CN111836899A - 制备用于通过酶还原合成光学活性β-氨基醇的中间体的方法以及新型合成中间体 - Google Patents
制备用于通过酶还原合成光学活性β-氨基醇的中间体的方法以及新型合成中间体 Download PDFInfo
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- CN111836899A CN111836899A CN201880080914.XA CN201880080914A CN111836899A CN 111836899 A CN111836899 A CN 111836899A CN 201880080914 A CN201880080914 A CN 201880080914A CN 111836899 A CN111836899 A CN 111836899A
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Abstract
本发明的主题是制备中间体的方法，该中间体用于通过酶还原相应的β‑氨基酮来合成光学活性的β‑氨基醇。本发明的主题还是所述新型合成中间体及其在制备活性药物成分中的用途，所述活性药物成分包括维兰特罗及其盐等。
Description
****
本发明的主题是制备中间体的方法，该中间体用于通过酶还原相应的β-氨基酮来合成光学活性的β-氨基醇。本发明的主题还是所述新型合成中间体及其在制备活性药物成分中的用途，所述活性药物成分包括维兰特罗及其盐等。
技术领域
氨基醇，特别是手性苯基-β-氨基醇是合成活性药物成分中非常重要的合成子；它们的基本结构例如存在于激素肾上腺素和去甲肾上腺素中，用于治疗心脏疾病的药物(例如索他洛尔和阿布他明(arbutamine))中，用于治疗哮喘或慢性阻塞性肺疾病(COPD)的药物(例如维兰特罗，沙丁胺醇，可尔特罗(colterol)，异丙肾上腺素)中，以及其他天然产物(例如天然抗病毒产物 (+)替巴胺(tembamide))中。
光学活性β-氨基醇也具有工业意义，因为它们可用作不同类型的不对称合成中的手性配体或助剂。
鉴于此类分子的重要性，这些年来已经开发了许多合成方法。
最初，最常用的合成途径是外消旋氨基醇的光学活性化学化合物的手性拆分，因为其在光学纯度方面很有希望，但是不幸的是，这种合成途径在产率上并不方便。
最近已经开发了不同的对映选择性合成方法，就产率而言，其比拆分更有效。例如，已知基于化学还原酮的方法和基于在立体选择性催化剂和配体存在下氢化的方法。
化学类型的对映选择性还原意味着使用潜在危险的试剂，非常昂贵的配体，并且通常不会产生对映体过量高于97-98％的醇。因此，获得的粗化合物需要随后的纯化。
氢化通常涉及使用高压，昂贵的金属催化剂，并且由于过度的还原(“过还原”)或由于分子其他部分的次级反应，常常会产生杂质。
还已知使用能够将羰基还原为羟基的生化试剂。在这些生化方法中，最常用于此类反应的是使用酵母菌。但是，酵母菌的使用带来许多缺点，例如由于往往逐渐改变的酵母菌的杂交品种的增殖，因为需要高度稀释而导致随时间推移结果难以再现，以及由于存在大量生物质而导致的所需产物的难以收集。
如申请WO2017/001907中所述，另一种生化方法提供了使用酶进行羰基、特别是α-卤素-酮的对映选择性还原。该方法提供了将卤代酮还原为卤代醇，然后用胺进行烷基化以产生所需氨基醇。缺点是，在存在胺(碱)的情况下，卤代醇往往会生成相应的环氧化物，在胺本身存在的情况下，该环氧化物会在1和2位低选择性地打开，从而导致副产品的形成。
反应方案：
因此，在WO2017/001907中使用的过程中，在酶还原结束时，对苄基 OH进行保护，以在胺烷基化之后将其脱保护。
为了解决上述问题，申请人尝试将β-氨基酮直接酶还原为β-氨基醇，以使胺基已经引入在所需的位置。然而，在这种类型的底物上使用酶表现出相当大的困难，并且不能有效地进行还原。
发明目的
本发明的目的是提供一种适合制备用于合成光学活性β-氨基醇的中间体的方法，即使在工业规模上也具有良好的产率和高的对映体过量。
本发明的另一个目的是提供一种适合于制备用于合成光学活性β-氨基醇的中间体的酶法，该方法克服了现有技术的缺点。
本发明的另一个目的是提供新颖的中间体，该中间体可以具体但不仅限于用于制备维兰特罗，肾上腺素，去甲肾上腺素，R-沙丁胺醇，R-可尔特罗，R-异丙肾上腺素，(-)-阿布他明及其盐。
发明详述
申请人惊人地发现，通过使用其中胺基已经失去了其碱性(例如通过转化成酰胺，酰亚胺或氨基甲酸酯基)的β-氨基酮，可以对其进行酶还原，获得光学活性氨基醇，其具有高产量和纯度。
因此，根据其中一个方面，本发明的主题是制备式(I)的光学活性化合物的方法，
其中，
-星号表示手性碳为(S)型或(R)型；
-X表示通过氮原子与式(I)的化合物连接的酰胺，酰亚胺或氨基甲酸酯残基；
-R1和R2独立地选自氢、-OPr、-CH2OPr、-OH、-CH2OH和C1-C4-烷氧基；其中Pr是羟基保护基，并且当式(I)的化合物中有两个Pr保护基时：
-所述两个Pr保护基可以彼此相同或不同；或
-所述两个Pr保护基与它们所连接的氧原子一起，可以形成与苯稠合的环；
所述方法包括式(II)的化合物的酶还原，
其中，X、R1和R2如上所定义。
根据一个优选的实施方式，式(I)的化合物为式(I’)的化合物，
其中，
-星号、R1和R2如上所定义；
-R3选自氢、烷基、烷氧基、芳基、烷基芳基和芳基烷基；
-R4选自氢、烷基、芳基、烷基芳基和芳基烷基；
或者
-R3和R4与它们所键合的羧酰胺基(HN-C＝O)一起构成酰亚胺。
在本文中，表述“手性碳为(S)型或(R)型”是指至少80％、优选至少90-95 ％、更优选98-99.9％的式(I)和(I’)的化合物为所述构型。
根据一个优选的实施方式，式(I)和(I’)的化合物的手性碳为(R)构型。
本文中的术语“烷基”是指饱和的，直链或支链的烷基残基，优选具有 1-6个碳原子，有利地具有1-4个碳原子，例如甲基或乙基。
本文中的术语“烷氧基”是指饱和的，直链或支链的烷氧基残基，优选具有1-6个碳原子，有利地具有1-4个碳原子，例如甲基或乙基。
本文中的术语“芳基”是指芳烃残基，优选自苯基和萘基。
本文中的术语“烷基芳基”是指被一个或多个如上所定义的烷基取代的芳族烃残基，优选自苯基和萘基。
术语“芳基烷基”在本文中是指被一个或多个如上所定义的芳基取代的如上所定义的饱和的，直链或支链的烷基残基，优选具有1至6个碳原子，有利地具有1至4个碳原子。
表述“羟基保护基”是指能够保护羟基功能而不干扰还原反应的任何保护基。这样的基团可以例如选自以下文献中提及的那些：T.W.Greene，约翰威立公司(John Wiley&Sons,Ltd)，“有机合成中的保护基(Protective Groups in Organic Synthesis)”，第5版，2014。
根据本发明的优选实施方式，如上所定义的-OPr基包括酯和丙酮化物。
根据本发明的其他保护基包括硅烷，例如甲硅烷基；或者，当存在两个Pr基时，所述硅烷保护基与它们所连接的两个氧原子一起可以形成与苯稠合的环。
根据另一个实施方式，当基团R1和R2在相邻的碳原子上并且有两个 Pr基时，所述两个Pr基表示连接至两个氧原子的羰基(＝CO)。
根据一个优选的实施方式，R1和R2均为-OH或OPr，其中Pr基可以彼此相同或不同，优选是相同的。
根据另一个优选的实施方式，R1和R2中的一个是OH或-OPr，另一个是-CH2OH或–CH2OPr。
根据另一个优选的实施方式，R1和R2与氢不同并且在苯环的相邻位置上，优选在苯环的3位和4位上。
根据另一个优选的实施方式，当R1和R2各自独立地为-OPr或-CH2OPr 时，它们形成与苯环稠合的环；在这种情况下，根据一个更优选的实施方式，它们位于苯环的相邻位置。
根据一个优选的实施方式，R3是氢，饱和的直链C1-C6烷基，优选甲基或乙基，R4是氢或甲基。
根据另一个优选的实施方式，R3和R4与它们所键合的羧酰胺基一起表示可能被取代的琥珀酰亚胺或邻苯二甲酰亚胺，有利地是琥珀酰亚胺或取代的琥珀酰亚胺，例如具有一个或多个氟原子。
优选的式(II)的化合物选自以下化合物：
其中X是选自以下的取代基：
其中ALK表示如上所定义的烷基，有利地是甲基或乙基，所述取代基 X通过氮原子与该分子连接，如虚线所示。
根据一个特别优选的实施方式，本发明的主题是制备式(I”)的光学活性化合物的方法，
其中，
-星号、R1和R2如上所定义；
-R3和R4与它们所键合的羧酰胺基(HN-C＝O)一起构成酰亚胺，
所述方法包括式(II”)的化合物的酶还原，
其中R1、R2、R3和R4如上所定义。
根据最后一个实施方式，优选地，Pr基形成与苯稠合的环，有利地具有下式：
仍然根据最后一个实施方式，优选地，所述酰亚胺是琥珀酰亚胺。
式(II)和(II”)的化合物可以根据本领域已知的方法容易地制备。
本发明的方法优选使用至少一种氧化还原酶，其优选是源自酵母菌或细菌，有利地源自细菌的多肽。
对映选择性酶还原可以通过使用悬浮在反应混合物中或者根据已知技术固定的氧化还原酶来进行。该酶可以被纯化，仅被部分纯化或可以被包含在细胞中。细胞本身可以处于天然状态，渗透状态或裂解状态。优选地，该酶在大肠杆菌(E.coli)中表达，并作为天然细胞的悬浮液使用。
根据一个优选的实施方式，在至少一种辅因子和至少一种使所述辅因子再生的共底物的存在下，用至少一种氧化还原酶进行所述酶还原。
式(II)或(II”)的化合物的酶还原过程可以例如在包含所述式(II)的化合物、氧化还原酶、作为辅因子的NADH或NADPH、共底物的反应混合物中进行。
根据一个优选的实施方式，在本发明的方法中使用的所述至少一种氧化还原酶具有选自以下的序列：序列SEQ ID No:1，在下文中也表示为“OX 56”，如EP1963516(IEP)中所述，和SEQ ID N°:2，在下文中也表示为“OX 62”，如EP1929001(巴斯夫(BASF))中所述。
根据一个更优选的实施方式，在本发明的方法中使用的所述至少一种氧化还原酶具有序列SEQ ID No:1。
该序列在本文所附的序列表中描述，并如下所示：
SEQ ID NO.1
Met Arg Leu Lys Gly Lys Ala Ala Ile Val Thr Gly Gly Ala Ser Gly IleGly Arg Ala Thr Ala Ile Arg Phe Ala Glu Glu Gly Ala Lys Val Ala Val Ser AspIle Asn Glu Glu Gly Gly Glu Glu Thr Val Arg Leu Ile Arg Glu Lys Gly Gly GluAla Ile Phe Val Gln Thr Asp Val Ala Asp Ser Lys Gln Val Ser Arg Leu Val GlnThr Ala Val Asp Ala Phe Gly Gly Leu His Ile Leu Phe Asn Asn Ala Gly Ile GlyHis Ser Glu Val Arg Ser Thr Asp Leu Ser Glu Glu Glu Trp Asp Arg Val Ile AsnVal Asn Leu Lys Gly Val Phe Leu Gly Ile Lys Tyr Ala Val Pro Val Met Lys GlnCys Gly Gly Gly Ala Ile Val Asn Thr Ser Ser Leu Leu Gly Ile Lys Gly Lys LysTyr Glu Ser Ala Tyr Asn Ala Ser Lys Ala Gly Val Ile Leu Leu Thr Lys Asn AlaAla Leu Glu Tyr Gly Lys Phe Asn Ile Arg Val Asn Ala Ile Ala Pro Gly Val IleAsp Thr Asn Ile Ile Thr Pro Trp Lys Gln Asp Glu Arg Lys Trp Pro Ile Ile SerLys Ala Asn Ala Leu Gly Arg Ile Gly Thr Pro Glu Glu Val Ala Asn Ala Val LeuPhe Leu Ala Ser Asp Glu Ala Ser Phe Ile Thr Gly Ala Thr Leu Ser Val Asp GlyGly Gly Leu Thr Phe
SEQ ID No.2
Met Thr Thr Thr Ser Asn Ala Leu Val Thr Gly Gly Ser Arg Gly Ile GlyAla Ala Ser Ala Ile Lys Leu Ala Gln Glu Gly Tyr Asn Val Thr Leu Ala Ser ArgSer Val Asp Lys Leu Asn Glu Val Lys Ala Lys Leu Pro Ile Val Gln Asp Gly GlnLys His Tyr Ile Trp Glu Leu Asp Leu Ala Asp Val Glu Ala Ala Ser Ser Phe LysGly Ala Pro Leu Pro Ala Arg Ser Tyr Asp Val Phe Val Ser Asn Ala Gly Val AlaAla Phe Ser Pro Thr Ala Asp His Asp Asp Lys Glu Trp Gln Asn Leu Leu Ala ValAsn Leu Ser Ser Pro Ile Ala Leu Thr Lys Ala Leu Leu Lys Asp Val Ser Glu ArgPro Val Asp Lys Pro Leu Gln Ile Ile Tyr Ile Ser Ser Val Ala Gly Leu His GlyAla Ala Gln Val Ala Val Tyr Ser Ala Ser Lys Ala Gly Leu Asp Gly Phe Met ArgSer Val Ala Arg Glu Val Gly Pro Lys Gly Ile His Val Asn Ser Ile Asn Pro GlyTyr Thr Lys Thr Glu Met Thr Ala Gly Ile Glu Ala Leu Pro Asp Leu Pro Ile LysGly Trp Ile Glu Pro Glu Ala Ile Ala Asp Ala Val Leu Phe Leu Ala Lys Ser LysAsn Ile Thr Gly Thr Asn Ile Val Val Asp Asn Gly Leu Ile Ala
已发现，具有的氨基酸序列中的至少60％、优选至少80％、有利地至少90％的氨基酸与SEQ ID No:1和SEQ ID No:2的氨基酸序列相同的多肽导致以高产率和高对映异构体选择性以(R)构型还原式(II)或(II”)的化合物。实际上，所获得的(R)构型的式(I)、(I’)和(I”)的化合物的对映体过量为至少约90％，优选至少约95％，更优选至少约99％。
根据本发明的一个有利的实施方式，辅因子选自烟酰胺腺嘌呤二核苷酸磷酸(NADP)和烟酰胺腺嘌呤二核苷酸(NAD)。
辅因子优选在反应混合物中的浓度为约0.01mM至约5mM，有利地为约0.05mM至约0.5mM。
根据本发明的一个有利的实施方式，共底物是仲醇，优选地是至多10 个碳原子的仲醇，例如2-丙醇，2-丁醇，2-戊醇，4-甲基-2-戊醇，2-庚醇和 2-辛醇，优选2-丙醇或4-甲基-2-戊醇，更优选2-丙醇。
根据一个优选的实施方式，共底物在反应混合物中的存在量为约10％至约80％(v/v)，更优选为约10％至约50％，有利地为15-25％。
优选地，在溶剂中，有利地在合适的缓冲剂的存在下，进行式(II)或(II”) 的化合物的酶还原过程。
根据已知技术，本发明的酶还原反应可以在单相体系或水/有机溶剂类型的双相体系中进行。在后一种情况下，可以将不参与辅因子再生的有机溶剂加入反应混合物中。这类溶剂的例子包括乙醚、叔丁基甲醚、二异丙醚、二丁醚、乙酸乙酯、乙酸丁酯、庚烷、己烷或环己烷。基于反应混合物的体积，这种溶剂可以以约1体积％至50体积％的比例存在。
当酶作为天然细胞的悬浮液使用时，反应混合物优选还原产生的每千克粗产物包含约100至2000g细胞。
所用的缓冲液可以例如选自磷酸钾缓冲液或三乙醇胺缓冲液，并且可以还包含用于使得酶稳定化的离子，例如镁离子源。可以存在于缓冲液中以使得酶稳定化的其他添加剂可以包括多元醇，例如甘油，山梨糖醇等；硫化合物，例如1,4-DL-二硫苏糖醇，谷胱甘肽，半胱氨酸等；氨基酸和肽或洗涤剂，例如DMSO。
优选的酶的稳定剂是多元醇，特别是甘油，其可以基于细胞悬浮液的重量以约10-80重量％，优选约50重量％的比例存在。
在式(II)或(II”)的化合物的还原过程中形成的氧化的辅因子通过共底物的氧化而再生，并且该氧化也可以通过氧化还原酶本身来催化。因此，本方法的特别实用且经济的优点是氧化还原酶既影响式(I)、(I’)和(I”)的化合物的还原，又影响共底物的氧化，因此不需要使用其他酶来进行辅因子的再生。
在添加所有组分之后，反应混合物的pH将在5至10之间，优选地在 7至9之间，并且最佳地为约7.5。根据本发明的酶还原在约10-45℃，优选约20-40℃，优选约35-40℃的温度下进行。
除了以高产率和高对映异构体选择性提供式(I)、(I’)和(I”)的醇之外，对映选择性还原的方法也是方便且环保的。
在上述反应条件下，在氧化还原酶的存在下，在约2-96小时内，优选在约4-24小时内，可以得到具有高光学纯度的(R)构型的式(I)、(I’)和(I”) 的化合物。在孵育期间，混合物的pH优选保持在上述范围内。对映选择性酶还原的效率可以用总转换数(TTN)表示，该总转换数是每摩尔所用辅因子产生的式(I)、(I’)和(I”)的手性醇的摩尔数。对映选择性酶还原的TTN为约 102至105，优选＞103。
根据一个实施方式，如上所述，在本发明的方法中使用的至少一种氧化还原酶具有选自序列SEQ.ID No:1和SEQ.ID No:2的序列。
除了序列SEQ ID No:1和SEQ ID No:2之外，还发现具有的氨基酸序列中的至少60％、优选至少80％、有利地至少90％的氨基酸与SEQ ID No: 1和SEQ ID No:2的氨基酸序列相同的多肽导致以高产率和高对映异构体选择性以(R)构型还原式(II)或(II”)的化合物。实际上，式(I)或(I’)的化合物的对映体过量为至少约90％，优选至少约95％，更优选至少约99％。
根据一个优选的实施方式，本发明的主题是对映体选择性还原如上报道的优选的式(II)和(II”)的化合物的方法，该方法包括使用选自序列SEQ.ID No:1和SEQ.ID No:2的至少一种酶，或具有的氨基酸序列中的至少60％、优选至少80％、有利地至少90％的氨基酸与SEQ ID No:1和SEQ ID No:2 的氨基酸序列相同的多肽。
根据本领域技术人员熟知的技术，例如通过用碱或酸处理，可以容易地将式(I)，(I’)和(I”)的化合物转化为相应的光学活性β-氨基醇。
上述反应的一些详细实例在以下实验部分中报道。
因此，可以理解，以完全出乎意料的方式发现，只要胺基被剥夺其碱性，就可以将β-氨基酮进行酶还原以产生光学活性的β-氨基醇。这个事实根本无法事先想到，其是立体选择性还原领域的重要技术进步。
式(I)、(I’)和(I”)的化合物是通用的合成中间体，并且可以容易地转化为活性药物成分，例如肾上腺素、去甲肾上腺素、维兰特罗、R-沙丁胺醇、 R-可尔特罗、R-异丙肾上腺素、(-)-阿布他明等。
根据另一方面，本发明的主题是选自以下化合物及其盐和/或水合物和 /或溶剂化物的式(I)的化合物：
根据另一方面，本发明的主题是选自以下化合物及其盐和/或水合物和 /或溶剂化物的式(II)的化合物：
根据另一方面，本发明的主题是使用选自式(I)、(I’)、(I”)、(II)或(II”)的化合物中的至少一种化合物制备选自肾上腺素和去甲肾上腺素或其盐中的一种的化合物。
根据另一方面，本发明的主题是使用选自式(I)、(I’)、(I”)、(II)或(II”)的化合物中的至少一种化合物制备维兰特罗或其盐中的一种。
根据另一方面，本发明的主题是使用具有式B、C的化合物及其盐和/ 或水合物和/或溶剂化物来制备维兰特罗的用途：
根据另一方面，本发明的主题是使用具有式Y、Z的化合物及其盐和/ 或水合物和/或溶剂化物来制备维兰特罗的用途：
在以下实验部分中描述的实施例仅是出于说明的目的，绝非限制性的。
实验部分
缩写
DMF＝二甲基甲酰胺
DCM＝二氯甲烷
MTBE＝甲基叔丁基醚
IPA＝2-丙醇
MP＝4-甲基-2-戊醇
THF＝四氢呋喃
DMS＝二甲基硫醚
分析方法
-UPLC纯度法(沃特斯公司(Waters)的Acquity UPLCTM)：
固定相：BEH SHIELD RP18 1.7μm 2.1x 50mm柱，流动相：H2O+ 0.05％TFA，CH3CN+0.05％TFA，梯度：5％至100％CH3CN。
-手性HPLC方法(HPLC Agilent 1200)：
固定相：CHIRALPAK AD-H 250x 4.6mm-5*m，流动相：庚烷/ MeOH/iPrOH 90:5:5+0.1％乙醇胺。
制备例1
酶溶液的制备
已用编码氧化还原酶的构建体pET21a-MIX转化了感受态大肠杆菌细胞Starbl21(DE3)(英杰公司(Invitrogen))。分别在含50μg/ml氨苄青霉素或 40μg/ml卡那霉素的200ml LB培养基(1％胰蛋白胨，0.5％酵母膏和1％ NaCl)中培养用构建体转化的细胞集落，直至在550nm处测得的光密度达到0.5。通过添加浓度为0.1mM的异丙基硫代半乳糖苷(IPTG)诱导重组蛋白的表达。在25℃和220转/分钟的条件下诱导16小时后，收集细胞并将其在-20℃冷冻。为了制备酶溶液，将30g细胞重悬于150ml三乙醇胺缓冲液(100mM，pH 7，2mM MgCl2，10％甘油)中，并使用高压均质机进行均化。随后，将酶溶液与150ml甘油混合并保存在-20℃。
实施例1
式(II)和(II”)的化合物的制备
Hal＝卤素，优选溴或氯
将5g化合物A(其中Hal＝Cl)溶解在50ml DMF中。将3.5克琥珀酰亚胺钾盐加入该溶液中。反应完全后，加入50ml水和100ml DCM。有机相经硫酸钠干燥，过滤并浓缩至残余物。添加60ml庚烷和10ml DCM，然后过滤本体，收集4.7g化合物B，以干燥形式提供4.5g化合物B，HPLC 纯度高于99％。
实施例2
将1g化合物B溶解在3ml 2-丙醇和4ml MTBE中。添加13ml pH＝8 的水性钾缓冲液，1mg NAD和5ml酶SEQ ID No:1(OX 56)。将本体在约35℃下搅拌直至酮完全转化为醇。分离的水相用DCM萃取两次，然后将有机相合并并浓缩至固体。产量900mg，HPLC纯度>96％，未检测到S 醇(手性HPLC分析)。
通过按照实施例2中所述进行操作，对化合物B和以下化合物进行了反应，条件和结果如表(I)所示：
实施例3
将350mg化合物C溶于11ml乙醇和约1g的20％苛性钠(20g/100ml) 中。将本体加热至回流并保持约1小时。在室温下用DCM萃取本体，然后将其用硫酸钠干燥，过滤并浓缩至残余物，从而获得210mg的化合物H。
序列表
<110> 欧伦股份公司 (OLON S.p.a.)
<120> 制备用于通过酶还原合成光学活性β-氨基醇的中间体的方法以及新型合成中间体
<130> 181223AD57
<160> 2
<170> PatentIn version 3.5
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<212> PRT
<213> 嗜热脱氮地芽孢杆菌 (Geobacillus thermodenitrificans)
<400> 1
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Ile Gly Arg Ala Thr Ala Ile Arg Phe Ala Glu Glu Gly Ala Lys Val
20 25 30
Ala Val Ser Asp Ile Asn Glu Glu Gly Gly Glu Glu Thr Val Arg Leu
35 40 45
Ile Arg Glu Lys Gly Gly Glu Ala Ile Phe Val Gln Thr Asp Val Ala
50 55 60
Asp Ser Lys Gln Val Ser Arg Leu Val Gln Thr Ala Val Asp Ala Phe
65 70 75 80
Gly Gly Leu His Ile Leu Phe Asn Asn Ala Gly Ile Gly His Ser Glu
85 90 95
Val Arg Ser Thr Asp Leu Ser Glu Glu Glu Trp Asp Arg Val Ile Asn
100 105 110
Val Asn Leu Lys Gly Val Phe Leu Gly Ile Lys Tyr Ala Val Pro Val
115 120 125
Met Lys Gln Cys Gly Gly Gly Ala Ile Val Asn Thr Ser Ser Leu Leu
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Gly Ile Lys Gly Lys Lys Tyr Glu Ser Ala Tyr Asn Ala Ser Lys Ala
145 150 155 160
Gly Val Ile Leu Leu Thr Lys Asn Ala Ala Leu Glu Tyr Gly Lys Phe
165 170 175
Asn Ile Arg Val Asn Ala Ile Ala Pro Gly Val Ile Asp Thr Asn Ile
180 185 190
Ile Thr Pro Trp Lys Gln Asp Glu Arg Lys Trp Pro Ile Ile Ser Lys
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Ala Asn Ala Leu Gly Arg Ile Gly Thr Pro Glu Glu Val Ala Asn Ala
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Val Leu Phe Leu Ala Ser Asp Glu Ala Ser Phe Ile Thr Gly Ala Thr
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Leu Ser Val Asp Gly Gly Gly Leu Thr Phe
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<213> 木兰假丝酵母 (Candida magnoliae)
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Met Thr Thr Thr Ser Asn Ala Leu Val Thr Gly Gly Ser Arg Gly Ile
1 5 10 15
Gly Ala Ala Ser Ala Ile Lys Leu Ala Gln Glu Gly Tyr Asn Val Thr
20 25 30
Leu Ala Ser Arg Ser Val Asp Lys Leu Asn Glu Val Lys Ala Lys Leu
35 40 45
Pro Ile Val Gln Asp Gly Gln Lys His Tyr Ile Trp Glu Leu Asp Leu
50 55 60
Ala Asp Val Glu Ala Ala Ser Ser Phe Lys Gly Ala Pro Leu Pro Ala
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Arg Ser Tyr Asp Val Phe Val Ser Asn Ala Gly Val Ala Ala Phe Ser
85 90 95
Pro Thr Ala Asp His Asp Asp Lys Glu Trp Gln Asn Leu Leu Ala Val
100 105 110
Asn Leu Ser Ser Pro Ile Ala Leu Thr Lys Ala Leu Leu Lys Asp Val
115 120 125
Ser Glu Arg Pro Val Asp Lys Pro Leu Gln Ile Ile Tyr Ile Ser Ser
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Val Ala Gly Leu His Gly Ala Ala Gln Val Ala Val Tyr Ser Ala Ser
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Lys Ala Gly Leu Asp Gly Phe Met Arg Ser Val Ala Arg Glu Val Gly
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Pro Lys Gly Ile His Val Asn Ser Ile Asn Pro Gly Tyr Thr Lys Thr
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Glu Met Thr Ala Gly Ile Glu Ala Leu Pro Asp Leu Pro Ile Lys Gly
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Ala
Claims (10)
1.一种制备式(I”)的光学活性化合物的方法，
其中，
-R1和R2独立地选自氢、-OPr、-CH2OPr、-OH、-CH2OH和C1-C4-烷氧基；其中Pr是羟基保护基，并且当式(I”)的化合物中有两个Pr保护基时：
-所述两个Pr保护基可以彼此相同或不同；或
-所述两个Pr保护基与它们所连接的氧原子一起，可以形成与苯稠合的环；
-R3和R4与它们所键合的羧酰胺基(HN-C＝O)一起构成酰亚胺，
所述方法包括式(II”)的化合物的酶还原，
其中R1、R2、R3和R4如上所定义。
2.如权利要求1所述的方法，其特征在于，所述两个Pr保护基与它们所连接的氧原子一起形成与苯稠合的环。
3.如权利要求2所述的方法，其特征在于，所述稠合环具有下式：
4.如权利要求1-3中任一项所述的方法，其特征在于，所述酰亚胺是琥珀酰亚胺。
5.如权利要求1至6中任一项所述的方法，其特征在于，所述酶还原通过至少一种氧化还原酶进行。
6.如权利要求5所述的方法，其特征在于，所述氧化还原酶具有选自序列SEQ ID No:1和SEQ ID No:2的序列，或者具有至少60％、优选至少80％、有利地至少90％的氨基酸与SEQID No:1和SEQ ID No:2的氨基酸序列相同的氨基酸序列。
7.如权利要求6所述的方法，其特征在于，所述氧化还原酶具有序列SEQ ID No:1。
8.如权利要求1-7中任一项所述的方法，其特征在于，在至少一种辅因子和至少一种使所述辅因子再生的共底物的存在下，用至少一种氧化还原酶进行所述酶还原。
9.一种化合物，其选自式B、C、Y、Z的化合物及其盐和/或水合物和/或溶剂化物：
10.如权利要求9所述的化合物在制备维兰特罗中的应用。
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| WO2009040080A1 (en) * | 2007-09-27 | 2009-04-02 | Iep Gmbh | Process for the enantioselective enzymatic reduction of intermediates |
| CN101768149A (zh) * | 2008-12-30 | 2010-07-07 | 成都地奥制药集团有限公司 | 一类新的β-氨基酮(醇)衍生物及其用途 |
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| US20200385366A1 (en) | 2020-12-10 |
| CN111836899B (zh) | 2024-06-25 |
| EP3728618A1 (en) | 2020-10-28 |
| US11053227B2 (en) | 2021-07-06 |
| WO2019123311A1 (en) | 2019-06-27 |
| BR112020012094A2 (pt) | 2020-11-17 |
| CA3085976A1 (en) | 2019-06-27 |
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