CN1401649A - 二烷基吡啶基硼烷的制备方法 - Google Patents
二烷基吡啶基硼烷的制备方法 Download PDFInfo
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- CN1401649A CN1401649A CN02142212A CN02142212A CN1401649A CN 1401649 A CN1401649 A CN 1401649A CN 02142212 A CN02142212 A CN 02142212A CN 02142212 A CN02142212 A CN 02142212A CN 1401649 A CN1401649 A CN 1401649A
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- China
- Prior art keywords
- alkyl
- group
- pyridine
- alkoxyl group
- reagent
- Prior art date
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- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 title claims description 38
- 229910000085 borane Inorganic materials 0.000 title claims description 37
- 238000004519 manufacturing process Methods 0.000 title description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 50
- -1 pyridine Grignard reagent Chemical class 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 33
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 239000011777 magnesium Substances 0.000 claims description 17
- 229910052749 magnesium Inorganic materials 0.000 claims description 15
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- 150000001350 alkyl halides Chemical class 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- KCDNYRPDKSGQCM-UHFFFAOYSA-N 4-[4-(3-chlorophenyl)-4-(pyrrolidine-1-carbonyl)piperidin-1-yl]-1-(4-fluorophenyl)butan-1-one Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC(C=2C=C(Cl)C=CC=2)(C(=O)N2CCCC2)CC1 KCDNYRPDKSGQCM-UHFFFAOYSA-N 0.000 claims description 9
- 150000004792 aryl magnesium halides Chemical class 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 3
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 claims description 3
- FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 claims description 2
- CCZWSTFVHJPCEM-UHFFFAOYSA-N 2-iodopyridine Chemical compound IC1=CC=CC=N1 CCZWSTFVHJPCEM-UHFFFAOYSA-N 0.000 claims description 2
- 150000001502 aryl halides Chemical class 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract description 5
- 150000004795 grignard reagents Chemical class 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 2
- 150000005748 halopyridines Chemical class 0.000 abstract 1
- 238000011065 in-situ storage Methods 0.000 abstract 1
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- 206010061218 Inflammation Diseases 0.000 description 4
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- 230000004054 inflammatory process Effects 0.000 description 4
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 4
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 4
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 4
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- OXWNRQVJLGMYLN-UHFFFAOYSA-N magnesium;pyridine Chemical compound [Mg].C1=CC=NC=C1 OXWNRQVJLGMYLN-UHFFFAOYSA-N 0.000 description 3
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- 150000003839 salts Chemical class 0.000 description 3
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- 229940122696 MAP kinase inhibitor Drugs 0.000 description 2
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- 125000002393 azetidinyl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
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- 210000000988 bone and bone Anatomy 0.000 description 2
- 230000005595 deprotonation Effects 0.000 description 2
- 238000010537 deprotonation reaction Methods 0.000 description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
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- 125000005843 halogen group Chemical group 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
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- 229940043355 kinase inhibitor Drugs 0.000 description 2
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- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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Abstract
本发明涉及通过格氏吡啶试剂与烷氧基二烷基硼烷或三烷基硼烷反应制备二烷基吡啶基硼烷的方法。该反应可在约0℃－约40℃的温度下进行。格氏吡啶试剂优选通过格氏试剂(RMgX)和卤代吡啶在适宜的溶剂中，如四氢呋喃中反应就地制备，然后加入烷氧基二烷基硼烷或三烷基硼烷形成二烷基吡啶基硼烷。
Description
发明背景
二烷基吡啶基硼烷是制备取代的吡啶衍生物的交叉偶合反应中的非常有用的试剂。取代的吡啶衍生物也可用于合成1999年11月11日出版的WO99/57101中提及的式1化合物，这些化合物是p38MAP激酶抑制剂的抑制剂。与p38MAP结合的化合物有效抑制骨的再吸收、炎症及基于其他免疫反应和炎症的病理学症状。本发明涉及一种制备二烷基吡啶基硼烷的改进方法。
目前合成这些物质的方法包括在溴代吡啶上进行锂-溴交换，然后用二乙基甲氧基硼烷和三乙基硼烷捕获锂代吡啶(lithiopyridine)。下列参考文献中提及了这类方法：(a)Ishikura，M.；Mano，T.；Oda，I.；Terashima，M.《杂环》(Heterocycles)1984，22，2471-2474；(b)Ishikura，M.；Ohta，T.；Tetrashima，M.Chem.Pharm.Bull.1983，31，4573-4577；(c)Morris，G.A.；Nguyen，S.T.Tetrahedron Lett.2001，42，2093-2096；(d)Labadie，S.S.；Rotstein，D.M.；Sjogren，E.B.；Talamas，F.X.，PCT国际申请99/57101，并以下列反应式说明。
反应式1
在金属-卤素交换中，为防止阴离子迁移、溴消除形成吡啶炔(pyridynes)、脱质子化、卤化物迁移以及烷基锂与吡啶加成，上面的反应须在低温下进行(＜-40℃/乙醚或＜-100℃/四氢呋喃中)(参见，(a)Gilman，H.；Spatz，S.M.J.Org.Chem.1951，16，1485-1494.b)Mallet，M.；Branger，G.；Marsaia，F.；Quenguiner，G.J.Organomet.Chem.1990，382，319-332)。该类反应需要使用低温增加了工业规模下生产大量这类物质的成本和困难。因此，需要一种用于商业生产的无需使用低温的二烷基吡啶基硼烷的制备方法。
发明概述
本发明涉及一种制备二烷基吡啶基硼烷的方法，该方法包括将格氏吡啶试剂与烷氧基烷基硼烷或三烷基硼烷反应。该反应可在约0-约40℃下进行。
本发明的一个优选方案涉及制备式2化合物的方法：
其中R1和R2各自独立地选自是C1-C10烷基；R3是H、C1-C10烷基、C2-C10链烯基、C2-C10炔基、-C(O)(C1-C10烷基)、-(CH2)t(C6-C10芳基)、-(CH2)t(4-10元杂环)、-C(O)(CH2)t(C6-C10芳基)或-C(O)(CH2)t(5-10元杂环)，其中t是0-5的整数；所述烷基可任选地包括1或2个选自O、S和-N(R6)-的杂原子部分，条件是两个O原子、两个S原子或者O和S原子彼此不直接相连；所述芳基和杂环R1基可任选地与C6-C10芳基、C5-C8饱和环状基团或5-10元杂环基稠合；前述杂环部分中的1或2个碳原子可任选地被氧代(＝O)基团取代；前述R1基团的-(CH2)t-部分可任选地包括碳-碳双键或三键，其中t是2-5的整数并且其中m是0-4；且前述的R3基团除H外可任选地被1-3个R4基团取代；包括将式1化合物其中R3如上式2中所定义并且X是卤素；与式R4BR1R2的化合物反应，其中R1和R2如上式2中所定义并且其中R4是C1-C10烷基或C1-C10烷氧基。
在一个优选的方案中，R1和R2各自独立地是C1-C5烷基。在另一个优选的方案中，R1和R2各自独立地是C1-C3烷基。在一个更优选的方案中，R1和R2各自独立地是甲基或乙基。
在本发明的一个优选方案中，R3是H、C1-C10烷基、C2-C10链烯基、C2-C10炔基、-C(O)(C1-C10烷基)、-(CH2)t(C6-C10芳基)，其中t是0-5的整数；所述烷基可任选地包括1或2个选自O、S和-N(R6)-的杂原子部分，条件是两个O原子、两个S原子或者O和S原子彼此不直接相连；所述芳基R1基可任选地与C6-C10芳基、C5-C8饱和环状基团或5-10元杂环基稠合；前述R1基团的-(CH2)t-部分可任选地包括碳-碳双键或三键，其中t是2-5的整数；且前述的R3基团除H外可任选地被1-3个R4基团取代；并且其中R4是C1-C10烷基或C1-C10烷氧基。
在本发明的一个优选方案中，X是Cl、Br或I。在一个更优选的方案中，X是Br。
除非另有说明，本文采用的术语“卤素”包括氟、氯、溴或碘。优选的卤素是氯、溴和碘。
除非另有说明，本文采用的术语“烷基”包括饱和的直链、环状或支链的一价烃基。应该清楚，所述烷基中的环状基团需要有至少三个碳原子。
除非另有说明，本文采用的术语“链烯基”包括具有至少一个碳-碳双键的一价烃基，并且如上面的烷基定义中所述，链烯基也可以是直链、环状或支链的。
除非另有说明，本文采用的术语“炔基”包括具有至少一个碳-碳三键的一价烃基，并且如上面的烷基定义中所述，炔基也可以是直链、环状或支链的。
除非另有说明，本文采用的术语“烷氧基”包括O-烷基，其中“烷基”定义如上。
除非另有说明，本文采用的术语“芳基”包括由芳族烃基通过除去一个氢衍生的有机基团，例如苯基或萘基。
除非另有说明，本文采用的术语“4-10元杂环”包括芳族的和非芳族的包含一个或多个选自O、S和N的杂原子的杂环基团，其中每个杂环基具有4-10个环系原子。非芳族的杂环基包括仅具有4个环系原子的基团，但芳族基团必须具有至少5个环系原子。4元杂环基团的实例是氮杂环丁烷基(由氮杂环丁烷得到)。5元杂环基的实例是噻唑基，10元杂环基的实例是喹啉基。非芳族杂环基的实例是吡咯烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶子基、吗啉代、硫代吗啉代、噻噁烷基、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、1，2，3，6-四氢吡啶基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二噁烷基、1，3-二氧杂环戊烷基、吡唑啉基、二噻烷基、二硫杂环戊烷基、二氢吡喃基、二氢噻吩基、二氢呋喃基、吡唑烷基、咪唑啉基、咪唑烷基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、3H-吲哚基和喹嗪基。芳族杂环基的实例是吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、中氮茚基、酞嗪基、哒嗪基、三嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、萘啶基和呋喃并吡啶基。前述基团，例如由上面列出的化合物衍生的，在可能的情况下，可以是C-连接的或N-连接的。例如，由吡咯衍生的基团可以是吡咯-1-基(N-连接的)或吡咯-3-基(C-连接的)。
本发明涉及制备二烷基吡啶基硼烷的方法，该方法包括将格氏吡啶试剂与烷氧基二烷基硼烷试剂或三烷基硼烷试剂反应。格氏吡啶试剂通过将烷基卤化镁或芳基卤化镁与卤代吡啶试剂反应来制备。优选就地制备格氏吡啶试剂。在本发明的另一个优选方案中，格氏吡啶试剂通过卤代吡啶、Mg(O)和烷基卤化物或芳基卤化物反应来制备。
在一个优选的方案中，格氏吡啶试剂是吡啶基氯化镁或吡啶基溴化镁。
在本发明的一个方案中，烷基卤化镁是C1-C10烷基卤化镁。在一个优选的方案中，烷基卤化镁是C1-C5烷基卤化镁。烷基卤化镁选自甲基氯化镁、乙基氯化镁、异丙基氯化镁、甲基溴化镁、乙基溴化镁和异丙基溴化镁。
在本发明的一个优选方案中，卤代吡啶试剂是氯代吡啶、溴代吡啶或碘代吡啶。在另一个更优选的方案中，卤代吡啶是3-溴代吡啶。
在本发明的一个方案中，烷氧基二烷基硼烷是C1-C10烷氧基二(C1-C10烷基)硼烷。烷氧基二烷基硼烷更优选是C1-C10烷氧基二(C1-C5烷基)硼烷。烷氧基二烷基硼烷最优选是C1-C10烷氧基二(C1-C2烷基)硼烷。在本发明的一个优选方案中，C1-C10烷氧基二烷基硼烷是烷氧基二甲基硼烷或C1-C10烷氧基二乙基硼烷。
在本发明的另一个方案中，烷氧基二烷基硼烷是C1-C5烷氧基二(C1-C10烷基)硼烷。在一个更优选的方案中，烷氧基二烷基硼烷是C1-C3烷基二(C1-C5烷基)硼烷。在本发明的一个方案中，烷氧基二烷基硼烷是甲氧基二(C1-C5烷基)硼烷或乙氧基二(C1-C5烷基)硼烷。
在本发明的一个方案中，烷氧基二烷基硼烷是甲氧基二乙基硼烷。
所述烷氧基二烷基硼烷试剂或所述三烷基硼烷试剂与所述格氏吡啶试剂之间的反应在约0℃-约40℃的温度下进行。在一个优选的方案中，该反应在约10℃-约25℃的温度下进行。
发明详述
本发明涉及通过格氏吡啶试剂与烷氧基二烷基硼烷或三烷基硼烷在约0℃-约40℃的温度下反应制备二烷基吡啶基硼烷的方法。在一个优选的方案中，如下制备二烷基吡啶基硼烷：将烷基卤化镁或芳基卤化镁与卤代吡啶反应，然后添加三烷基硼烷或烷氧基二烷基硼烷。
使用卤化物-锂交换反应制备官能化吡啶，根据所使用的溶剂，该反应必须在-100℃--40℃的低温下进行。低温可防止副反应，例如卤化物-金属交换期间发生的脱质子化、溴化锂的消除或其它反应。如果官能化吡啶是工业环境中所需的，在低温下进行反应通常成本高并且不方便。现有技术已知，相应的格氏试剂在达到高得多的温度(＞25℃)下是动力学稳定的。但是，由相应的吡啶卤化物和镁(O)直接生成制备镁吡啶(magnesiopyridines)异常困难((a)Harris，S.A.lowa State Coll.J.Sci.1932，6，425；(b)Overhoff，J.；Proost，W.Rec.Trav.Chim.1938，57，179-184；(c)Proost，W.；Wibaut，J.P.Rec.Trav.Chim.1940，59，971；(d)Lai，Y-H.Synthesis，1981，585-604；和(e)Nakane，M.；Hutchinson，C.R.J.Org.Chem.1978，43，3922-3931)。
使用镁-卤素交换反应由杂芳基卤化物和烷基或芳基卤化镁生成杂芳基格氏试剂是众所周知的。((a)Abarbri，M.；Thibonnet，J.；Berillon，L.；Dehmel，F.；Rottlaender，M.；Knochel，P.J.Org.Chem.2000，65，4618-4634；(b)Rottlander，M.；Boymond，L.；Berillon，L.；Lepretre，A.；Varchi，G.；Avolio，S.；Laaziri，H.；Queguiner，G.；Ricci，A.；Cahiez，G.；Knochel，P.Chem.Eur.J.2000，6，767-770；(c)Lepretre，A.；Turck，A.；Ple，N.；Knochel，P.；Queguiner，G.Tetrahedron 2000，56，265-273；(d)Shimura，A.；Momotake，A.；Togo，H.；Yokoyama，M.Synthesis 1999，495-499；(e)Kondo，Y.；Yoshida，A.；Sato，S.；Sakamoto，T Heterocycles 1996，42，105-108；(f)Turner，R.M.；Lindell，S.D.；Ley，S.V.J.Org.Chem.1991，56，5739-5740；(g)Abarbri，M.；Dehmel，F.；Knochel，P.TetrahedronLett.1999，40，7449-7453；(h)Dehmel，F.；Abarbri，M.；Knochel，P.Synlett.2000，345-346；和(i)Felding，J.；Kristensen，J.；Bjerregaard，T.；Sander，L.；Vedso，P.；Begtrup，M.J.Org.Chem.1999，64，4196-4198)。吡啶基格氏试剂也可通过芳基吡啶基亚砜与格氏试剂的配体交换反应生成(Shibutani，T.；Fuj ihara，H.；Furukawa，N.Heteroat.Chem.1991，2，521-531)。杂芳基格氏试剂也可由吡啶基卤化物、镁(O)和反应性烷基卤化物，如乙基溴直接生成(夹带方法(Entrainment Method))。通过与化学计算量的烷基或芳基格氏试剂直接反应形成吡啶基格氏试剂是本领域众所周知的((a)Paradies，H.H.；Gorbing，M.Angew.Chem.Int.Ed.1969，8，279；(b)Martin，G.J.；Mechin，B.；Leroux，Y.；Paulmier，C.；Meunier，J.C.J.Organomet.Chem.1974，67，327-339；(c)Furukawa，N.；Shibutani，T.；Fujihara，H.Tetrahedron Lett.1987，28，5845-5848；(d)Trecourt，F.；Breton，G.；Bonnet，V.；Mongin，F.；Marsais，F.；Queguiner，G.TetrahedronLett.1999，40，4339-4342；(e)Berillon，L.；Lepretre，A.；Turck，A.；Ple，N.；Queguiner，G.；Cahiez，G.；Knochel，P.Synlett.1998，1359-1360；和(f)Trecourt，F.；Breton，G.；Bonnet，V.；Mongin，F.；Marsais，F.；Queguiner，G.Tetrahedron2000，56，1349-1360)。该方法可在40℃高的较宽温度范围内进行并在温和反应条件下生成卤代镁吡啶。该卤代镁吡啶可通过在约0℃-约40℃下与二烷基烷氧基硼烷或三烷基硼烷反应转化为相应的二烷基吡啶基硼烷。该反应以与相应的锂化吡啶在低温下的反应制得该产物可比的产率和质量产生所需的二乙基吡啶基硼烷。
本发明的方法可用于合成需要吡啶取代基的化合物。例如下示的WO99/57101式(1)的p38 MAP吡唑激酶抑制剂可以存在有吡啶取代基：
其中A、B、R1、R2、R3、R4、R5和R6如WO 99/57101中所定义，该文献全文引入本文以供参考。因此，本发明的方法可用于引入下示的WO99/57101的实施例23(5-氨基-1-(2，4-二甲基苯基)-4-)3-(吡啶-3-基)苯甲酰基]吡唑盐酸盐)中的吡啶(而不是其中例举的用传统的正丁基锂试剂引入吡啶取代基的方法)，
式(1)化合物及其可药用盐和溶剂化物(下文共同称为“治疗化合物”)可通过口服、透皮(如通过贴剂的使用)、非胃肠或局部给药。口服给药是优选的。式(1)化合物及其可药用盐和溶剂化物的单次或分次(即，多次)给药通常最理想地是以约1.0mg-约500mg每天，优选约1mg-约100mg每天的剂量范围给药。所述治疗化合物的单次或分次给药通常以约0.01mg-约10mg/kg体重/天的日剂量范围给药。可根据被治疗者的体重和适应症以及所选择的特定给药途径进行变化。在某些情况下，低于上述范围低限的剂量水平可能就足够了，但在其它情况下可能要使用较高的剂量但不会引起任何有害的副作用，假定这类较高的剂量一天分为数个低剂量给药。
治疗化合物可单独或者与可药用载体或者稀释剂结合通过前面所示的两种途径之一给药，这种给药可以是单次或多次剂量的。更具体地说，本发明的新的治疗化合物可以以多种不同的剂型形式给药，即，它们可与各种可药用的惰性载体结合以下列剂型形式给药：片剂、胶囊、锭剂、糖锭、硬糖果剂、粉末、喷雾剂、霜剂、软膏、栓剂、胶冻、凝胶、糊剂、洗剂、油膏、酏剂、糖浆等。这类载体包括固体稀释剂或填充剂、无菌水性溶媒和各种非毒性的有机溶剂等。再者，口服药物组合物可以是适当增甜的和/或调味的。
对于口服给药，包含各种赋形剂，例如微晶纤维素、柠檬酸钠、碳酸钙、磷酸二钙和甘油的片剂可以包含各种崩解剂，例如淀粉(并且优选玉米、土豆或木薯淀粉)、藻酸和某些复合硅酸盐；以及制粒粘合剂，如聚乙烯吡咯烷酮、蔗糖、明胶和阿拉伯胶。此外，润滑剂，如硬脂酸镁、月桂基硫酸钠和滑石也经常用于压片目的。也可使用类似的固体组合物作为明胶胶囊中的填充剂；在这一点上，优选的材料也包括乳糖和高分子量聚乙二醇。当需要口服水性悬浮液和/或酏剂时，可将活性成分与各种甜味剂或调味剂、着色剂或颜料混合，并且如果需要，与乳化剂和/或悬浮剂以及稀释剂，如水、乙醇、丙二醇、甘油及其各种组合物一起混合。
对于非胃肠给药，可使用治疗化合物的芝麻油或花生油或者含水丙二醇溶液。如果需要，含水溶液可以是适当缓冲的并且首先应使液体稀释剂等渗。这些含水溶液适用于静脉注射目的。油性溶液适用于关节内、肌内和皮下注射目的。本领域普通技术人员通过标准的制药技术都很容易在无菌条件下完成所有这些溶液的制备。
此外，也可局部施用治疗化合物，根据标准制药实践，优选以霜剂、胶冻、凝胶、糊剂、油膏等形式进行局部施用。
治疗化合物也可施用于人以外的哺乳动物。对哺乳动物的施用剂量取决于动物的种类和所治疗的疾病或病症。治疗化合物可以以胶囊、大丸剂、片剂或液体兽用顿服药形式对动物施用。治疗化合物也可以以注射或者植入物形式对动物施用。这类制剂按照标准兽药实践以常规方式制备。或者，治疗化合物可以与动物饲料一起施用，为此，可制备浓缩的饲料添加剂或预混物，用于与普通动物饲料混合。
表现出p38 MAP激酶抑制剂活性的式(1)化合物可用于治疗由细胞因子(cykotines)介导的疾病，例如抑制骨的再吸收、炎症以及其它基于免疫反应和炎症的病理症状。式(1)化合物作为p38 MAP激酶抑制剂的活性可使用WO99/57101中描述的分析方法确定。
提供下列实施例用于说明本发明。它们不是旨在、也不应被理解为是对本发明的一种限制。说明书和权利要求书对本发明进行了全面描述。
实施例1
二乙基-3-吡啶基硼烷 
在0℃和氮气氛下，往2M异丙基氯化镁的四氢呋喃溶液(200ml，0.4mol)中用45分钟加入3-溴吡啶(34.5ml，0.36mol)，在添加期间使反应混合物的温度保持在10-25℃。加毕，在0℃下再搅拌混合物1小时。在10-25℃(用冰浴冷却)下，用30分钟滴加二乙基甲氧基硼烷(52.6ml，0.4mol)。将反应混合物在0℃下搅拌1小时后，使反应物升至室温过夜。在0℃下反应物用2N HCl(200ml)处理。用碳酸钠将水层的pH调至7，该混合物用乙酸乙酯萃取(3×150ml)，用盐水洗涤(150lm)，经硫酸钠干燥并真空浓缩。将粗品加到异丙醇中使成浆状物并过滤，得到白色固体的产物(41.5g，0.282mol)，产率78％。所记录的制得物质的NMR光谱和熔点与购自Aldrich Chemical Company，Millwaukee，Wisconsin的二乙基-3-吡啶基硼烷的NMR光谱和熔点一致。
1HNMR(CDCl3)δ8.0(d，J＝5Hz，1H)，7.7(d，J＝6Hz，1H)，7.5(s，1H)，7.2(dd，
J＝1.9，8Hz，1H)，0.6(m，2H)，0.4(m，6H).13CNMR(CDCl3)δ149.3，144.0，141.1，123.6，
14.6，9.3.mp 172.0℃-175.5℃.
实施例2
二乙基-3-(5-溴吡啶基)硼烷
按照实施例1描述的方法制备二乙基-3-(5-溴吡啶基)硼烷，不同的是用3，5-二溴吡啶代替3-溴吡啶。反应得到的回收产率为66％
1HNMR(CDCl3)：8.1(s，1H)，7.9(s，1H)，7.4(s，1H)，0.6(m，4H)，0.4(m，6H).
C13NMR(CDCl3)：147.4，146.8，142.5，121.2，14.6，9.2.MS：228.2(M+1).
实施例3
二乙基-4-吡啶基硼烷
按照实施例1描述的方法制备二乙基-4-吡啶基硼烷，不同的是用4-溴吡啶代替3-溴吡啶。反应得到的回收产率为88％
1HNMR(CDCl3)：8.00(d，J＝5.8Hz，2H)，7.25(d，J＝5.4Hz，2H)，0.73(m，4H)，0.52(m，
6H).C13NMR(CDCl3)：142.5，129.2，17.5，9.5.
Claims (15)
1、一种制备二烷基吡啶基硼烷的方法，包括将格氏吡啶试剂与烷氧基二烷基硼烷试剂或三烷基硼烷试剂反应。
2、权利要求1的方法，其中的格氏吡啶试剂通过将烷基卤化镁或芳基卤化镁与卤代吡啶试剂反应制备。
3、权利要求1的方法，其中的烷氧基二烷基硼烷是C1-C10烷氧基二(C1-C10烷基)硼烷。
4、权利要求1的方法，其中的烷氧基二烷基硼烷是C1-C5烷氧基二(C1-C10烷基)硼烷。
5、权利要求1的方法，其中的所述烷氧基二烷基硼烷试剂或所述三烷基硼烷试剂与所述吡啶格氏试剂之间的反应在约0℃-约40℃的温度下进行。
6、权利要求1的方法，其中所述格氏吡啶试剂通过将卤代吡啶、Mg(O)与烷基卤化物或芳基卤化物反应制备。
7、权利要求1的方法，其中吡啶格氏试剂是吡啶基氯化镁。
8、权利要求1的方法，其中烷氧基二烷基硼烷是甲氧基二乙基硼烷。
9、权利要求1的方法，其中所述反应在约0℃的温度下反应。
10、一种制备二烷基吡啶基硼烷的方法，包括将烷基卤化镁或芳基卤化镁与卤代吡啶反应，然后加入烷氧基二烷基硼烷或三烷基硼烷。
11、权利要求10的方法，其中的烷基卤化镁是C1-C10烷基卤化镁。
12、权利要求10的方法，其中的芳基卤化镁是C6-C10芳基卤化镁。
13、权利要求10的方法，其中的卤代吡啶是氯代吡啶、溴代吡啶或碘代吡啶。
14、权利要求10的方法，其中的烷氧基二烷基硼烷是C1-C10烷氧基二(C1-C10烷基)硼烷。
15、一种制备式2化合物的方法：
其中R1和R2各自独立地选自是C1-C10烷基；R3是H、C1-C10烷基、C2-C10链烯基、C2-C10炔基、-C(O)(C1-C10烷基)、-(CH2)t(C6-C10芳基)、-(CH2)t(4-10元杂环)、-C(O)(CH2)t(C6-C10芳基)或-C(O)(CH2)t(5-10元杂环)，其中t是0-5的整数；所述烷基可任选地包括1或2个选自O、S和-N(R6)-的杂原子部分，条件是两个O原子、两个S原子或者O和S原子彼此不直接相连；所述芳基和杂环R1基可任选地与C6-C10芳基、C5-C8饱和环状基团或5-10元杂环基稠合；前述杂环部分中的1或2个碳原子可任选地被氧代(＝O)基团取代；前述R1基团的-(CH2)t-部分可任选地包括碳-碳双键或三键，其中t是2-5的整数；且前述的R3基团除H外可任选地被1-3个R4基团取代并且其中m是0-4；
包括将式1化合物，
其中R3如上式2中所定义并且X是卤素；
与式R4BR1R2的化合物反应，其中R1和R2如上式2中所定义并且其中R4是C1-C10烷基或C1-C10烷氧基。
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| CN117402184A (zh) * | 2023-12-15 | 2024-01-16 | 山东国邦药业有限公司 | 一种二乙基甲氧基硼烷的制备方法 |
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| WO2017087643A1 (en) * | 2015-11-17 | 2017-05-26 | Viamet Pharmaceuticals, Inc. | 4-((6-2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1h-1,2,4-triazol-1-yl)propyl)pyridin-3-yl)oxy)benzonitrile and processes of preparation |
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- 2002-08-26 RU RU2002122947/04A patent/RU2002122947A/ru unknown
- 2002-08-26 KR KR1020020050579A patent/KR20030019112A/ko not_active Application Discontinuation
- 2002-08-26 PL PL02355706A patent/PL355706A1/xx unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103483366A (zh) * | 2013-09-05 | 2014-01-01 | 润泽制药(苏州)有限公司 | 甲氧基二乙基硼烷的制备方法 |
| CN103483366B (zh) * | 2013-09-05 | 2017-02-08 | 润泽制药(苏州)有限公司 | 甲氧基二乙基硼烷的制备方法 |
| CN117402184A (zh) * | 2023-12-15 | 2024-01-16 | 山东国邦药业有限公司 | 一种二乙基甲氧基硼烷的制备方法 |
| CN117402184B (zh) * | 2023-12-15 | 2024-04-26 | 山东国邦药业有限公司 | 一种二乙基甲氧基硼烷的制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| IL151379A0 (en) | 2003-04-10 |
| ZA200206778B (en) | 2004-02-23 |
| EP1288217A2 (en) | 2003-03-05 |
| ATE321766T1 (de) | 2006-04-15 |
| US20030083312A1 (en) | 2003-05-01 |
| PL355706A1 (en) | 2003-03-10 |
| EP1288217A3 (en) | 2003-09-17 |
| DE60210224T2 (de) | 2007-01-11 |
| CZ20022642A3 (cs) | 2003-09-17 |
| EP1288217B1 (en) | 2006-03-29 |
| CA2399834A1 (en) | 2003-02-27 |
| HU0202868D0 (zh) | 2002-10-28 |
| DE60210224D1 (de) | 2006-05-18 |
| KR20030019112A (ko) | 2003-03-06 |
| JP2003096084A (ja) | 2003-04-03 |
| BR0203371A (pt) | 2003-05-27 |
| US6570017B2 (en) | 2003-05-27 |
| HUP0202868A3 (en) | 2004-04-28 |
| HUP0202868A2 (hu) | 2003-06-28 |
| RU2002122947A (ru) | 2004-03-10 |
| CA2399834C (en) | 2006-08-22 |
| YU59502A (sh) | 2004-12-31 |
| ES2256416T3 (es) | 2006-07-16 |
| MXPA02008364A (es) | 2003-03-04 |
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