CN102906063B - 制备异丝氨酸衍生物的方法 - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 42
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical class NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 title abstract description 18
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- 239000011541 reaction mixture Substances 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 13
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 229910021617 Indium monochloride Inorganic materials 0.000 claims description 8
- APHGZSBLRQFRCA-UHFFFAOYSA-M indium(1+);chloride Chemical compound [In]Cl APHGZSBLRQFRCA-UHFFFAOYSA-M 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
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- 238000009833 condensation Methods 0.000 claims description 7
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- 238000002360 preparation method Methods 0.000 claims description 5
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
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- BYOBCYXURWDEDS-IUCAKERBSA-N (2s,3s)-2-amino-3-phenylmethoxybutanedioic acid Chemical compound OC(=O)[C@@H](N)[C@@H](C(O)=O)OCC1=CC=CC=C1 BYOBCYXURWDEDS-IUCAKERBSA-N 0.000 description 1
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- QFAADIRHLBXJJS-ZAZJUGBXSA-N amastatin Chemical compound CC(C)C[C@@H](N)[C@H](O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC(O)=O QFAADIRHLBXJJS-ZAZJUGBXSA-N 0.000 description 1
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- NEXSMEBSBIABKL-UHFFFAOYSA-N hexamethyldisilane Chemical compound C[Si](C)(C)[Si](C)(C)C NEXSMEBSBIABKL-UHFFFAOYSA-N 0.000 description 1
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- 229910052744 lithium Inorganic materials 0.000 description 1
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- LFVPHXOOLUCFFB-UHFFFAOYSA-N methyl 3-amino-2-hydroxypropanoate Chemical compound COC(=O)C(O)CN LFVPHXOOLUCFFB-UHFFFAOYSA-N 0.000 description 1
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- NQXSBCTYTMQGGJ-ICAZUDSDSA-N propan-2-yl (2r,3s)-4-cyclohexyl-2-hydroxy-3-[[(2s)-3-(1h-imidazol-5-yl)-2-[[(2r)-4-morpholin-4-yl-2-(naphthalen-1-ylmethyl)-4-oxobutanoyl]amino]propanoyl]amino]butanoate Chemical compound C([C@@H]([C@@H](O)C(=O)OC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](CC(=O)N1CCOCC1)CC=1C2=CC=CC=C2C=CC=1)C1CCCCC1 NQXSBCTYTMQGGJ-ICAZUDSDSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/30—Preparation of optical isomers
- C07C227/32—Preparation of optical isomers by stereospecific synthesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及以高非对映异构体选择性方式来制备异丝氨酸衍生物的“一锅”方法。根据本发明的方法包括将被保护的环氧丙酸与亚胺反应获得在-OH和-COOH基团上都被保护的异丝氨酸，将所得中间体脱保护生成异丝氨酸或异丝氨酸1-4C-烷基酯的步骤。获得作为主要异构体的纯的苏式衍生物。
Description
本发明涉及以高非对映异构体选择性方式来制备异丝氨酸衍生物的“一锅”方法。
发明背景
α-羟基-β-氨基酸(异丝氨酸)是重要的靶点，因为这些氨基酸存在于具有重要生物学价值的分子中，例如被称为Ornicorrugatin1的新的脂肽的铁载体；KRI-13142，其是一种有效的人肾素抑制剂多肽；抑氨肽酶素3，其是具有免疫调节、抗肿瘤和抗菌活性的四肽；Microginin4；苏式-β-苄氧基天冬氨酸(TBOA)5，其是针对EAAT的全部亚型的第一个不可转运的阻断剂；以及大多数是紫杉烷(taxan)衍生物6。
从立体化学角度，很好地定义了上述氨基酸的生物学需求，且通常苏式(2R,3S)异构体是有活性的，并因此是优选的。
通过C-2/C-3键的形成制备异丝氨酸化合物的合成方法是已知的，其通过亚磺酰亚胺与被保护的α-羟基-酯7a,b的烯醇锂盐反应，或者单一的亚胺与酯的烯醇锂盐反应以及随后的氧化过程7c。上述反应的主要缺点是：第一种方式7a,b使用昂贵的亚磺酰亚胺，其合成并不容易。第二种方式仅获得中等的产率，并且需要使用昂贵试剂(氧杂氮杂环丙烷)的氧化步骤以引入α-羟基基团。根据其它合成方法7d，将单一的亚胺衍生物与α-甲氧基烯酮硅烷基缩醛在酸性条件下反应。用α-OMe基团官能化的异丝氨酸化合物以中等产率和非对映异构体选择性地形成。此外，α-OMe基团必须在独立的步骤中脱保护。最终，已知N-芳基亚胺与危险的芳基重氮乙酸酯在高化学计量过量的情况下缩合且使用昂贵的铑催化剂来促进7e。异丝氨酸衍生物根据取代型式以可变的非对映异构体选择性和中等产率获得。影响全部已知合成方法的主要困难是获得纯的对映异构体，因为除了参考文献7d之外的全部方法都在起始试剂中使用了手性助剂，因此在缩合过程中生成四种非对映异构体。
发明描述
本发明涉及获得通式1化合物的方法，其中R1是直链或支链的(C1-C6)-烷基基团、未取代或取代的芳基或杂芳基基团，R2是直链或支链的(C1-C6)-烷基基团、芳基烷基基团)；R3是H、(C1-C4)-烷基基团。全部立体异构体都包含在式1范围内。
优选的式1化合物是这些化合物，其中R1是iBu、芳基、噻吩基，R2是PhCH2、正丁基，且R3是H、烷基(C1-C4)。
优选式1的苏式非对映异构体(2R＊,3S＊)。
本发明的方法在流程图1中描述，其中R1、R2和R3基团如上文所述。
其包括将基本上等摩尔量的通式3的硅烷基烯醇酯(其中R4是Me、Et且R5是Me、Et)和通式4的亚胺反应，其中R1是直链或支链的(C1-C6)-烷基基团、芳基烷基基团、未取代或取代的芳基基团、杂芳基基团，R2是直链或支链的(C1-C6)-烷基基团或芳基烷基基团，得到通式(3R＊,5S＊,6S＊,1'S＊)-5和(3R＊,5S＊,6S＊，1'R*)-6的中间体，其中R1是直链或支链的(C1-C6)-烷基基团、芳基烷基基团、未取代或取代的芳基基团、杂芳基基团；R2是直链或支链的(C1-C6)-烷基基团、芳基烷基基团；R4是Me或Et基团。中间体5和6通过水解直接转化为通式(2R＊,3S＊)-1和(2R＊，3R＊)-1'的异丝氨酸衍生物，其中R3是H，或者通过醇解转化为通式(2R＊，3S＊)-1和(2R＊,3R＊)-1'的异丝氨酸衍生物，其中R3是(C1-C4)-烷基基团。
3和4之间的缩合由质子酸(proticacid)和路易斯酸(0.1-1当量)催化。
代表性的路易斯催化剂是ZnCl2、CoCl2、InCl3、NbCl5、Eu(OTf)3、PdCl2、SnCl2和MgBr2。已显示，产物5和6的分配以及因此产物(2R＊，3S＊)-1和(2R＊,3R＊)-1'的分配取决于路易斯酸的类型。
路易斯酸例如InCl3和SnCl2和MgBr2提供了较好的苏式非对映异构体选择性(即，增加优选的对映异构体(2R＊,3S＊)-1的形成)和较高的反应产率。因此，优选InCl3、SnCl2和MgBr2。
所述反应可以在宽的温度范围即-70°C到25°C内进行。最好的结果在-40和-30°C之间获得。因此该范围是优选的。
所述反应有利地在疏质子的极性溶剂中进行，例如二甲基甲酰胺、乙腈、二氯甲烷、氯仿、四氢呋喃。优选乙腈和二氯甲烷。
如果需要，全部产物都可以使用标准方法纯化。
使用适当的醇R3OH在三甲基硅烷基氯的存在下进行醇解。
根据本发明的优选形式，其提供了关于产率和非对映异构体选择性的最佳结果，该反应以“一锅反应”方式进行，其避免了对全部中间体的分离，并在简单的结晶步骤后获得了最终纯的苏式非对映异构体。
根据该方法，亚胺4首先从醛(R1CHO)和胺(R2NH2，其中优选PhCH2NH2)在乙腈中于室温下并在分子筛的存在下或者经乙腈/水共沸混合物的蒸馏原位生成。将反应温度降至-30°C，并加入硅烷基衍生物3。随后加入催化剂，并将该混合物搅拌1小时。将粗的反应混合物直接用三甲基硅烷基氯在醇中的溶液处理，并在结晶后分离纯的非对映异构体(2R＊，3S＊)-1(其中R3是(C1-C4)-烷基基团)。
如果需要，本发明的方法可以通过从对映异构体纯的化合物3(R4=Me,R5=Et)开始反应来直接获得对映异构体纯的化合物(因此避免了拆分步骤)。
根据流程图2从对应的内酯2获得化合物3。
化合物2(R4=Me)是可以通过常规方法8c获得的已知化合物。化合物2(R4=Et)、3(R4=Me,R5=Et)、3(R4=R5=Et)是新的化合物，它们及其制备方法也是本发明的一部分。通过非常有效的“一锅”方案直接从2,3-丁二酮、羟乙酸和原甲酸乙酯的混合物开始，在催化量的H2SO4存在下制备新的内酯2(R4=Et)。化合物3以良好的产率从2在-78°C下经使用六甲基二硅烷基胺锂(LHMDS)在THF中的溶液并用Et3SiCl作为硅烷化试剂(流程图2)进行制备。短的反应时间是有利的。
根据本发明优选的特征，亚胺4是从相应的醛和胺在原位制备，并将反应混合物立即与化合物3反应，因而避免将它们困难且低产率地进行分离，因为亚胺已知是很不稳定的化合物。
发明优点
本发明的方法是有优势的，因为该方法的简便性，其不需要任何中间体的分离以及麻烦的色谱纯化。
需要温和的条件对羟基和羧基基团脱保护。这是重要的，因为完全避免了外消旋化的风险。良好的产率和非对映异构体选择性是另一个重要的优势。
本方法提供了异丝氨酸衍生物的外消旋混合物，其可以通过常规方法分离。但是，如果需要，该拆分步骤可以容易地避免，如果使用对映异构体纯的被保护的环氧丙酸10，可直接获得对映异构体纯的化合物。
实施例
将InCl3在200°C在真空下预先除水2小时。
5,6-二乙氧基-5,6-二甲基-[1,4]-二噁烷-2-酮。将2,3-丁二酮(4.6mL,46.22mmol)和羟乙酸(3.07g,40.40mmol)溶于原甲酸乙酯(40mL)中，并加入催化量的H2SO4。将反应混合物在25°C放置1小时。加入NaHCO3的饱和溶液(10mL)，并将该混合物用AcOEt萃取(3x30mL)。将有机层用Na2SO4除水，并将该粗的反应混合物经硅胶色谱纯化(环己烷/AcOEt,10:1)，结晶后得到纯的化合物2(R4=Et,52%)。白色固体，mp37°C(CH2Cl2/戊烷,0°C)。IR(NaCl)νmax1752cm-1;1HNMR(CDCl3)δ4.32,4.23(AB系统,J16.6,2H),3.79-3.69(m,2H),3.58(q,J7.2,2H),1.53(s,3H),1.41(s,3H),1.21(t,J6.9,3H),1.99(t,J7.0,3H);13CNMR(CDCl3)δ168.1,105.2,97.8,60.5,58.8,57.3,18.8,17.9,15.9,15.7,15.3。MS(ESI)m/z341.4[M+23]+;分析计算值C10H18O5:C,55.03;H,8.31;实测值C,55.12;H,8.38。
5,6-二甲氧基-5,6-二甲基-[1,4]-二噁烯-2-基氧基)三乙基硅烷。将内酯2(R4=Me)(3.23g,17mmol)溶于无水THF(35mL)中，并将该混合物在N2中冷却至-78°C。将LHMDS(4.52g,27mmol)溶于THF(10mL)中，并随后逐滴加入。加完后，将该混合物再搅拌10分钟，然后加入TESCl(4mL,26mmol)。随后将所得溶液加温至25°C，并继续搅拌过夜。随后减压除去THF，并将戊烷(50mL)加入该残余物中。将所得混悬液用硅藻土过滤，并真空除去溶剂，得到粗的化合物，将其在真空下蒸馏(120°C,0.8mmHg)。得到纯的化合物3(R4=Me,R5=Et)(4.26g,82%)，为无色油状物。IR(NaCl)νmax1719,1149,740cm-1;1HNMR(CDCl3)δ5.52(s,1H),3.37(s,1H),3.22(s,1H),1.45(s,3H),1.38(s,3H),1.06-0.94(m,9H),0.75-0.67(m,6H);13CNMR(CDCl3)δ143.9,104.3,96.6,90.4,49.5,48.6,17.6,17.1,6.6,4.8。MS(ESI)m/z218.9;分析计算值C14H28O5Si:C,55.23;H,9.27;实测值C,55.11;H,9.15。
5,6-二乙氧基-5,6-二甲基-[1,4]-二噁烯-2-基氧基)三乙基硅烷。硅烷基衍生物3(R4=R5=Et)(4.8g,85%)是按照上述合成方案制备，但是将碱加入2(R4=Et)(3.7g,17mmol)和TESCl的混合物中。无色油状物(130°C,0.8mmHg)。IR(NaCl)νmax1721,1149,744cm-1;1HNMR(CDCl3)δ5.50(s,1H),3.68-3.63(m,2H),3.51(q,J7.0,2H),1.46(s,3H),1.40(s,3H),1.22-1.03(m,6H),1.02-0.88(m,9H),0.75-0.63(m,4H),0.55(q,J10.8,2H);13CNMR(CDCl3)δ143.8,104.3,100.2,96.4,57.4,56.6,18.4,17.9,15.9,15.7,6.6,4.9。MS(ESI)m/z355.2[M+23]+;分析计算值C16H32O5Si:C,57.79;H,9.70;实测值C,57.60;H,9.58。
制备化合物5和6。方法A.在氮气中和搅拌下将亚胺4(0.66mmol)溶于无水MeCN(1.2mL)中。随后将反应混合物冷却至-30°C，并一次加入无水InCl3(73mg,0.33mmol)。在该温度下搅拌搅拌10分钟，逐滴加入硅烷基衍生物3(0.66mmol)在无水MeCN(1mL)中的溶液。将反应混合物搅拌1小时，并随后用饱和NaHCO3溶液(1mL)猝灭。将该粗物质用AcOEt(3x5mL)萃取，并将收集的有机相用盐水洗涤，用Na2SO4干燥，过滤并在真空下除去溶剂。将该粗物质用硅胶快速色谱法纯化。化合物5/6(R4=Et)经快速柱色谱纯化(SiO2;正己烷/Et2O,7:2;流速：30mL/min)。在这些最后的情况下，仅分离出异构体5。方法B.在装有磁力搅拌棒和氮气入口的二颈圆底烧瓶中操作，将合适的醛(苯甲醛:60μL,0.59mmol;异戊醛:63μL,0.59mmol)和胺(苄基胺:79μL,0.59mmol)在分子筛(60mg,在真空下200°C下活化2小时)的存在下溶于MeCN(1.5mL)。1小时后，将反应混合物在-30°C冷却，并一次加入无水InCl3(65.3mg,0.29mmol)。在该温度下搅拌10分钟后，逐滴加入硅烷基烯醇醚3(R4=Me,R5=Et)(180.2mg,0.59mmol)在无水MeCN(1mL)中的溶液。将反应混合物搅拌1小时。将反应混合物如上述方法所述进行后处理，并分别分离5/6(R1=Ph,R2=Bn,R4=Me)或5/6(R1=Me2CHCH2,R2=Bn,R4=Me)。
(3R＊,5S＊,6S＊)-3-(1'-N-苄基氨基-1'-苯基-甲基)-5,6-二甲氧基-5,6-二甲基-[1,4]-二噁烷-2-酮(5,6:R1=Ph,R2=Bn,R4=Me)。柱色谱:AcOEt/环己烷,1:5;方法A:65%(4:1),5:52%,6:13%。方法B:5:71%,6:16%。
1'S＊-5(R1=Ph,R2=Bn,R4=Me):108°C(正戊烷/CH2Cl2)。IR(KBr)νmax3372,1744cm-1;1HNMR(CDCl3)δ7.40-7.22(m,10H),4.31,4.28(AB系统,J2.9,2H),3.60,3.51(AM系统,J13.2,2H),3.21(s,3H),3.14(s,3H),3.00-2.00(br,1H,交换),1.47(s,3H),1.37(s,3H);13CNMR(CDCl3)δ169.2,140.8,139.7,128.7,128.6,128.5,127.2,105.1,98.6,75.7,63.6,51.1,50.1,49.5,18.4,17.2。MS(ESI)m/z386.0[M+1]+;分析计算值C22H27NO5:C,68.55;H,7.06;N,3.63;实测值C,68.43;H,7.14;N,3.56。
1'R＊-6(R1=Ph,R2=Bn,R4=Me):浅黄色油状物。IR(NaCl)νmax3318,1748cm-1;1HNMR(CDCl3)δ7.41-7.26(m,10H),4.54,4.30(AB系统,J2.7,2H),3.75,3.56(AM系统,J13.2,2H),3.33(s,3H),2.77(s,3H),2.76(brs,1H,交换),1.37(s,3H),1.36(s,3H);13CNMR(CDCl3)δ168.1,140.5,138.4,129.7,128.7,128.2,127.8,127.4,105.1,98.6,74.7,63.4,51.5,49.6,49.5,18.3,17.2。MS(ESI)m/z386.2[M+1]+;分析计算值C22H27NO5:C,68.55;H,7.06;N,3.63;实测值C,68.40;H,7.15;N,3.51。
(3R＊,5S＊,6S＊)-3-(1'-N-苄基氨基-3'-甲基-丁基)-5,6-二甲氧基-5,6-二甲基-[1,4]-二噁烷-2-酮(5,6:R1=Me2CHCH2,R2=Bn,R4=Me)。柱色谱:当以低流速在硅胶色谱(AcOEt/环己烷,1:5)上分离两种异构体时，化合物5和6是不稳定的，并且观察到产率的剧烈下降。由于这个原因，仅有主要异构体5(R1=Me2CHCH2,R2=Bn,R4=Me)以纯的形式分离。或者，当该粗的反应混合物在中性氧化铝色谱(环己烷/Et2O,7:1)上分离时，该化合物的混合物获得较好的产率。方法A:74%。
1'S＊-5(R1=Me2CHCH2,R2=Bn,R4=Me):浅黄色油状物。IR(NaCl)νmax3339,1747cm-1;1HNMR(CDCl3)δ7.37-7.19(m,5H),4.17(d,J2.6,1H),3.78(s,2H),3.28-3.24(m,1H),3.28(s,3H),3.24(s,3H),1.90(brs,1H,交换),1.80-1.60(m,1H),1.50-1.38(m,2H),1.46(s,3H),1.37(s,3H),0.91(d,J6.6,3H),0.86(d,J6.3,3H);13CNMR(CDCl3)δ170.1,141.2,128.5,128.3,126.9,105.0,98.3,72.5,57.5,51.8,50.1,49.3,40.8,25.4,23.0,22.98,18.2,17.1。分析计算值C20H31NO5:C,65.73;H,8.55;N,3.83;实测值C,65.60;H,8.70;N,3.71。
(3R＊,5S＊,6S＊)-3-(1'--N-n-丁基-1'-苯基-甲基)-5,6-二甲氧基-5,6-二甲基-[1,4]-二噁烷-2-酮(5,6:R1=Ph,R2=Me(CH2)3,R4=Me)。柱色谱:AcOEt/环己烷,1:5;方法A:68%(3.2:1),5:52%,6:16%。
1'S＊-5(R1=Ph,R2=Me(CH2)3,R4=Me):浅黄色油状物。IR(NaCl)νmax3343,1755cm-1;1HNMR(CDCl3)δ7.33-7.21(m,5H),4.26,4.22(AB系统,J2.7,2H),3.31(s,3H),3.11(s,3H),2.55-2.20(m,3H,1H交换),1.55-1.20(m,4H),1.44(s,3H),1.35(s,3H),0.83(t,J7.0,3H);13CNMR(CDCl3)δ169.2,139.9,128.3,128.2,127.3,104.9,98.4,75.5,63.9,49.9,49.3,46.7,32.6,20.5,18.1,17.0,14.2。MS(ESI)m/z352.1[M+1]+;分析计算值C19H29NO5:C,64.93;H,8.32;N,3.99;实测值C,64.80;H,8.47;N,3.87。
1'R＊-6(R1=Ph,R2=Me(CH2)3,R4=Me):浅黄色油状物。IR(NaCl)νmax3323,1747cm-1;1HNMR(CDCl3)δ7.37-7.24(m,5H),4.53,4.24(AB系统,J3.5,2H),3.32(s,3H),2.75(s,3H),2.75-2.40(m,3H,1H交换),1.60-1.20(m,4H),1.35(s,3H),1.33(s,3H),0.86(t,J7.1,3H);13CNMR(CDCl3)δ168.1,138.4,129.4,127.5,127.4,104.9,98.5,74.0,63.7,49.4,49.3,47.2,32.3,20.6,18.1,17.0,14.2。MS(ESI)m/z352.1[M+1]+;分析计算值C19H29NO5:C,64.93;H,8.32;N,3.99;实测值C,64.78;H,8.43;N,3.88。
(3R＊,5S＊,6S＊,1'S＊)-3-(1'-N-苄基氨基-1'-苯基-甲基)-5,6-二乙氧基-5,6-二甲基-[1,4]-二噁烷-2-酮(5:R1=Ph,R2=Bn,R4=Et)。方法A:74%;Mp154°C,分解(CH2Cl2/Et2O)。IR3344,1749cm-1;1HNMR(CDCl3)δ7.38-7.17(m,10H),4.30,4.23(AB系统,J2.5,2H),3.66,3.43(AM系统,J13.2,2H),3.73-3.19(m,4H),3.00-2.00(br,1H,交换),1.49(s,3H),1.38(s,3H),1.06(t,J6.9,3H),0.87(t,J6.9,3H);13CNMR(CDCl3)δ169.2,140.5,139.7,128.6,128.5,128.4,128.3,127.5,127.0,105.0,98.2,75.5,63.2,58.3,57.3,50.8,18.9,17.7,15.2,15.1。MS(ESI)m/z414.0[M+1]+;分析计算值C24H31NO5:C,69.71;H,7.56;N,3.39;实测值C,69.58;H,7.68;N,3.27。
(3R＊,5S＊,6S＊1'S＊)-3-(1'-N-苄基氨基-1'-(3,4-亚甲二氧基)苯基-甲基)-5,6-二乙氧基-5,6-二甲基-[1,4]-二噁烷-2-酮(5:R1=Ph,R2=3,4-OCH2O-Ph,R4=Et)。87%.Mp112°C(正戊烷/CH2Cl2);IR(NaCl)νmax3459,1736cm-1;1HNMR(CDCl3)δ7.26-7.22(m,5H),6.94(s,1H),6.77(s,2H),5.98(s,2H),4.18(brs,2H),3.65,3.42(AM系统,J13.2,2H),3.78-3.20(m,4H),2.55-1.80(br,1H,交换),1.49(s,3H),1.40(s,3H),1.09(t,J7.0,3H),0.88(t,J7.0,3H);13CNMR(CDCl3)δ169.0,147.9,147.0,140.5,133.9,128.6,128.3,127.0,122.0,108.6,108.1,104.9,101.1,98.2,75.6,62.9,58.3,57.4,50.6,18.9,17.8,15.2,15.0。MS(ESI)m/z458.1[M+1]+;分析计算值C25H31NO7:C,65.63;H,6.83;N,3.06;实测值C,65.45;H,7.00;N,2.96。
化合物5和6甲醇解的通用方法：在搅拌下于25°C将化合物5(R1=Ph,R2=Bn,R4=Me;R1=Ph,R2=Bn,R4=Et)或6(R1=Ph,R2=Bn,R4=Me)(0.225mmol)溶于0.5M的TMSCl在MeOH的溶液中(1.0ml,0.5mmol)持续10分钟。除去溶剂，并将残余物结晶，得到纯的化合物1或1'(R1=Ph,R2=Bn)[1:97%，来自5(R1=Ph,R2=Bn,R4=Me);1:95%，来自5(R1=Ph,R2=Bn,R4=Et);1':80%，来自6(R1=Ph,R2=Bn,R4=Me)。
“一锅”法制备3-(氨基)-2-羟基-丙酸甲酯衍生物1/1'方法C)：按照通用方法进行4(R1=Ph,R2=Bn)和3(R4=R5=Et)之间的反应。粗的反应混合物的1HNMR分析显示存在非对映异构体5(R1=Ph,R2=Bn,R4=Et)和仅有痕量的6(R1=Ph,R2=Bn,R4=Et)(HPLC:ASCENTISSI150x4.6mm,3μm,0.8mL/min,λ=210nm,正己烷/异丙醇,98:2;92:8)。按照上文所述的方法将粗的反应混合物用MeOH/TMSCl处理，并在重结晶后获得甲基酯衍生物1(R1=Ph,R2=Bn,R3=Me)(60%)。其余部分的化合物1(R1=Ph,R2=Bn,R3=Me;10%)在硅胶柱色谱(环己烷/AcOEt,4:1)后分离。方法D):在氮气中操作，在分子筛(60mg,在200°C下在真空中活化2小时)的存在下将合适的醛(0.59mmol)和苄基胺(79μL,0.59mmol)溶于MeCN(1.5mL)中，并将该混合物搅拌1小时。或者，亚胺4在MeCN中生成，随后将共沸混合物MeCN/H2O蒸发。加入MeCN(2mL)，并将该混合物搅拌10分钟，蒸发溶剂。重复相同的方案，并最后加入MeCN(1.5mL)。将反应混合物在-30°C下冷却，随后加入化合物3(R4=R5=Et)(0.59mmol)和催化剂(InCl3或MgBr2,0.29mmol)，并继续搅拌1小时。将粗的反应混合物按照上文所述甲醇解的方法用MeOH/TMSCl处理，并在结晶后或者快速硅胶柱色谱后分离甲基酯衍生物1。
3-(苄基氨基)-2-羟基-3-苯基-丙酸甲酯:d.e.83%(柱色谱(AcOEt/环己烷,1:4)。(2R＊,3S＊):74%。Mp107°C(正戊烷/Et2O),(107-108°C)9。1HNMR(CDCl3)δ7.41-7.22(m,10H),4.26,3.95(AX系统,J4.1,2H),3.77,3.49(AM系统,J13.2,2H),3.70(s,3H),3.00-2.00(br,2H,交换)。(2R＊,3R＊):10%。Mp99°C(正戊烷/CH2Cl2),(98-99°C)9。1HNMR(CDCl3)δ7.38-7.22(m,10H),4.54,4.06(AX系统,J4.0,2H),3.78,3.61(AM系统,J12.8,2H),3.60(s,3H),3.00-2.00(br,2H,交换)。
3-(苄基氨基)-2-羟基-3-(4-硝基苯基)-丙酸甲酯:d.e.83%(柱色谱:AcOEt/环己烷,1:3)。(2R＊,3S＊):74%。Mp147-149°C(正己烷/CH2Cl2).IR(KBr)νmax3491,1729cm-1;1HNMR(CDCl3)δ8.23,7.53（AA'XX'系统,J8.8,4H),7.38-7.10(m,5H),4.25,4.06(AM系统,J3.3,2H),3.76,3.43(AM系统,J13.5,2H),3.75(s,3H),3.20-2.00(brs,2H,交换)。13CNMR(CDCl3)δ173.4,147.9,147.6,139.6,128.9,128.5,128.3,127.4,123.9,74.6,62.9,52.8,50.8。MS(ESI+)m/z353.1。
3-(苄基氨基)-2-羟基-3-(4-甲氧基苯基)-丙酸甲酯:d.e.83%.柱色谱(AcOEt/环己烷,1:3)。(2R＊,3S＊):72%。IR(KBr)νmax3491,1733cm-1;1HNMR(CDCl3)δ7.40-7.18(m,7H),6.90(d,J8.8,2H),4.22,3.89(AM系统,J4.1,2H),3.82(s,3H),3.75,3.47(AM系统,J13.2,2H),3.70(s,3H),2.80-1.90(brs,2H,交换)。
3-(苄基氨基)-2-羟基-3-(4-氯苯基)-丙酸甲酯:d.e.82%.柱色谱(AcOEt/环己烷,1:4)。(2R＊,3S＊):73%。Mp106-108°C(正己烷/CH2Cl2)。IR(KBr)νmax3491,1729cm-1;1HNMR(CDCl3)δ7.40-7.10(m,9H),4.21,3.91(AM系统,J3.6,2H),3.71(s,3H),3.75,3.45(AM系统,J14.5,2H),3.70(s,3H),2.80-1.90(brs,2H,交换)。
3-(苄基氨基)-2-羟基-5-甲基-己酸甲酯:d.e.87%(柱色谱:Et2O/正己烷,1:4)。(2R＊,3S＊):68%。Mp89-90°CIR(NaCl)νmax3467,1739cm-1;1HNMR(CDCl3)δ7.40-7.20(m,5H),4.05(d,J2.2,2H),3.80-3.60(2H,overl.),3.73(s,3H),3.03(dt,J7.0,1.8,1H),2.50-2.05(br,2H,交换),1.80-1.60(m,1H),1.50-1.20(m,2H),0.92(d,J1.8,3H),0.86(d,J1.8,3H);13CNMR(CDCl3)δ175.3,140.5,128.5,128.4,127.3,72.0,57.4,52.3,52.0,41.6,25,3,23.0,22.7。MS(ESI+)m/z266.1。
3-(苄基氨基)-2-羟基-3-噻吩基-丙酸甲酯:d.e.79%(柱色谱AcOEt/环己烷,1:4)。(2R＊,3S＊):73%。油状物。IR(NaCl)νmax3467,1739cm-1;1HNMR(CDCl3)δ7.38-7.20(m,6H),7.03-6.95(m,2H),4.33,4.22(AB系统,J3.7,2H),3.83,3.55(AM系统,J13.5,2H),3.74(s,3H),3.00-2.00(br,2H,交换);13CNMR(CDCl3)δ173.6,143.6,140.0,128.5,128.4,127.3,126.6,126.0,125.3,75.2,59.2,52.7,50.8。MS(ESI+)m/z314.1。
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Claims (9)
1.通式1化合物的制备方法
其中R1是直链或支链的(C1-C6)-烷基基团，或噻吩基；R2是直链或支链的(C1-C6)-烷基基团、苄基；R3是H、(C1-C4)-烷基基团，
包括：
-将通式3的硅烷基烯醇酯，其中R4是Me、Et且R5是Me、Et，和通式4的亚胺反应，其中R1和R2如上文所定义；
-将所得的通式(3R*,5S*,6S*,1'S*)-5和(3R*,5S*,6S*,1'R*)-6的中间体醇解或水解，其中R1和R2如上文所定义；R4是Me或Et基团，
2.如权利要求1所述的方法，其中化合物3和4之间的缩合由质子酸和路易斯酸催化。
3.如权利要求2所述的方法，其中缩合是在选自InCl3、SnCl2或MgBr2的路易斯酸催化下进行。
4.如权利要求2所述的方法，其中缩合温度是从-40℃到-30℃的范围。
5.如权利要求2所述的方法，其中缩合是在疏质子的极性溶剂中进行，所述溶剂选自二甲基甲酰胺、乙腈、二氯甲烷、氯仿、四氢呋喃。
6.如权利要求1-5中任一项所述的方法，其中使用醇R3OH在三甲基硅烷基氯的存在下进行醇解，其中R3是(C1-C4)-烷基基团。
7.如权利要求1-5中任一项所述的方法，其是以“一锅反应”方式进行，不必分离中间体，通过结晶获得最终的纯的苏式非对映异构体。
8.如权利要求7所述的方法，包括：
-从醛R1CHO和胺R2NH2在乙腈中于室温下，并在分子筛的存在下或者通过乙腈/水共沸混合物的蒸馏原位生成亚胺4，其中R1和R2如权利要求1所定义；
-在-30℃下加入硅烷基衍生物3，随后加入催化剂；
-将粗的反应混合物用三甲基硅烷基氯的醇溶液处理，并在结晶后分离纯的非对映异构体(2R*,3S*)-1，其中R3是(C1-C4)-烷基基团。
9.如权利要求8所述的方法，其中胺R2NH2是PhCH2NH2。
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| CN1051725A (zh) * | 1989-11-16 | 1991-05-29 | 美国辉瑞有限公司 | 戊二酸衍生物及其制备方法 |
| US5767316A (en) * | 1995-11-17 | 1998-06-16 | Ajinomoto Co., Inc. | Process for producing 3-amino-2-oxo-1-halogenopropane derivatives |
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