除去。在真空中除去挥发物，加入EtOAc(1.9L)和足量的1或6N NaOH，直至pH为2-7。然后加入足量的5％NaHCO3，调节pH至8-9。分离有机层，用1×5％NaHCO3洗涤，干燥(MgSO4)，过滤，浓缩至褐色的油/液体。将粗油/液体用足量甲苯共沸干燥两次。随着游离碱沉淀出来，形成浆液。将残余物溶于500mL甲苯，加入1.6L 1N HCl/乙醚溶液，导致固体破碎。加热，直至匀化/固体分解。如果必要的话，可以加入200mL EtOAc，以利于分解。冷却后，真空过滤分离固体44。6-(2,6-Difluoro-phenylamino)-2-(4-fluoro-phenyl)-nicotinic acid methyl ester (44): Palladium acetate (13.2 g, 59 mmol , 0.04 equiv), racemic BINAP (36.6 g, 59 mmol, 0.04 equiv), followed by 1.9 L of toluene. The heterogeneous slurry was heated to 50 °C under nitrogen for 2 h, cooled to 30 °C, and then pyridyl chloride 41 (386.4 g, 1.45 mol, 1.0 equiv), Boc-2,6-difluoroaniline 42 ( 386.4 g, 1.69 mol, 1.2 equiv) and K 3 PO 4 (872 g, 4.1 mol, 2.8 equiv), followed by a 1.9 L toluene rinse. The heterogeneous reaction mixture was heated to 100°C overnight, monitored by HPLC. When HPLC showed complete conversion of the reaction to 43 [T ret 41 = 17 minutes, T ret 43 = 20.5 minutes, T ret 44 = 17.6 minutes, monitored at 229 nm] (usually between 18-20 hours), the reactants were After cooling to room temperature, the contents were diluted with 1.94L EtOAc. To this was added 1 x 1.94L 6N HCl, and the two layers were filtered through celite. The wet cake of celite was rinsed with 2 x 1.9 L EtOAc. The layers were separated and the organic layer was washed with 1 x 1.9 L brine, dried ( MgSO4 ), filtered and concentrated to a brown viscous oil. To remove the Boc protecting group, the oil was dissolved in 1.94 L of dichloromethane and 388 mL of TFA was added. The reaction was stirred overnight to facilitate Boc removal. The volatiles were removed in vacuo, EtOAc (1.9 L) and enough 1 or 6N NaOH were added until the pH was 2-7. Then add enough 5% NaHCO 3 to adjust the pH to 8-9. The organic layer was separated, washed with 1 x 5% NaHCO3 , dried ( MgSO4 ), filtered and concentrated to a brown oil/liquid. The crude oil/liquid was azeotropically dried twice with sufficient toluene. A slurry was formed as the free base precipitated out. The residue was dissolved in 500 mL of toluene and 1.6 L of 1 N HCl/ether solution was added causing the solid to break up. Heat until homogenized/solids decompose. If necessary, 200 mL of EtOAc can be added to facilitate decomposition. After cooling, solid 44 was isolated by vacuum filtration.

实施例6Example 6

Figure A20048000713700401
Figure A20048000713700401

6-[1-(2，6-二氟-苯基)-脲基]-2-(4-氟-苯基)-烟酸甲基酯(56)：向用氮净化过的烧瓶加入44的氨基酯HCl盐(262g，0.67mol，1.0当量)，继之以1.2L甲苯。向不均匀混合物加入光气(1.4L的1.93M甲苯溶液，2.7mol，4.0当量)，将反应物在氮下加热至50℃过夜。用HPLC监测反应生成-NC(O)Cl部分的进程[Tret44＝17.6分钟，Tret氨甲酰基中间体＝19.7分钟，Tret56＝16.4分钟，在229nm下监测]。一旦氮完全反应，将褐色溶液冷却至大约-5℃，缓慢递加NH4OH(0.84L，12.4mol，18.5当量)。随着加入接近完成，有固体生成。将浆液与1L水搅拌，真空过滤收集。将湿滤饼用1×390mL甲苯洗涤，以除去后洗脱的杂质。6-[1-(2,6-Difluoro-phenyl)-ureido]-2-(4-fluoro-phenyl)-nicotinic acid methyl ester (56): Add 44 to a nitrogen-purged flask Amino ester HCl salt (262 g, 0.67 mol, 1.0 eq) followed by 1.2 L of toluene. Phosgene (1.4 L of a 1.93M solution in toluene, 2.7 mol, 4.0 equiv) was added to the heterogeneous mixture and the reaction was heated to 50° C. under nitrogen overnight. The progress of the reaction to the -NC(O)Cl moiety was monitored by HPLC [T ret 44 = 17.6 min, Tret carbamoyl intermediate = 19.7 min, T ret 56 = 16.4 min, monitored at 229 nm]. Once the nitrogen was completely reacted, the brown solution was cooled to about -5°C and NH4OH (0.84 L, 12.4 mol, 18.5 equiv) was slowly added incrementally. As the addition neared completion, solids formed. The slurry was stirred with 1 L of water and collected by vacuum filtration. The wet cake was washed with 1 x 390 mL of toluene to remove post-eluting impurities.

实施例7Example 7

Figure A20048000713700402
Figure A20048000713700402

1-(2，6-二氟-苯基)-1-[6-(4-氟-苯基)-5-羟甲基-吡啶-2-基]-脲(57)：向用氮净化过的烧瓶加入脲-酯56(10.0g，24.92mmol，1.0当量)，继之以10mL THF。将混合物冷却至0-5℃。向冷却过的溶液历经20-30分钟滴加DIBAL-H/THF溶液(149.5mL，149.5mmol，6.0当量)。将混合物在15-20℃下搅拌，同时用HPLC监测反应进展[Tret56＝16.4分钟，Tret57＝14.0分钟，在229nm下监测]。将反应混合物猝灭至冷却了的(5-10℃)15％H2SO4水溶液(150mL)中。猝灭完成后，将混合物搅拌10-15分钟。向混合物加入TBME(150mL)。将混合物在50℃下加热60分钟。将混合物冷却至环境温度，除去水层。将有机层浓缩至大约35mL剩余体积。然后重复稀释和浓缩过程。将剩余混合物冷却至0-2℃，在该温度下保持45分钟。抽吸过滤收集灰白色固体57，使用冷的甲苯(25mL)作为冲洗溶剂。将固体在真空和环境温度下干燥3-5小时，得到80％的校正收率。1-(2,6-Difluoro-phenyl)-1-[6-(4-fluoro-phenyl)-5-hydroxymethyl-pyridin-2-yl]-urea (57): Purged with nitrogen The cleaned flask was charged with urea-ester 56 (10.0 g, 24.92 mmol, 1.0 eq) followed by 10 mL of THF. The mixture was cooled to 0-5 °C. To the cooled solution was added DIBAL-H/THF solution (149.5 mL, 149.5 mmol, 6.0 equiv) dropwise over 20-30 minutes. The mixture was stirred at 15-20°C while monitoring the progress of the reaction by HPLC [T ret 56 = 16.4 min, T ret 57 = 14.0 min, monitored at 229 nm]. The reaction mixture was quenched into cooled (5-10 °C) 15% aqueous H2SO4 (150 mL). After quenching was complete, the mixture was stirred for 10-15 minutes. To the mixture was added TBME (150 mL). The mixture was heated at 50°C for 60 minutes. The mixture was cooled to ambient temperature and the aqueous layer was removed. The organic layer was concentrated to approximately 35 mL remaining volume. Then repeat the dilution and concentration process. The remaining mixture was cooled to 0-2°C and maintained at this temperature for 45 minutes. The off-white solid 57 was collected by suction filtration using cold toluene (25 mL) as a rinse solvent. The solid was dried under vacuum at ambient temperature for 3-5 hours to give 80% corrected yield.

实施例8Example 8

Figure A20048000713700411
Figure A20048000713700411

(2-羟基-乙基)-氨基甲酸6-[1-(2，6-二氟-苯基)-脲基]-2-(4-氟-苯基)-吡啶-3-基甲基酯(58)：向用氮净化过的烧瓶加入苄型醇57(7.1g，19.0mmol，1.0当量)和CDI(6.2g，38.0mmol，2.0当量)，继之以71mL THF。将溶液在室温下搅拌1-2小时，然后试验性猝灭到无水乙腈/过量乙醇胺中。如果活化不完全，可以加入额外的CDI，直至猝灭试验显示完全转化。一旦猝灭试验显示完全转化为58，缓慢加入2.0当量乙醇胺(0.64mL，38mmol)猝灭反应。将反应物在室温下搅拌2小时，HPLC分析[Tret57＝14.2分钟，Tret58＝13.6分钟，在229nm下监测]指示完全转化为58。在真空下除去THF，将残余物溶于71mL乙酸乙酯，用NH4Cl水溶液(2×71mL)、继之以盐水(1×71mL)洗涤。将有机层用EtOAc共沸干燥(2×71mL)。将残余物用71mL EtOAc再生，过滤，重新浓缩。向最终的残余物加入7.1mL EtOAc和63mL甲苯，然后温和加热至35-40℃。冷却后，有白色固体生成，真空过滤分离，用冷甲苯洗涤。(2-Hydroxy-ethyl)-carbamic acid 6-[1-(2,6-difluoro-phenyl)-ureido]-2-(4-fluoro-phenyl)-pyridin-3-ylmethyl Ester (58): To a nitrogen purged flask was added benzyl alcohol 57 (7.1 g, 19.0 mmol, 1.0 eq) and CDI (6.2 g, 38.0 mmol, 2.0 eq) followed by 71 mL of THF. The solution was stirred at room temperature for 1-2 hours, then quenched experimentally into anhydrous acetonitrile/excess ethanolamine. If activation is not complete, additional CDI can be added until quenching assays show complete conversion. Once the quenching assay showed complete conversion to 58, 2.0 equiv of ethanolamine (0.64 mL, 38 mmol) was slowly added to quench the reaction. The reaction was stirred at room temperature for 2 hours and HPLC analysis [T ret 57 = 14.2 min, T ret 58 = 13.6 min, monitored at 229 nm] indicated complete conversion to 58. THF was removed under vacuum, the residue was dissolved in 71 mL ethyl acetate, washed with aqueous NH4Cl (2 x 71 mL), followed by brine (1 x 71 mL). The organic layer was azeotropically dried with EtOAc (2 x 71 mL). The residue was regenerated with 71 mL of EtOAc, filtered and reconcentrated. To the final residue was added 7.1 mL of EtOAc and 63 mL of toluene, followed by gentle heating to 35-40 °C. After cooling, a white solid formed which was isolated by vacuum filtration and washed with cold toluene.

实施例9Example 9

Figure A20048000713700421
Figure A20048000713700421

2-(2，4-二氟苯基)-6-(2，6-二氟苯基氨基)-烟酸乙基酯(63)：在配有液上机械搅拌器、加热套、回流冷凝器和热电偶的1L4颈圆底烧瓶中加入61(50g)、Cs2CO3(150g)和0.15L NMP。将溶液剧烈搅拌，加热至65℃，此时向悬液历经10分钟加入42(60g)的0.10L NMP溶液。在65℃下加热18小时，HPLC显示大约85％的61转化为所需的Boc加合物。此时提高温度至75℃，加热另外18小时后，HPLC分析显示大约97％的61转化为所需的Boc加合物62(未显示)。然后将混合物冷却至20℃，一次性倒入2.0L水中，在配有液上机械搅拌器和热电偶的4颈3L圆底烧瓶中搅拌。作为加入NMP溶液的结果，水的温度从22℃升至27℃。然后将悬液冷却至15℃，过滤收集黄褐色固体，用水冲洗，在滤器上吸干2小时。2-(2,4-difluorophenyl)-6-(2,6-difluorophenylamino)-nicotinic acid ethyl ester (63): equipped with a liquid mechanical stirrer, heating mantle, reflux condensation 61 (50 g), Cs 2 CO 3 (150 g) and 0.15 L of NMP were charged to a 1 L 4-neck round bottom flask with a detector and thermocouple. The solution was stirred vigorously and heated to 65 °C, at which point 42 (60 g) in 0.10 L of NMP was added to the suspension over 10 min. Heating at 65°C for 18 hours, HPLC showed approximately 85% conversion of 61 to the desired Boc adduct. At this point the temperature was raised to 75°C and after heating for an additional 18 hours, HPLC analysis showed approximately 97% conversion of 61 to the desired Boc adduct 62 (not shown). The mixture was then cooled to 20 °C, poured into 2.0 L of water all at once, and stirred in a 4-necked 3 L round bottom flask equipped with an overhead mechanical stirrer and a thermocouple. As a result of the addition of the NMP solution, the temperature of the water rose from 22°C to 27°C. The suspension was then cooled to 15°C, and the tan solid was collected by filtration, rinsed with water, and blotted dry on the filter for 2 hours.

在配有液上机械搅拌器和热电偶的2L 4颈圆底烧瓶中加入该黄褐色固体和0.8L CH2Cl2。向搅拌的溶液一次性加入70mL TFA。在环境温度下搅拌2小时后，HPLC检测没有Boc保护的物料，借助旋转蒸发浓缩混合物。将油性残余物溶于0.7L EtOAc，用0.7L饱和NaHCO3处理，在此期间产生气体。将EtOAc层用0.25L饱和NaCl洗涤，借助旋转蒸发浓缩。向所得褐色的油加入0.2L EtOAc，将溶液用HCl的Et2O溶液(0.4L的2.0M溶液)处理，搅拌60分钟。过滤收集产物63，为黄色粉末(70.5％收率)。A 2 L 4 neck round bottom flask equipped with an overhead mechanical stirrer and thermocouple was charged with the tan solid and 0.8 L CH2Cl2 . To the stirred solution was added 70 mL of TFA in one portion. After stirring at ambient temperature for 2 hours, HPLC detected material without Boc protection, and the mixture was concentrated by rotary evaporation. The oily residue was dissolved in 0.7 L EtOAc and treated with 0.7 L saturated NaHCO 3 during which time gas evolved. The EtOAc layer was washed with 0.25 L of saturated NaCl, concentrated by rotary evaporation. To the resulting brown oil was added 0.2 L of EtOAc and the solution was treated with HCl in Et2O (0.4 L of a 2.0 M solution) and stirred for 60 minutes. The product 63 was collected by filtration as a yellow powder (70.5% yield).

将粗盐在4mL EtOH/g粗产物中加热至回流，然后冷却至环境温度，可以使产物重结晶。The product can be recrystallized by heating the crude salt to reflux in 4 mL of EtOH/g crude product and then cooling to ambient temperature.

尽管我们已经如上介绍了本发明的一些实施方式，不过显然可以改变基本构成，以提供采用本发明方法的其他实施方式。因此，将被领会的是本发明的范围受到随附权利要求而非上面举例介绍的具体实施方式的限定。While we have described some embodiments of the invention above, it will be apparent that the basic structure can be altered to provide other embodiments employing the method of the invention. It is therefore to be appreciated that the scope of the invention is to be defined by the appended claims rather than by the specific embodiments exemplified above.

Claims (59)

  1. The method of 1, production formula (I) diarylamine compound or its salt:
    Described method is included in and makes formula (II) compound and formula (III) amine link coupled step under the existence of an alkali metal salt or transition-metal catalyst:
    Ar 1-X Ar 2-NH-Y
    (II) (III)
    Wherein:
    Ar 1And Ar 2Be Q independently;
    Wherein each Q is aryl or heteroaryl ring system, alternatively with have the heteroatomic saturated or unsaturated 5-8 of 0-4 unit ring and condense;
    Wherein Q is replaced by one or more substituting groups on one or more annular atomses alternatively, and described substituting group is independently selected from halogen; C 1-C 6Aliphatic group is alternatively by N (R ') 2, OR ', CO 2R ', C (O) N (R ') 2, OC (O) N (R ') 2, NR ' CO 2R ', NR ' C (O) R ', SO 2N (R ') 2, N=CH-N (R ') 2Or OPO 3H 2Replace; C 1-C 6Alkoxyl group is alternatively by N (R ') 2, OR ', CO 2R ', C (O) N (R ') 2, OC (O) N (R ') 2, NR ' CO 2R ', NR ' C (O) R ', SO 2N (R ') 2, N=CH-N (R ') 2Or OPO 3H 2Replace; Ar 3CF 3OCF 3OR '; SR '; SO 2N (R ') 2OSO 2R '; SCF 3NO 2CN; N (R ') 2CO 2R '; CO 2N (R ') 2C (O) N (R ') 2NR ' C (O) R '; NR ' CO 2R '; NR ' C (O) C (O) R '; NR ' SO 2R '; OC (O) R '; NR ' C (O) R 2NR ' CO 2R 2NR ' C (O) C (O) R 2NR ' C (O) N (R ') 2OC (O) N (R ') 2NR ' SO 2R 2NR ' R 2N (R 2) 2OC (O) R 2OPO 3H 2And N=CH-N (R ') 2
    R ' is selected from hydrogen; C 1-C 6Aliphatic group; Perhaps 5-6 unit's carbocyclic ring or heterocycle ring system are replaced by 1 to 3 substituting group alternatively, and described substituting group is independently selected from halogen, C 1-C 6Alkoxyl group, cyano group, nitro, amino, hydroxyl and C 1-C 6Aliphatic group;
    R 2Be C 1-C 6Aliphatic group is alternatively by N (R ') 2, OR ', CO 2R ', C (O) N (R ') 2Or SO 2N (R ') 2Replace; Perhaps carbocyclic ring or heterocycle ring system are alternatively by N (R ') 2, OR ', CO 2R ', C (O) N (R ') 2Or SO 2N (R ') 2Replace;
    Ar wherein 3Be aryl or heteroaryl ring system, alternatively with have the heteroatomic saturated or unsaturated 5-8 of 0-4 unit ring and condense;
    Ar wherein 3Replaced by one or more substituting groups on one or more annular atomses alternatively, described substituting group is independently selected from halogen; C 1-C 6Aliphatic group is alternatively by N (R ') 2, OR ', CO 2R ', C (O) N (R ') 2, OC (O) N (R ') 2, NR ' CO 2R ', NR ' C (O) R ', SO 2N (R ') 2, N=CH-N (R ') 2Or OPO 3H 2Replace; C 1-C 6Alkoxyl group is alternatively by N (R ') 2, OR ', CO 2R ', C (O) N (R ') 2, OC (O) N (R ') 2, SO 2N (R ') 2, NR ' CO 2R ', NR ' C (O) R ', N=CH-N (R ') 2Or OPO 3H 2Replace; CF 3OCF 3OR '; SR '; SO 2N (R ') 2OSO 2R '; SCF 3NO 2CN; N (R ') 2CO 2R '; CO 2N (R ') 2C (O) N (R ') 2NR ' C (O) R '; NR ' CO 2R '; NR ' C (O) C (O) R '; NR ' SO 2R '; OC (O) R '; NR ' C (O) R 2NR ' CO 2R 2NR ' C (O) C (O) R 2NR ' C (O) N (R ') 2OC (O) N (R ') 2NR ' SO 2R 2NR ' R 2N (R 2) 2OC (O) R 2OPO 3H 2With-N=CH-N (R ') 2
    X is a leavings group;
    Y is-C (O)-O-Z;
    Z is C 1-C 6Aliphatic group, benzyl, Fmoc ,-SO 2R ' or Q, its condition is that Q is not replaced by X or alkynes;
  2. 2,, further comprise the step of from link coupled amine, removing group Y production (I) compound according to the method for claim 1.
  3. 3, according to the process of claim 1 wherein that this method carries out with transition-metal catalyst.
  4. 4, according to the method for claim 3, wherein this transition-metal catalyst comprises palladium.
  5. 5, according to the method for claim 4, wherein this catalyzer is PdL n, wherein
    Each L is independently selected from-OAc ,-O-tolyl, halogen, PPh 3, dppe, dppf, dba and BINAP; N is integer 0-4.
  6. 6, according to the method for claim 3, wherein making formula (II) compound and formula (III) amine link coupled step is to carry out in the presence of alkali.
  7. 7, according to the method for claim 6, wherein this alkali is selected from KOtBu, NaOtBu, K 3PO 4, Na 2CO 3And Cs 2CO 3
  8. 8, according to the process of claim 1 wherein that this method carries out with an alkali metal salt.
  9. 9, method according to Claim 8, wherein this an alkali metal salt is selected from the salt of potassium, rubidium or cesium ion.
  10. 10, according to the method for claim 9, wherein this an alkali metal salt is selected from salt of wormwood or cesium carbonate.
  11. 11, according to the method for claim 10, wherein this an alkali metal salt is a cesium carbonate.
  12. 12, according to the process of claim 1 wherein X be selected from by-Cl ,-Br ,-I ,-F ,-OTf ,-group that OTs, iodine and diazo are formed.
  13. 13, according to the process of claim 1 wherein that Y is Boc.
  14. 14,, be used to produce following formula diarylamine compound according to the method for claim 1:
    Figure A2004800071370004C1
    Be included in and make formula 21 compounds and formula 22 amine link coupled steps under the existence of an alkali metal salt or transition-metal catalyst:
    Figure A2004800071370005C1
    Wherein:
    R 3Be selected from aliphatic group; Aryl; Perhaps by aliphatic group, aryl, nitro, CN, CO 2R ', CO 2N (R ') 2, OR ', NCO 2R ', NR ' C (O) N (R ') 2Or OC (O) N (R ') 2The aryl that replaces; Its condition is R 3It or not the tertiary butyl;
    G 1, G 2, G 3, G 4And G 5Be independently selected from aryl, nitro, CN, OR ', the CO of hydrogen, aliphatic group, aryl, replacement 2R ', CO 2N (R ') 2, NR ' CO 2R ', NR ' C (O) N (R ') 2, OC (O) N (R ') 2, F, Cl, Br, I, O-TOs, O-Ms, OSO 2R ' and OC (O) R ';
    X and Y are defined as claim 1.
  15. 15,, further comprise the step of from link coupled amine, removing group Y production 24 compounds according to the method for claim 14.
  16. 16, according to the method for claim 14, wherein this method is carried out with transition-metal catalyst.
  17. 17, according to the method for claim 16, wherein this transition-metal catalyst comprises palladium.
  18. 18, according to the method for claim 17, wherein this catalyzer is PdL n, wherein
    Each L is independently selected from-OAc ,-O-tolyl, halogen, PPh 3, dppe, dppf, dba and BINAP; N is integer 0-4.
  19. 19, according to the method for claim 16, wherein making formula 21 compounds and formula 22 amine link coupled steps is to carry out in the presence of alkali.
  20. 20, according to the method for claim 19, wherein this alkali is selected from KOtBu, NaOtBu, K 3PO 4, Na 2CO 3And Cs 2CO 3
  21. 21, according to the method for claim 14, wherein this method is carried out with an alkali metal salt.
  22. 22, according to the method for claim 21, wherein this an alkali metal salt is selected from the salt of potassium, rubidium or cesium ion.
  23. 23, according to the method for claim 22, wherein this an alkali metal salt is selected from salt of wormwood or cesium carbonate.
  24. 24, according to the method for claim 23, wherein this an alkali metal salt is a cesium carbonate.
  25. 25, according to the method for claim 14, wherein X be selected from by-Cl ,-Br ,-I ,-F ,-OTf ,-group that OTs, iodine and diazo are formed.
  26. 26, according to the method for claim 14, wherein Y is Boc.
  27. 27,, be used to produce following formula diarylamine compound or its salt according to the method for claim 1:
    Figure A2004800071370006C1
    Described method is included in and makes formula 41a compound and formula 42a amine link coupled step under the existence of an alkali metal salt or transition-metal catalyst:
    Figure A2004800071370006C2
    Wherein X and Y are that as above claim 1 is defined.
  28. 28,, further comprise the step of from link coupled amine, removing group Y production 44 compounds according to the method for claim 27.
  29. 29, according to the method for claim 27, wherein this method is carried out with transition-metal catalyst.
  30. 30, according to the method for claim 29, wherein this transition-metal catalyst comprises palladium.
  31. 31, according to the method for claim 30, wherein this catalyzer is PdL n, wherein
    Each L is independently selected from-OAc ,-O-tolyl, halogen, PPh 3, dppe, dppf, dba and BINAP; N is integer 0-4.
  32. 32, according to the method for claim 29, wherein making formula 41a compound and formula 42a amine link coupled step is to carry out in the presence of alkali.
  33. 33, according to the method for claim 32, wherein this alkali is selected from KOtBu, NaOtBu, K 3PO 4, Na 2CO 3And Cs 2CO 3
  34. 34, according to the method for claim 27, wherein this method is carried out with an alkali metal salt.
  35. 35, according to the method for claim 34, wherein this an alkali metal salt is selected from the salt of potassium, rubidium or cesium ion.
  36. 36, according to the method for claim 35, wherein this an alkali metal salt is selected from salt of wormwood or cesium carbonate.
  37. 37, according to the method for claim 36, wherein this an alkali metal salt is a cesium carbonate.
  38. 38, according to the method for claim 27, wherein X be selected from by-Cl ,-Br ,-I ,-F ,-OTf ,-group that OTs, iodine and diazo are formed.
  39. 39, according to the method for claim 27, wherein Y is Boc.
  40. 40,, be used to produce following formula diarylamine compound or its salt according to the method for claim 1:
    Figure A2004800071370008C1
    Described method is included in and makes formula 61a compound and formula 42a amine link coupled step under the existence of an alkali metal salt or transition-metal catalyst:
    Figure A2004800071370008C2
    Wherein X and Y are that as above claim 1 is defined.
  41. 41,, further comprise the step of from link coupled amine, removing group Y production 63 compounds according to the method for claim 40.
  42. 42, according to the method for claim 40, wherein this method is carried out with transition-metal catalyst.
  43. 43, according to the method for claim 42, wherein this transition-metal catalyst comprises palladium.
  44. 44, according to the method for claim 43, wherein this catalyzer is PdL n, wherein
    Each L is independently selected from-OAc ,-O-tolyl, halogen, PPh 3, dppe, dppf, dba and BINAP; N is integer 0-4.
  45. 45, according to the method for claim 42, wherein making formula 61a compound and formula 42a amine link coupled step is to carry out in the presence of alkali.
  46. 46, according to the method for claim 45, wherein this alkali is selected from KOtBu, NaOtBu, K 3PO 4, Na 2CO 3And Cs 2CO 3
  47. 47, according to the method for claim 40, wherein this method is carried out with an alkali metal salt.
  48. 48, according to the method for claim 47, wherein this an alkali metal salt is selected from the salt of potassium, rubidium or cesium ion.
  49. 49, according to the method for claim 48, wherein this an alkali metal salt is selected from salt of wormwood or cesium carbonate.
  50. 50, according to the method for claim 49, wherein this an alkali metal salt is a cesium carbonate.
  51. 51, according to the method for claim 40, wherein X be selected from by-Cl ,-Br ,-I ,-F ,-OTf ,-group that OTs, iodine and diazo are formed.
  52. 52, according to the method for claim 40, wherein Y is Boc.
  53. 53,, be used to produce following formula diarylamine compound or its salt according to the method for claim 40:
    Described method is included in and makes formula 61 compounds and formula 42 amine link coupled steps under the existence of suitable an alkali metal salt or transition-metal catalyst:
    Figure A2004800071370010C1
  54. 54,, further comprise the step of from link coupled amine, removing Boc group production 63 compounds according to the method for claim 53.
  55. 55, according to the method for any claim 53 or 54, wherein this method is carried out with cesium carbonate.
  56. 56, according to the method for claim 54, further comprise the following steps:
    (a) make formula 63 compounds and alkali reaction; With
    (b) reaction mixture that in step (a), generates of acidifying, production 75 compounds:
  57. 57, according to the method for claim 56, wherein the alkali in the step (a) is NaOH.
  58. 58, according to the method for claim 56, wherein the acid in the step (b) is HCl.
  59. 59, according to the method for claim 56, further comprise the following steps:
    (c) make the reaction of formula 75 compounds and trichloromethylchloroformate; With
    (d) the reaction mixture NH that will in step (c), generate 4OH handles, production 76 compounds:
    Figure A2004800071370010C3
CN200480007137A 2003-02-10 2004-02-10 Process for preparing N-heteroaryl-N-arylamines by reacting N-aryl carbamates with haloheteroaryls and analogous processes Expired - Fee Related CN100579965C (en)

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CN102348690A (en) * 2009-02-13 2012-02-08 沃泰克斯药物股份有限公司 Production method of phenyl-6-(1-(phenyl)ureido)nicotinamides
CN102378756A (en) * 2009-02-13 2012-03-14 沃泰克斯药物股份有限公司 Solid form of 2-(2,4-difluorophenyl)-6-(1-(2,6-difluorophenyl)ureido)nicotinamide
CN103102329A (en) * 2013-01-24 2013-05-15 华东师范大学 Synthetic method of 2,3-dihydro-[1,4]-benzothiazine compound
US12084458B2 (en) 2021-02-19 2024-09-10 Sudo Biosciences Limited Substituted pyridines, pyridazines, and pyrimidines as TYK2 inhibitors
US12122785B2 (en) 2021-02-19 2024-10-22 Sudo Biosciences Limited Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102348690A (en) * 2009-02-13 2012-02-08 沃泰克斯药物股份有限公司 Production method of phenyl-6-(1-(phenyl)ureido)nicotinamides
CN102378756A (en) * 2009-02-13 2012-03-14 沃泰克斯药物股份有限公司 Solid form of 2-(2,4-difluorophenyl)-6-(1-(2,6-difluorophenyl)ureido)nicotinamide
CN103102329A (en) * 2013-01-24 2013-05-15 华东师范大学 Synthetic method of 2,3-dihydro-[1,4]-benzothiazine compound
CN103102329B (en) * 2013-01-24 2015-04-08 华东师范大学 Synthetic method of 2,3-dihydro-[1,4]-benzothiazine compound
US12084458B2 (en) 2021-02-19 2024-09-10 Sudo Biosciences Limited Substituted pyridines, pyridazines, and pyrimidines as TYK2 inhibitors
US12103937B2 (en) 2021-02-19 2024-10-01 Sudo Biosciences Limited Substituted pyridines and pyridazines as TYK2 inhibitors
US12122785B2 (en) 2021-02-19 2024-10-22 Sudo Biosciences Limited Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors

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