CN103396426A - 手性硼酸衍生物及其制备方法和应用 - Google Patents
手性硼酸衍生物及其制备方法和应用 Download PDFInfo
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- CN103396426A CN103396426A CN201310294398XA CN201310294398A CN103396426A CN 103396426 A CN103396426 A CN 103396426A CN 201310294398X A CN201310294398X A CN 201310294398XA CN 201310294398 A CN201310294398 A CN 201310294398A CN 103396426 A CN103396426 A CN 103396426A
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- carbon
- phenyl
- boric acid
- alkyl
- straight
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- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical class OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 150000002466 imines Chemical class 0.000 claims abstract description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
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- 239000003513 alkali Substances 0.000 claims abstract description 6
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 6
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 5
- -1 catechu phenolic ester Chemical class 0.000 claims description 62
- 229910052799 carbon Inorganic materials 0.000 claims description 60
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000002585 base Substances 0.000 claims description 18
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 17
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
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- 125000003118 aryl group Chemical group 0.000 claims description 8
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 8
- 239000002243 precursor Substances 0.000 claims description 8
- 150000001345 alkine derivatives Chemical class 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
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- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 3
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- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 150000001721 carbon Chemical group 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 2
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- 239000012046 mixed solvent Substances 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
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- 125000006239 protecting group Chemical group 0.000 claims description 2
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- 229910000077 silane Inorganic materials 0.000 claims description 2
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- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000005942 tetrahydropyridyl group Chemical group 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- 125000004423 acyloxy group Chemical group 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
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- LDPIQRWHBLWKPR-UHFFFAOYSA-N aminoboronic acid Chemical class NB(O)O LDPIQRWHBLWKPR-UHFFFAOYSA-N 0.000 description 21
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Classifications
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
本发明属于有机化学领域，涉及手性硼酸的衍生物及其制备方法和应用，公开了具有通式（I）结构的手性硼酸衍生物，通过不饱和亚胺或酮与二硼烷试剂，以氮杂卡宾配体和碱为催化剂合成。这种硼酸衍生物可用于制备治疗肿瘤或糖尿病的药物，也可以作为中间体制备其他药物。本发明合成方法可提高收率和立体选择性，降低药物制备成本，简化合成路线，具有较好的经济效益。
Description
技术领域
本发明涉及属手性硼酸的衍生物及其制备方法和应用。
背景技术
在自然界中，虽然不存在天然的氨基硼酸类化合物，但是其中的硼酸基团具有很特殊的天然氨基羧酸的伪饰性，从而让它具有引人入胜的生物活性，所述的与天然氨基酸特征类似的氨基硼酸类化合物为具有如下结构的化合物：
其中：R为天然氨基酸特征的各种取代基。
近年来氨基硼酸作为丝氨酸酶拮抗性的关键药效基团，在药物设计中越来越受到关注。由于硼原子独特的物理化学性质和空间结构（具有空的p轨道和较小的原子半径）， 
氨基硼酸可以被设计成各种具有重要作用的水解酶抑制剂。如文献Shenvi,al.,US4499082(1985)Shenvi等揭示肽基氨基硼酸TM-1类化合物可以作为蛋白水解酶的抑制剂，文献Kentter,Shenvi,al.,US5187157(1993)，US5242904（1993），US5250720（1993）Kentter,Shenvi揭示肽基氨基硼酸TM-1类化合物同样可以作为胰岛素样丝氨酸水解酶的可逆性抑制剂，可作用于凝血酶，血浆激肽释放酶，血纤维蛋白溶酶，文献Kleeman,al.,US5169841(1992).Kleeman揭示N端连接肽基的氨基硼酸TM-2类化合物具有抑制肾素的活性，Kettner,al.,WO200102424(2001)Kettner等揭示肽基的氨基硼酸TM-3类化合物具有抑制C型肝炎病毒的作用，Kinder,al.,US5106948(1992)Kinder等报道了N端连接肽基的氨基硼酸TM-2类化合物具有抑制肿瘤细胞生长的作用，同样Bachovchin,al.,WO20070005991(2007)Bachovchin等揭示了肽基氨基硼酸TM-4类化合物具有抑制纤维原细胞活化蛋白(FPA)的作用，这预示着该类化合物具有抗肿瘤的活性，后期的相关研究表明具有抑制胰腺癌的潜质，Fleming;Paul E.al.,WO2011123502(2011)Fleming和Paul E.等揭示了含有环丙基的氨基硼酸TM-5类化合物具有抑制肿瘤细胞增长的作用，FDA近期批准了首例含
氨基硼酸的骨髓瘤抑制剂Bortezomib，该新药已用于临床。另外，文献a)Snow,R.et.al.,J.Am.Chem.Soc.,1994,116,10860-10869.b)Jack H.Lai,William W.Bachovchin,et.al.,J.Med.Chem.2007,50,2391-2398.c)George R.Lankas,et.al.,Diabetes,2005,54,2988-2994.报导，肽基的脯氨基硼酸是二肽基脯氨基酶IV(DPP-4)的非常有效的抑制剂，可以作为II型糖尿病的很有前景的治疗药物，其中美国Phenomix公司的PT-100已完成FDA的III期临床。
文献：
Snow,R.et.al.,J.Am.Chem.Soc.,1994,116,10860-10869.：
Jack H.Lai,William W.Bachovchin,et.al.,J.Med.Chem.2007,50,2391-2398.
George R.Lankas,et.al.,Diabetes,2005,54,2988-2994.
K.Augustyns,P.Van der Veken,K.Senten and A.Haemers,Current Medicinal Chemistry,2005,12,971-998.
Pieter Van der Veken,Achiel Haemers and Koen Augustyns,Current Topics in Medicinal Chemistry,2007,7,621-635.
Daniel J Drucker,Michael A Nauck,Lancet,2006;368:1696–705.
作为氨基硼酸乃至相应的光学纯对应异构体在化学合成方面研究，其实用性和多样性方面仍然有很大的挑战，特别是有效、简洁的立体选择性合成方面。以重要的丝氨酸水解酶抑制剂的关键中间体--脯氨基硼酸的合成为例，一般采用多步合成及拆分的方法，多以Pinanediol二硼烷酯和吡咯或四氢吡咯为起始原料，如文献E.Scott Priestley,Carl P.Decicco,US20030008828,(2003,1).的报导，第一条路线合成方法步骤长，收率低，第二条路线立体选择性不好，所用碱试剂对湿度敏感，操作性差，反应式如下所示：
目前有
氨基硼酸的不对称合成的方法很少，实际上只有二种方法被报道。一种是在学术和工业界被广泛使用的Mattheson的方法，如文献：Donald S.Matteson and Kizhakethil M.Sadhu,J.Am.Chem.SOC.1981,103,5241-5242.的报导，是利用含有手性辅基的Pinanediol二硼烷酯制备氯硼酸酯，然后进一步转化为氨基硼酸，该方法中，氨基硼酸的侧链都是由烷基硼酸衍生的，这大大限制了它们的商品化的可能，反应式如下：
Dupont制药公司的Kettner利用把侧链做成亲电试剂对Matteson的方法做了拓展，如文献Sharada Jagannathan,Timothy P.Forsyth,and Charles A.Kettner,J.Org.Chem.2001,66,6375-6380.的报导，尽管在一定程度上丰富了氨基硼酸的多样性，但就其所用的试剂和适用的范围仍具有很大的局限性。反应式如下：
上述制备氨基硼酸的方法都需经过多步的合成，如果直接通过一步直接构建目标化 合物的方法最为理想，而有关硼对于碳杂双键的加成报道很少，文献Grace Mann,Kevin D.John,and R.Tom Baker，Org.Lett.,2000,2(14),2105-2108.Baker等报道了一例N-芳基芳香醛亚胺在铂络合物催化下与Bis(catecholato)diboron(B2cat2)反应得到消旋的氨基硼酸酯，反应式如下：
在此基础上，直接的用手性叔丁基亚磺酰胺诱导的不对称合成方法，由Ellman发展成功，见文献Melissa A.Beenen,Chihui An,and Jonathan A.Ellman,J.Am.Chem.Soc.2008,130,6910–6911的报导，该方法利用频哪醇二硼烷酯在(ICy)CuOtBu/叔丁醇钠的催化下与手性叔丁基亚磺酰亚胺反应得到手性
氨基硼酸衍生物，尽管它具有高立体选择性和对脂肪链烷基取代亚胺底物收率较高的优点，然而就目前该方法仍然存在二个方面的问题，1）它使用了NHC的叔丁氧铜的卡宾铜络合物作为催化剂，该催化剂只能在特定的场所（如手套箱）中制备和存放，这限制了它的工业化运用前景；2）Ellman的方法在底物类型上存在局限性，通常对于烷基氨基硼酸的收率好(收率：74-88%)，而试验发现，芳基氨基硼酸的收率不好(收率：52-61%)，甚至得不到目标产物；
Ellman的方法的核心是使用含手性亚砜辅基的叔丁基亚磺酰胺底物对Cu(I)-氮杂卡宾催化的硼酯加成反应进行立体化学诱导。自从Wanzlick和Ofele在1968年首次报道了 氮杂卡宾(NHC)与金属络合物以来，陆续已有许多稳定、可分离的该类化合物被报道，而该类化合物在催化有机金属反应时常常获得很好的效果，见文献a)Herrmann,W.A.Angew.Chem.Int.Ed.2002,41,1290-1309.b)Zinn,F.K.;Viciu,M.S.;Nolan,S.P.Annu.Rep.Prog.Chem.,Sect.B.2004,100,231-249.c)Scott,N.M.;Nolan,S.P.Eur.J.Inorg.Chem.2005,1815-1828的报导；
从给电子强度的角度来看，氮杂卡宾与富电性的膦化合物比较相似，是一类中性的2-电子给予体。可与多种过渡金属形成络合物，配位性质与富电子的有机膦配体相似，但二者立体化学性质又有明显的区别，见文献：a)Scholl,M.;Trnka,T.M.;Morgan,J.P.;Grubbs,R.H.Tetrahedron Lett.1999,40,2247-2250.b)Scholl,M.;Ding,S.;Lee,C.W.;Grubbs,R.H.Org.Lett.1999,1,953-956.c)Trnka,T.M.;Grubbs,R.H.Acc.Chem.Res.2001,34,18-29.d)Huang,J.K.;Stevens,E.D.;Nolan,S.P.;Petersen,J.L.J.Am.Chem.Soc.1999,121,2674-2678.e)Ackermann,L.;Furstner,A.;Weskamp,T.;Kohl,F.J.;Herrmann,W.A.Tetrahedron Lett.1999,40,4787-4790.的报导；
与金属的相互作用以σ-键为主，金属d轨道向卡宾的π反馈作用相对较弱,是一类典型的中性σ-配体，见文献：a)Bielawski,C.W.;Grubbs,R.H.Angew.Chem.Int.Ed.2000,39,2903-2906.b)Bielawski,C.W.;Benitez,D.;Grubbs,R.H.Science,2002,297,2041-2044.的报导；
利用氮杂卡宾(NHC)金属络合物催化的反应都被成功地运用到Heck,Suzuki-Miyaura,Kumada,Sonogashira,Still,Negishi,Buchwald-Harting反应中，见文献：
Herrmann,W.A.,Reisinger,C.P.,Siegler,M.,J.Organomet.Chem.1998,557,93-96.
Zhang,C.,Huang,J.,Trudell,M.L.,Nolan,S.P.,J.Org.Chem.,1999,64,3804-3805.
Grasa,G.A.,Nolan,S.P.,Org.Lett.,2001,3,119-122.
Huang,J.,Nolan,S.P.J.Am.Chem.Soc.,1999,121,9889-9890.b)Bohm,V.P.W.,Gstottmayr,C.W.K.,Weskamp,T.,Herrmann,W.A.,Angew.Chem.Int.Ed.2001,40,3387-3389.
Eckhardt,M.,Fu,G.C.,J Am.Chem.Soc.,2003,125,13642-13643.b)Aitenhoff,G.,Wuertz,S.,Glorius,F.Tetrahedron Lett.2006,47,2925-2928.
Grasa,G.A.,Nolan,S.P.,Org.Lett.,2001,3,119-122.
Hadei,N.,Kantchev,E.A.B.,Obrien,C.J.,Organ,M.G.,J.Org.Chem.,2005,70,8503-8507.
J.Huang,G.Grasa,S.P.Nolan,Org.Lett.,1999,1,1307-1309.b)Stauffer,S.R.,Lee,S.,Stambuli,J.P.,Hauck,S.I.,Hartwig,J.F.,Org.Lett.,2000,2,1423-1426.c)Marion,N.,Navarro,O.,Mei,J.,Stevens,E.D.,Scott,N.M.,Nolan,S.P.,J.Am.Chem.Soc.,2006,128,4101-4111
1993年，报道第一例Cu(I)-氮杂卡宾(NHC)络合物{[(NHC)2Cu][O3SCF3]}，见文献：Arduengo,A.J.III.,Dias,H.V.R.,Calabrese,J.C.,Davidson,F.,Organometallics,1993,12,3405-3409.的报导；
文献：Jurkauskas,V.,Sadighi,J.P.,Buchwald,S.L.,Org.Lett.,2003,5,2417-2420.报导，Buchwald小组用铜(I)与现产生氮杂卡宾制备了单NHC支持铜(I)络合物，证明Cu(I)-氮杂卡宾(NHC)络合物是典型的二协同体，它随着氮上取代基与金属配合能力的增加，它的协同力也明显增加。并把它运用在不饱和羰基类化合物的碳碳双键的还原，文献：Kang-Sang Lee,Adil,R.Zhugralin and Amir H.Hoveyda,J.Am.Chem.Soc.,2009,131,7253-7255.报导，Hoveyda小组利用氮杂卡宾在无金属盐存在下来催化不饱和羰基类化合物和二硼酸酯反应，构建硼酸酯羰基化合物。
纵观氨基硼酸的构建方法、氮杂卡宾本身及其铜络合物在催化二硼烷试剂对碳杂双键加成反应中的运用，其他研究小组到目前为止，从反应的机理到方法学都存在的一定的空缺和没有探索清楚的地方，特别是氮杂卡宾作为小分子催化的反应机理的研究和发展手性氮杂卡宾催化剂立体选择性的构建手性氨基硼酸研究方面，而该领域研究将直接推动该类化合物库构建和合成方法多样性的发展，从而对新药的研发具有极其重要的作用重要的作用。
发明内容
本发明的目的是在前次申请专利（申请号：201210194758.4）的基础上，继续公开一种多样性的手性氨基硼酸衍生物及其制备方法和应用，以克服现有技术存在的上述缺陷，满足相关领域发展的需要。
本发明所述的多样性的手性氨基硼酸衍生物，为具有式（Ⅰ）所示结构的化合
其中：
R1和R2联合为儿茶酚酯、频哪醇酯、二甲氨基酯或(1S,2S,3R,5S)-(＋)-2,3-蒎烷二醇(Pinanediol)酯；优选为儿茶酚酯。
R3选自氢、C1-C12的直链或支链烷烃基、取代的C1-C12直链或支链烷烃基、或3-12个碳的环烷烃基或取代的C3-C12的环烷基、苯基或取代苯基、芳杂环或取代芳杂环；
优选的，R3为氢或C1-C12的直链或支链烷烃基、取代的C1-C12直链或支链烷烃基、1苯基或取代苯基。
X为或
R5为氢、含1-12个碳的直链或支链烷烃基、含2-6个碳的烯烃基、含2-6个碳的炔烃基、芳环基、芳杂环基或卤素、胺基或取代胺基。
优选的，R5为氢、1-12个碳的直链烷烃基、3-12个碳环烷烃基、含3-12个碳的支链烷烃基，或羟基、巯基、卤素取代的含1-12个碳原子的直链烷烃基、3-12个碳环烷烃基或含3-12个碳的支链烷烃基，或胺基，或苯基、取代苯基、含氮的芳杂环基取代的胺基，或者带保护基的胺基。
R7为氢或含1-12个碳的直链或支链烷烃基。
R6为氢、1-12个碳的直链烷烃基或3-12个碳环烷烃基、含3-12个碳的支链烷烃基、含2-6个碳的烯烃基、含2-6个碳的炔烃、芳环基、芳杂环基、硅烷基或取代硅烷基，取代的含1-12个碳的直链烷烃基或环烷烃基、取代的含1-12个碳的支链烷烃基、取代的含2-6个碳的烯烃基、取代的含2-6个碳的炔烃、取代的芳环基或取代的芳杂环基。
优选的，R6为1-6个碳的直链烷烃基、1-6个碳的支链烷烃基、1-6个碳的直链烷氧基、苯基或取代苯基。
更优选的，R3为氢、甲基、乙基、丙基、异丙基、丁基、苯基、吡啶基、嘧啶基、四氢吡啶基；
R4为叔丁基亚磺酰基；R7为氢或甲基；
R5为氢、甲基、乙基、丙基、丁基、羟甲基、羟乙基、羟丙基、苯甲基、苯基、甲 基苯基、氟苯基、氯苯基、环丙基、环丁基、环戊基、环己基、吡啶基、甲胺基、乙胺基；
R6为甲氧基、乙氧基、苯基、甲基苯基或乙基苯基。
更优选的，所述的多样性的手性硼酸衍生物为：
本发明式（Ⅰ）化合物的制备方法，包括如下步骤：
在氮杂卡宾前体和碱催化下，将如通式（II’）所示的α,β-不饱和亚胺化合物或通式（III’）所示的α,β-不饱和酮与二硼烷试剂在质子性溶剂中进行搅拌反应，反应温度为15-30℃，反应时间为1～48小时（优选为24-48小时），然后从反应产物中收集式（II）或（III）化合物；
向反应后的混合物中加入乙酸乙酯稀释，并洗涤有机层；再用乙酸乙酯萃取水层，合并有机层并干燥过滤，减压浓缩；产品以硅胶或者用水失活的硅胶进行层析纯化。
反应通式如下：
R1～R7的定义同上；
所述的碱选自叔丁醇钠、碳酸钠、碳酸钾、三乙胺、1,5-二氮双环[5,4,0]十一烯-5、氟化铯、碳酸铯或氢化钠；
所述质子性溶剂选甲醇、乙醇、异丙醇、特戊醇、二氟乙醇、三氟乙醇、二氟甲醇、三氟甲醇、甲硫醇、乙硫醇、异丙硫醇、水及其混合溶剂等；
所述氮杂卡宾前体为具有如下化学结构的化合物：
其中：R6代表未取代及取代的1-6个碳的烷基、取代的1-6个碳的烷氧基、卤素、硝基、氨基、取代或并环的苯、芳环或芳杂环等；优选的为氢、3-氟、3-硝基、3-甲基、3-甲氧基或苯并；M，Q为氮或碳；R7代表1-8个碳烷基、1-8个的碳烯烃基、1-8个碳的炔烃基或芳基；X-代表氟、氯、溴或碘离子；
Ar1代表苯基、取代苯基或芳杂环基，取代苯基的取代基为甲基、氟、甲氧基，氰基或硝基；芳杂环基为吡啶基、6-甲基吡啶基、萘基、吡嗪基、吡咯基、噻吩基或嘧啶基；
其中，优选的氮杂卡宾前体为：
所述氮杂卡宾前体的制备方法，可参照以下专利（专利名称：多样性的芳基并咪唑类季铵盐及其制备方法和应用，申请号：201210195065.7）。
其中，代表性的α,β-不饱和的亚胺或酮II’和III’的化学结构为：
所述二硼烷试剂（硼酸酯）为具有如式B所示结构的化合物：
其中：R1、R2的定义同上所述。
所述二硼烷试剂可商品化采购。
优选的，所述二硼烷试剂选自儿茶酚酯、频哪醇酯、二甲氨基酯、(1S,2S,3R,5S)-(＋)-2,3-蒎烷二醇（Pinanediol）酯；具体结构如下所示：
频哪醇酯二硼烷 儿茶酚酯二硼烷 Pinanediol酯二硼烷 二甲氨基酯二硼烷
各个组分的摩尔比如下：
化合物I’∶二硼烷试剂：氮杂卡宾配体：碱＝1∶1～3∶0.05～0.2∶0.05～0.2；
本发明的多样性的手性氨基硼酸，可以用于制备治疗肿瘤或糖尿病的药物，也可以作为中间体各种具有重要治疗作用的药物（肿瘤，二型糖尿病，丙肝，病毒等）。
本发明有益效果是：所述的多样性的手性硼酸衍生物，其中通过本发明制备所涉及的许多化合物是目前其他合成方法无法制备的，为新药研究提供了丰富的该类型化合物库；可以提高收率和立体选择性，可以降低该类药物的制备成本和简化合成路线。具有好的经济效益。
具体实施方式
通用方法1：
将0.2mmol卡宾氮杂前体即配体L-08’（0.1eq.），0.2mmol碳酸铯（0.1eq.），2mmolα,β-不饱和的亚胺或酮（1eq.），2mmol硼酸酯（1eq.）和溶剂甲醇（20ml），加入反应瓶中，反应液浅黄色，在15～30℃下搅拌24-48hr；用TLC监测反应进程。反应结束后加入EA（30ml）稀释，并用K2CO3洗涤有机层。之后用EA（2×30ml）萃取水层。合并有机层用Na2SO4干燥，过滤，减压浓缩。产品用硅胶或者用水失活的硅胶进行柱层析分离，展开剂使用石油醚/乙酸乙酯体系。
甲醇可以用乙醇、异丙醇、特戊醇、二氟乙醇、三氟乙醇、二氟甲醇、三氟甲醇、甲硫醇、乙硫醇、异丙硫醇、水或者上述混合物代替。
实施例1
加入318mg（2mmol）的亚胺Compound28’，采用通用方法1，反应24小时。反应混合物通过用水失活过的硅胶经行柱层析纯化，展开剂为石油醚/乙酸乙酯体系。所得产物为性状在室温条件下为淡黄色油状物494mg(yield86%);1H NMR(400MHz,DMSO-d6,δ):7.52(d,J=9.6Hz,1H),5.97(dd,J1=9.6Hz,J2=13.6Hz,1H),4.94(m,1H),1.46(d,J=7.6Hz,1H),1.18(s,12H),1.13(s,9H);13C NMR(100MHz,DMSO-d6,δ):129.5,104.4,83.3,56.0,25.1,22.9,12.5;MS(ESI-TOF)m/z:288.2[M+H]+。
实施例2
加入346mg（2mmol）的亚胺Compound29’，采用通用方法1，反应24小时。反应混合物通过用水失活过的硅胶经行柱层析纯化，展开剂为石油醚/乙酸乙酯体系。所得产物为性状在室温条件下为淡黄色油状物536mg(yield89%);1H NMR(400MHz,CDCl3,δ):6.05(dd,J1=10.0Hz,J2=13.6Hz,1H),5.12(m,1H),4.96(d,J=10.4Hz,1H),1.80(t,J=7.2Hz,1H),1.25(s,21H),1.08(d,J=7.2Hz,3H);13C NMR(100MHz,CDCl3,δ):126.5,114.8,83.2,56.2,24.7,24.7,22.5,18.8,15.7;MS(ESI-TOF)m/z:302.2[M+H]+。
实施例3
加入374mg（2mmol）的亚胺Compound30’，反应24小时。反应混合物通过用水失活过的硅胶经行柱层析纯化，展开剂为石油醚/乙酸乙酯体系。所得产物为性状在室温条件下为淡黄色油状物573mg(yield91%);1H NMR(400MHz,CDCl3,δ):5.98(dd,J1=10.4Hz,J2=14.0Hz,1H),5.14(d,J=14.0Hz,1H),5.01(d,J=10.0Hz,1H),1.24(s,9H),1.23(s,12H),1.05(s,6H);13C NMR(100MHz,CDCl3,δ):125.3,120.5,83.2,56.2,24.9,24.6,24.5,24.4,22.5;MS(ESI-TOF)m/z:316.2[M+H]+。
实施例4
加入498mg（2mmol）的亚胺Compound31’，采用通用方法1，反应24小时。反应混合物通过用水失活过的硅胶经行柱层析纯化，展开剂为石油醚/乙酸乙酯体系。所得产物为性状在室温条件下为淡黄色油状物643mg(yield90%);1H NMR(400MHz,CDCl3,δ):7.35(d,J=8.0Hz,2H),7.18(d,J=8.0Hz,2H),5.44(t,J=8.0Hz,1H),4.86(s,1H),2.37(s,3H),1.71(dd,J1=4.8Hz,J2=8.0Hz,2H),1.27(s,9H),1.24(s,12H);13C NMR(100MHz,CDCl3,δ):138.0,137.9,133.3,129.5,129.0,110.4,83.3,55.9,24.8,24.8,22.7,21.3;MS(ESI-TOF)m/z:358.3[M+H]+。
实施例5
加入320mg（2mmol）的亚胺Compound33’，采用通用方法1，反应24小时。反应混合物通过用水失活过的硅胶经行柱层析纯化，展开剂为石油醚/乙酸乙酯体系。所得产物为性状在室温条件下为淡黄色油状物507mg(yield88%);1HNMR(400MHz,DMSO-d6,δ):7.85(d,J=8.0Hz,2H),7.33(d,J=8.0Hz,2H),3.05(m,1H),2.38(s,3H),1.25(dd,J1=7.6Hz,J2=13.6Hz,1H),1.16(d,J=4.0Hz,12H),0.93(d,J=7.6Hz,9H);13CNMR(100MHz,DMSO-d6,δ):199.9,143.8,134.7,129.7,128.4,83.0,42.6,25.0,24.9,21.6,15.5,12.5;MS(ESI-TOF)m/z:289.2[M+H]+。
实施例6
加入292mg（2mmol）的亚胺Compound33-1’，采用通用方法1，反应24小时。反应混合物通过用水失活过的硅胶经行柱层析纯化，展开剂为石油醚/乙酸乙酯体系。所得产物为性状在室温条件下为淡黄色油状物471mg(yield86%);1HNMR(400MHz,DMSO-d6,δ):7.84(d,J=8.4Hz,2H),7.31(d,J=8.0Hz,2H),3.07(m,2H),2.37(s,3H),1.16 (s,12H),0.87(t,J=6.8Hz,2H);13CNMR(100MHz,DMSO-d6,δ):200.2,143.7,134.5,129.6,128.3,83.0,33.6,25.3,25.0,21.6,5.4;MS(ESI-TOF)m/z:275.2[M+H]+。
实施例7
加入416mg（2mmol）的亚胺Compound34’，采用通用方法1，反应24小时。反应混合物通过用水失活过的硅胶柱层析纯化，展开剂为石油醚/乙酸乙酯体系。所得产物为性状在室温条件下为淡黄色油状物571mg(yield85%);1HNMR(400MHz,CDCl3,δ):8.00(d,J=7.2Hz,2H),7.57(m,1H),7.46(m,2H),7.33(m,4H),7.22(m,1H),3.59(dd,J1=10.8Hz,J2=18.0Hz,1H),3.45(dd,J1=5.2Hz,J2=18.4Hz,1H),2.83(dd,J1=5.2Hz,J2=10.8Hz,1H),1.28(s,6H),1.20(s,6H);13C NMR(100MHz,CDCl3,δ):199.7,142.0,136.8,132.9,128.5,128.4,128.1,125.6,83.4,43.3,24.6,24.5;MS(ESI-TOF)m/z:337.2[M+H]+。
实施例8
加入324mg（2mmol）的亚胺Compound33-2’，采用通用方法1，反应24小时。反应混合物通过硅胶经行柱层析纯化，展开剂为石油醚/乙酸乙酯体系。所得产物为性状在室温条件下为白色固体505mg(yield87%);mp67.6-68.5°C;1HNMR(400MHz,CDCl3,δ):7.27(m,4H),7.17(m,1H),3.67(s,3H),2.92(dd,J1=15.6Hz,J2=10.0Hz,1H),2.76(dd,J1=10.0Hz,J2=6.0Hz,1H),2.69(dd,J1=15.6Hz,J2=6.0Hz,1H),1.22(d,J=18.0Hz,12H);13CNMR(100MHz,CDCl3,δ):173.8,141.3,128.5,128.2,125.7,83.6,51.6,37.1, 24.6,24.5;MS(ESI-TOF)m/z:291.2[M+H]+;HRMS(ESI-TOF)m/z:calcd for C16H24BO4[M+H]+291.1762,Found291.1768.
实施例9
（1）取实施例1～8的化合物进行DPIV抑制检测，检测方法为：将样品溶解于0.01M盐酸溶液中（pH=2），配制为浓度1mg/10μl的溶液。再将样品与990μl pH=8的缓冲液中（含0.1mol/L羟乙基哌嗪乙硫磺酸HEPES和0.14mol/LnaCl），混合液室温下放置过夜。20μl浓度2.5μmol/L二肽基肽酶IV（DPIV）溶液用40ml pH=8的缓冲液（同上）稀释。底物为浓度0.1mg/ml的L-丙氨酰-L-脯氨酸-对硝基苯胺。底物和酶置于96孔板，并加入样品后在室温下摇床内孵育5分钟，再静置5分钟，410nm光检测，与空白组对照。
（2）取实施例1～8的化合物，用96孔板法进行FAP抑制的检测。
结果如表1。
表1
| 实施例化合物 | IC50(μM)DPIV（pH=8.0） | FAP IC50(μM) |
| 1 | 44 | 0.51 |
| 2 | 51 | 0.62 |
| 3 | 51 | 0.52 |
| 4 | 34 | 0.48 |
| 5 | 62 | 0.56 |
| 6 | 71 | 0.67 |
| 7 | 75 | 0.82 |
| 8 | 67 | 0.87 |
Claims (10)
1.一种手性硼酸衍生物，其特征在于，结构式如式（I）所示：
其中，R1和R2联合为儿茶酚酯、频哪醇酯、二甲氨基酯或(1S,2S,3R,5S)-(＋)-2,3-蒎烷二醇酯；
R3为氢、C1-C12直链或支链烷烃基、取代的C1-C12直链或支链烷烃基、C3-C12的环烷基或取代的C3-C12的环烷基、苯基或取代苯基、芳杂环或取代芳杂环；
X为或
R4为叔丁基亚磺酰基、苄基、烷酰氧基、芳酰氧基、对甲苯基磺酰基、对甲氧基苯基或对硝基苯基磺酰基；
R5为氢、3-8个碳的饱和或不饱和环烃基、含氮或氧的2-8个碳的环状烃基、含1-12个碳的直链或支链烷烃基、含2-6个碳的烯烃基、含2-6个碳的炔烃基、芳环基、芳杂环基或卤素、胺基或取代胺基；
R7为氢或含1-12个碳的直链或支链烷烃基；
R6为氢、1-12个碳的直链烷烃基或3-12个碳环烷烃基、含3-12个碳的支链烷烃基、含2-6个碳的烯烃基、含2-6个碳的炔烃、芳环基、芳杂环基、硅烷基或取代硅烷基，取代的含1-12个碳的直链烷烃基或环烷烃基、取代的含1-12个碳的支链烷烃基、取代的含2-6个碳的烯烃基、取代的含2-6个碳的炔烃、取代的芳环基或取代的芳杂环基。
2.权利要求1所述的手性硼酸衍生物，其特征在于，所述的R1和R2联合为儿茶酚酯。
3.权利要求1所述的手性硼酸衍生物，其特征在于，R3为氢、1-12个碳的直链烷烃基、3-12个碳环烷烃基、含3-12个碳的支链烷烃基，或羟基、巯基、卤素取代的含1-12个碳原子的直链烷烃基、3-12个碳环烷烃基或含3-12个碳的支链烷烃基，或苯基、取代苯基。
所述的R5为氢、1-12个碳的直链烷烃基、3-12个碳环烷烃基、含3-12个碳的支链烷烃基，或羟基、巯基、卤素取代的含1-12个碳原子的直链烷烃基、3-12个碳环烷烃基或含3-12个碳的支链烷烃基，或胺基，或苯基、取代苯基、含氮的芳杂环基取代的胺基，或者带保护基的胺基；
所述的R6为1-6个碳的直链烷烃基、1-6个碳的支链烷烃基、1-6个碳的直链烷氧基、苯基或取代苯基。
4.权利要求1所述的手性硼酸衍生物，其特征在于，所述的R3为氢、甲基、乙基、丙基、异丙基、丁基、苯基、吡啶基、嘧啶基、四氢吡啶基；
所述的R4为叔丁基亚磺酰基；所述的R7为氢或甲基；
所述的R5为氢、甲基、乙基、丙基、丁基、羟甲基、羟乙基、羟丙基、苯甲基、苯基、甲基苯基、氟苯基、氯苯基、环丙基、环丁基、环戊基、环己基、吡啶基、甲胺基、乙胺基；
所述的R6为甲氧基、乙氧基、苯基、甲基苯基或乙基苯基。
5.权利要求1-4任一项所述的手性硼酸衍生物，的制备方法，其特征在于，包括如下步骤：
在氮杂卡宾前体和碱催化下，将如通式（II’）所示的α,β-不饱和亚胺化合物或者通式（III’）所示的α,β-不饱和酮与二硼烷试剂在质子性溶剂中进行反应，然后从反应产物中收集式（II）或（III）的化合物；反应通式如下：
反应温度为15℃～30℃，反应时间为1～48小时，其中R1-R7的定义如权利要求1～4所述；
所述的亚胺类化合物或酮、二硼烷试剂、氮杂卡宾前体和碱的用量比为1：1～3：0.05～0.2：0.05～0.2。
6.权利要求5所述手性硼酸衍生物的制备方法，其特征在于，所述质子性溶剂选甲醇、乙醇、异丙醇、特戊醇、二氟乙醇、三氟乙醇、二氟甲醇、三氟甲醇、甲硫醇、乙硫醇、异丙硫醇、水及其混合溶剂。
7.权利要求5所述手性硼酸亚胺衍生物的制备方法，其特征在于，所述的氮杂卡宾前体选自以下化合物：
所述的碱为碳酸铯、碳酸钾或碳酸钠。
8.权利要求5所述手性硼酸亚胺衍生物的制备方法，其特征在于，向反应后的混合物中加入乙酸乙酯稀释，并洗涤有机层；再用乙酸乙酯萃取水层，合并有机层并干燥过滤，减压浓缩；产品以硅胶或者用水失活的硅胶进行层析纯化。
9.权利要求1～4所述的手性硼酸衍生物用于制备治疗糖尿病或肿瘤的药物。
10.权利要求1～4所述的手性硼酸衍生物用于治疗糖尿病或肿瘤的药物制备的中间体。
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| CN103030656A (zh) * | 2011-09-30 | 2013-04-10 | 北京大学 | 蛋白酶体抑制剂硼替佐米及其类似物的合成方法 |
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| G.W. KABALKA，ET AL.: "The syntheses and in vivo biodistribution of novel boronated unnatural amino acids", 《APPLIED RADIATION AND ISOTOPES》, vol. 61, 31 December 2004 (2004-12-31), pages 1111 - 1115, XP004526505, DOI: doi:10.1016/j.apradiso.2004.05.012 * |
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| KUN WEN ET AL.: "Improving Carbene-Copper-Catalyzed Asymmetric Synthesis of α-Aminoboronic Esters Using Benzimidazole-Based Precursors", 《J. ORG. CHEM.》, vol. 78, 5 March 2013 (2013-03-05), pages 3405 - 3409 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2018000402A1 (zh) * | 2016-07-01 | 2018-01-04 | 苏州大学张家港工业技术研究院 | 二(β-二亚胺基)稀土胺化物在催化酮和硼烷硼氢化反应中的应用 |
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| CN105418663A (zh) | 2016-03-23 |
| CN103396426B (zh) | 2016-09-28 |
| CN105418663B (zh) | 2017-12-22 |
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