CN115461333A - 用于制备手性哌嗪-2-甲酸的方法 - Google Patents
用于制备手性哌嗪-2-甲酸的方法 Download PDFInfo
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- CN115461333A CN115461333A CN202180031458.1A CN202180031458A CN115461333A CN 115461333 A CN115461333 A CN 115461333A CN 202180031458 A CN202180031458 A CN 202180031458A CN 115461333 A CN115461333 A CN 115461333A
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- piperazine
- carboxylic acid
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- hydrolase
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
- C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
本发明涉及用于制备式(I)的手性哌嗪‑2‑甲酸或其盐的新型方法。所述式(I)的手性哌嗪‑2‑甲酸衍生物是用于制备可用于治疗和预防乙型肝炎病毒感染的稠合杂芳基二氢嘧啶的关键中间体。
Description
本发明涉及用于制备式I的手性哌嗪-2-甲酸的新型方法
式I的手性哌嗪-2-甲酸衍生物是用于制备可用于治疗和预防乙型肝炎病毒感染的稠合杂芳基二氢嘧啶的关键中间体(PCT公开WO 2015/132276)。
Eichhorn等人Tetrahedron Asymmetry,Vol.8,No.15,pp.2533-2536,1997已经描述了一种用于制备手性哌嗪-2-甲酸的方法。外消旋哌嗪-2-甲酰胺已能够与来自土生克雷伯氏菌(Klebsiella terrigena)和伯克氏菌属(Burkholderia sp.)的细菌细胞动力学分离。然而，对于技术规模的合成，期望的是使用经分离和表征的酶在更高的酶和底物浓度下运行该方法。因此，本发明的目的是创造一种可以在技术规模上实施的方法。
可以通过以下概述的方法来实现该目的，该方法括以下步骤
a)将式II的吡嗪-2-甲酰胺进行催化氢化
以形成式III的哌嗪-2-甲酰胺
以及
b)将式III的哌嗪-2-甲酰胺用水解酶进行酶促转化，以形成式I的手性哌嗪-2-甲酸或其盐
在此，阐述以下定义以说明和定义用于描述本发明的各种术语的含义和范围。
术语“氨基保护基”是指通常用于阻碍氨基基团的反应性的酸或路易斯酸敏感性取代基。合适的酸或路易斯酸敏感性氨基保护基团在中描述Green T.,“ProtectiveGroups in Organic Synthesis”,4th Ed.by Wiley Interscience,2007,Chapter 7,696ff.。针对PG的合适氨基保护基团因此可以选自Boc(叔丁氧基羰基)、苄基、4-甲氧基苄基、二苯甲基、Fmoc(芴基甲氧基羰基)、Cbz(苄氧基羰基)、Moz(对甲氧基苄基羰基)、Troc(2,2,2-三氯乙氧基羰基)、Teoc(2-(三甲基甲硅烷基)乙氧基羰基)、Adoc(金刚烷氧基羰基)、甲酰基、乙酰基或环丁氧基羰基。优选的氨基保护基团是Boc。
螺旋键
代表
因此指示分子的手性。
当化学结构中存在手性碳时，意指与该手性碳相关联的所有立体异构体都涵盖于作为纯立体异构体以及其混合物的结构中。
步骤a)
步骤a)需要将式II的吡嗪-2-甲酰胺进行催化氢化
以形成式III的哌嗪-2-甲酰胺
吡嗪-2-甲酰胺是一种广泛市售的化合物。
催化氢化通常在金属氢化催化剂和溶剂的存在下用氢气进行。
金属氢化催化剂中合适的金属是钯或铂，优选钯。
金属常常施加在选自碳或氧化铝的惰性支持物上，优选在碳上。支持物上的常见金属负载(w/w)为0.5％至20％，优选3％至15％，更优选8％至12％。最优选的金属氢化催化剂是10％钯碳(10％Pd/C)。
相对于吡嗪-2-甲酰胺起始材料，金属氢化催化剂的用量常为3％至20％w/w，通常为10％w/w。
溶剂可以是有机溶剂，该有机溶剂选自脂肪醇诸如如甲醇或乙醇、或水或它们的混合物的有机溶剂。优选的溶剂是水。
催化氢化适宜地在20℃至相应溶剂的沸腾温度，(优选30℃至60℃，更优选35℃至45℃)的反应温度以及5bar至50bar(优选15bar至25bar)的氢气压力下进行。
在最优选的实施例中，在40℃的反应温度和20bar的氢气压力下，使用10％Pd/C10％w/w催化剂在水中进行催化氢化。
所得哌嗪-2-甲酰胺可以通过本领域技术人员已知的工序分离，如通过从反应混合物中分离催化剂和随后从滤液中除去溶剂。
然而，在优选的实施例中，哌嗪-2-甲酰胺不被分离并且在从反应混合物中分离出催化剂之后在步骤b)中被进一步处理。
在进一步优选的实施例中，催化剂在从反应混合物中分离后，可以重复使用数次，通常至少5次，而不会明显降低性能。如果适用，催化剂性能的下降可以通过添加新鲜催化剂来补偿。
步骤b)
步骤b)需要式III的哌嗪-2-甲酰胺用水解酶的酶促转化，以形成式I的手性哌嗪-2-甲酸。
适用于酶促转化的水解酶通常是肽酶、酰胺酶或它们的混合物。
在优选的实施例中，选择有潜力形成具有至少90％、优选至少95％、更优选至少98％的对映体过量的式Ia的(S)-哌嗪-2-甲酸的水解酶。
能够形成式Ia的(S)-哌嗪-2-甲酸的优选水解酶的代表具有的氨基酸序列与SEQID NO 1的氨基酸序列有至少80％、至少85％、至少90％或至少95％的同一性。
SEQ ID NO 1。
一些酶或酶混合物是可市售的，如来自Novozymes的
1000L，它是来自米曲霉(Aspergillus oryzae)的肽酶制剂；来自Amano Enzyme Inc的Acylase Amano；和来自Fluka的来自青霉属(Penicillium sp.)的Acylase。
在优选的实施例中，可以使用来自Novozymes的酶混合物
1000L或含有如上定义的SEQ ID NO 1的水解酶的酶制剂。
在另一个优选的实施例中，SEQ ID NO 1的水解酶可以通过在合适的宿主例如巴斯德毕赤酵母(Pichia pastoris)中表达酶并分泌到发酵培养基中来获得。
SEQ ID NO 1的水解酶优选是亮氨酸酰胺肽酶2(LAP2)。
替代地，可以选择能够形成式Ib的(R)-哌嗪-2-甲酸的水解酶
形成(R)-对映体的市售酶可以是例如来自Advanced Enzyme Technologies的ADDZYME枯草芽孢杆菌(Bacillus subtilis)蛋白酶。
酶促转化在10℃至50℃、优选20℃至30℃的反应温度在先前氢化步骤中使用的溶剂中、优选在水中进行。
基材负载常常保持在低于30％w/v，优选在1％w/v与25％w/v之间。
通常，该反应不需要额外的缓冲液，因为氨基酸将反应pH缓冲在7.3与8.3之间。
一些酶，如SEQ ID NO 1的水解酶，可能需要添加金属辅因子如锌，该金属辅因子以合适的盐的形式添加。
一旦酶促转化完成，式I的哌嗪-2-甲酸可以按照本领域技术人员已知的工序分离。
然而，在优选的实施例中，通过向反应混合物中加入HCl浓度为10％至37％的盐酸水溶液以如下方式将具有式I的手性哌嗪-2-甲酸的反应混合物转化为其盐酸盐：将反应混合物的温度保持在10℃至30℃、优选15℃至25℃的范围内。
进一步优选在加入盐酸之前在30℃至50℃的温度在30mbar至120mbar的减压下浓缩反应混合物。
在这些条件下，式I的手性哌嗪-2-甲酸，优选式Ia的哌嗪-2-甲酸，通常以盐酸盐形式沉淀，并且可以在过滤和用盐酸水溶液洗涤滤饼之后以及干燥之后，以结晶形式获得。
步骤c)
步骤c)引入是任选的并需要氨基保护基团PG以形成式IV的手性哌嗪-2-甲酸衍生物，
其中PG代表氨基保护基团。
合适的氨基保护基团如上定义，最优选的氨基保护基团PG是Boc(叔丁氧基羰基)。
对于引入Boc基团，可以使用典型的硼化剂如二碳酸二叔丁酯(Boc2O)或2-(叔丁氧基羰氧基氧基亚氨基)-2-苯乙腈(Boc ON)，但优选Boc2O。
反应通常在碱的存在下进行，该碱选自碱性碳酸盐如碳酸钾、碳酸钠或碳酸钙，碱性碳酸氢盐如碳酸氢钠，碱性氢氧化物如氢氧化钠，或叔胺如三乙胺。优选地使用碱性碳酸盐，更优选碳酸钾。合适的溶剂是水、甲醇、乙醇、乙酮、乙腈、二噁烷或它们的混合物。在优选的实施例中，使用水与乙酮的混合物。
反应温度一般选自在-15℃和30℃之间，优选地15℃和30℃之间。
在优选的实施例中，形成式IVa的(2S)-4-叔丁氧基羰基哌嗪-2-甲酸。
在本发明的进一步实施例中，本发明的方法可以应用于制备式X化合物或其药用盐、或对映体或非对映体的方法中，
其中
R1为卤素或C1-6-烷基；
R2为氢或卤素；
R3为氢或卤素；
R4为C1-6-烷基；
R5为氢或羧基；
R6为氢；
R7为C1-6-烷基、C3-7-环烷基、-CmH2m-COOH、-CmH2m-C3-7-环烷基-COOH或羧基苯基；
m为1-6。
式X化合物连同m和R1至R7的含义和定义以及获得其的方法在PCT公开WO 2015/132276中公开，该专利通过引用并入本文。式X对应于WO 2015/132276中的式IAA(第22页)。
更优选式XX化合物
其中R1至R4和R7如上所述。
用于制备式XX化合物的方法中的必要中间体是中间体式IX或其对映体或非对映体。
其中R7如上文所概括。
式X化合物的制备进一步包括步骤
d)将式IV的手性哌嗪-2-甲酸或其盐，
其中PG为氨基保护基团，与胺R7-NH2，其中R7如上所述，在偶联剂和碱的存在下进行转化，以形成式V的混合脲或其盐，
其中PG和R7如上所述；
e)将式V的混合脲进行环化，以形成式VI的乙内酰脲，
其中PG和R7如上所述；
f)将式VI的乙内酰脲进行还原，以形成式VII的环脲，
其中PG和R7如上所述；以及
g)脱保护并形成式IX化合物。
在优选的实施例中，中间体IX可以为式IXa或IXb
其中R7如上文所定义。
在更优选的实施例中，中间体IX是式IXa。
式IVb的手性哌嗪-2-甲酸衍生物的盐可以通过本领域已知的方法制备。
钠盐可以例如通过将式IV的手性哌嗪-2-甲酸衍生物与甲醇氢氧化钠水溶液以类似于M.Laars等人,Tetrahedron:Asymmetry 21(2010)562–565的4.3.6的示例的方式进行反应来制备。
方案1进一步示出了中间体IX的形成。
方案1
混合脲(V)可以从胺R7’-NH2盐通过其与手性哌嗪-2-甲酸或其盐(IVb)在偶联剂如羰基二咪唑(CDI)和合适的碱如三乙胺的存在下进行偶联来制备。合适的手性哌嗪-2-甲酸盐(IVb)是碱金属盐如钠盐或钾盐，或者铵盐如三乙铵盐。混合脲(V)适当地与草酰氯进行环合反应提供海因(VI)。随后用选自BH3·THF或NaBH4的还原剂在BF3·THF的存在下进行还原可以得到环脲(VII)。在R7’是酯基团的情况下，用氢氧化钠或氢氧化钾水溶液进行皂化产生相应的酸(VIII)。化合物(VII)或(VIII)的Boc脱保护可以用在MIBK中的浓HCl来实现，以形成化合物(IX)。具有绝对构象的化合物(IXa)或(IXb)可以根据方案1采用相应的手性起始物质化合物(IVb)来获得。
实例
缩写：
a％＝面积％
AOX I＝醇氧化酶I
BMMY＝缓冲的甲醇混合介质(带有)酵母提取物
df＝膜厚度
GC＝气相色谱法
ID＝内径
L＝长度
MeOH＝甲醇
MIBK＝甲基异丁基酮
OD＝光密度
RCF＝相对离心力
RRT＝相对保留时间
XRF＝X-射线荧光
YPD＝酵母提取物蛋白胨葡萄糖
实例1
(S)-哌嗪-2-甲酸
a)rac-哌嗪-2-甲酰胺的制备
在压力容器中将吡嗪-2-甲酰胺(100g,812mmol)悬浮在300mL水中，该压力容器随后用氩气惰化。将10％Pd/C(干燥，10.0g)添加至反应混合物，额外添加30mL水来冲洗反应器壁。将反应器密封，将气氛交换成氢气，并将反应混合物加热至40℃。将气氛调节至20barH2并将混合物在40℃搅拌18h，同时维持容器内恒定氢气压力20bar，并记录随时间的气体消耗。将反应器冷却至室温，将气氛交换成氩气，并通过GC分析来检查反应进程(转化率>99a％,97a％标题化合物)。将混合物用额外170mL水过滤以得到水溶液，然后通过缓慢添加浓(37％)HCl水性溶液(55mL,655mmol)将其pH调节至7.8，同时保持其温度低于25℃。将所得溶液直接经受后续步骤而无需分离产物。
GC方法描述：固定相：Agilent HP-5(L＝30m,ID＝0.32mm,df＝0.25μm,最大温度350℃)；温度程序：开始于100℃，加热速率10℃/min直到350℃，在350℃的保持时间为2min，然后冷却速率40℃/min直到100℃，在100℃的保持时间为0.75min；运行时间34.0min；入口模式：恒定压力；入口初始压力：5.0psi；入口初始流速0.727mL/min，100℃(起始烘箱温度)；初始速度16.05cm/s，100℃(起始烘箱温度)；分流比，分流流速1:30，41.38mL/min；进料量1.0μL；入口温度280℃；检测器温度320℃；检测器H2流速(燃料流速)40mL/min；检测器空气流速(氧化剂流速)400mL/min；检测器N2流速(恒定构成)30mL/min；保留时间：吡嗪-2-甲酰胺＝4.56min(RRTapprox＝0.71)，rac-哌嗪-2-甲酰胺＝6.46min(RRT＝1.0)。
b)rac-哌嗪-2-甲酰胺的制备(催化剂重复使用)
在配备有具有2μm熔块的深管的压力容器中将吡嗪-2-甲酰胺(10g,81.2mmol)悬浮在50mL水中。然后将容器用氩气堕化。将10％Pd/C(干燥，1.0g)添加至反应混合物，并将反应器密封，将气氛交换成氢气，并将反应混合物加热至40℃。将气氛调节至20bar H2并将混合物在40℃搅拌18h，同时维持容器内恒定氢气压力20bar，并记录随时间的气体消耗。将反应器冷却至室温，将气氛交换成氩气，并使用过压的Ar将反应混合物通过深管过滤出反应器。所得的溶液通过GC和XRF光谱进行分析，以确定痕量Pd的存在。将容器去压力，并再次装入10g吡嗪-2-甲酰胺和水(50mL)，以重复使用经过滤的催化剂来重复氢化。该工序重复5次，一直实现>98a％转化率和>92a％产率(如通过GC分析判定的)，并且溶液中Pd的水平一直<2ppm(如通过XRF光谱分析判定的)。
c)(S)-哌嗪-2-甲酸二盐酸盐的制备
向实例1a的rac-哌嗪-2-甲酰胺溶液的pH调节溶液(105g；812mmol溶于约555mL水，pH 7.8)添加酶催化剂(
1000L(Novozyme)，50mL)，并在室温下搅拌反应22h。反应通过HPLC来监测，并在20h后显示47a％酸形成。将所得的反应混合物在减压下浓缩至约400mL(30-120mbar,45℃)并随后历经45min将浓(37％)HCl水溶液添加至反应混合物(190mL,2.28mol)以沉淀出(S)-哌嗪-2-甲酸二盐酸盐并搅拌4h，以便确保产物完全沉淀。将所得的晶体过滤出并用HCl(3N,120mL,360mmol)洗涤，并在减压(5mbar,45℃,24h)下干燥，从而以38％产率(62g)得到期望的产物，其纯度为87a％并且>99％ee。
LC手性方法描述(对于ee测定)-固定相：Astec Chirobiotic T(L＝25cm,ID＝4.6mm,粒径＝5μm)。
洗脱液：A)磷酸钾50mM pH 7.0B)甲醇；泵程序：isocratic 90A:10B，运行时间13min，流速：1.0mL/min；柱烘箱温度：10℃；进样量：2μL；检测：DAD 198nm。
保留时间：(S)-哌嗪-2-甲酸＝4.42min，(R)-哌嗪-2-甲酸＝4.82min，rac-哌嗪-2-甲酰胺＝10.43min。
(S)-哌嗪-2-甲酸二盐酸盐的NMR数据。
1H NMR(600MHz,D2O)δppm：4.17(dd,J＝11.3,3.9Hz,1H),3.91(dd,J＝14.1,3.8Hz,1H),3.73(dt,J＝14.0,3.3Hz,1H),3.69-3.63(m,1H),3.48-3.41(m,2H),3.39-3.33(m,1H)。
d)使用Seq.ID 1的制剂来制备(S)-哌嗪-2-甲酸
d1)SEQ ID NO:1的酶制剂：
将酶DNA序列整合到毕赤酵母(Pichia pastoris)表达/整合质粒中，并且在线性化后，通过同源重组将序列稳定整合到Mut+野生型毕赤酵母菌株的基因组中的AOX I位点。使用Zeocin抗生素抗性标记来选择具有整合表达盒的重组菌株。靶蛋白的表达受内源诱导型AOX I启动子的控制，并且表达的蛋白质经由具有毕赤酵母(S.cerevisiae)α交配因子分泌信号肽的可切割的N-末端融合物分泌到培养上清液中。
使重组菌株的单个克隆的过夜培养物在没有抗生素选择的YPD培养基中生长(Sigma Aldrich Y1375，现成的培养基粉末)。
为了产生该酶，使用500mL摇瓶，向BMMY培养基(110mL)中的表达培养物接种相应的YPD过夜培养物至最终OD600为1。通过添加1％MeOH(v/v)激活AOX启动子来诱导培养物中的靶蛋白表达。在3天的表达过程中添加补充的1.5％(v/v)甲醇，每24h两次(在3天期间合计6x1.5mL100％MeOH)，同时在28℃以180rpm摇晃培养物。
在3天后，表达培养上清液通过离心(RCF 12000xg,15min)来澄清化，在-80℃冷冻，随后冻干(-80℃/100μbar)，不进行任何进一步的处理步骤。
所得的冻干粉未经任何进一步纯化步骤而使用。
d2)(S)-哌嗪-2-甲酸的制备
将rac-哌嗪-2-甲酰胺(2g,15mmol)溶解在2N HCl(6mL,12mmol)中，并添加水(2mL)以得到rac-2-哌嗪甲酰胺的20％(w/v)溶液，其pH为7.8。向该溶液的等分试样(1mL)添加含有SEQ ID NO 1.的酶制剂(100mg，冻干粉末)和ZnCl2溶液(1M,20μL)。
将反应在室温和摇晃下在Eppendorf ThermoMixer C中温育2天。
反应混合物以22a％和>98％ee.形成期望的产物(S)-哌嗪-2-甲酸。
实例2
(S)-哌嗪甲酸二盐酸盐
a)(S)-哌嗪甲酸二盐酸盐(Flavourzyme)的制备
向实例1a的rac-2-哌嗪甲酰胺溶液的pH调节溶液(105g；812mmol溶于约555mL水，pH 7.8)添加酶催化剂(100g，
1000L(Novozymes))，并在室温下搅拌反应21h。反应通过HPLC监测并显示出52％酸形成。
将所得反应混合物在减压(30-120mbar,45℃)下浓缩至约530g并随后冷却至20-23℃(冰冷却)，之后历经30min添加浓(37％)HCl水溶液(190mL,2.28mol,2.8eq.)，以沉淀出(S)-哌嗪甲酸二盐酸盐。进一步搅拌4.5h确保在室温完成产物沉淀。
将所得的晶体过滤出并用HCl(3N,120mL,360mmol)洗涤，并在高真空下干燥过夜，从而以40％产率(69g)得到期望的产物，其纯度为97a％并且99.1％ee。
b1)亮氨酸酰胺肽酶2(LAP2)的酶制剂
与实例1,d1)类似地产生酶，变化之处在于表达在发酵器中以10L规模以本领域技术人员已知的方式进行。
2个平行培养的10L LAP2进料批次毕赤酵母生物反应器以进料批次模式使用甘油作为碳源生长26h。在耗尽甘油进料后，通过脉冲添加100％甲醇的培养体积的3％来诱导重组LAP2蛋白的表达，这在耗尽先前脉冲后重复约26次，合计96h运行时间。将上清液合并并且使用0.2μM PES Repligen中空纤维膜过滤(12L/min进料流速，0.07MPa跨膜压力)；剩余的1.2L滞留物用4x500mL dH2O洗涤，然后丢弃。使用10kDa mPES Repligen中空纤维膜将所得的滤液浓缩至约2L(12L/min进料流速，0.12MPa跨膜压力)。使用10L的25mM乙酸钠缓冲液、100mM NaCl、0.5mM ZnCl2、pH 5.6缓冲液，使浓缩物在12L/min进料流速和0.12MPa跨膜压力下以恒定体积进行缓冲液交换。然后将所得溶液浓缩至约1.25L并使用0.2μm mPES瓶顶过滤器进行无菌过滤。
b2)(S)-哌嗪甲酸二盐酸盐(LAP 2)的制备
向实例1a的rac-2-哌嗪甲酰胺溶液的经pH调节的溶液(105g；812mmol溶于约555mL水，pH 7.8)。添加酶催化剂(25ml亮氨酸酰胺肽酶2(LAP 2)制剂；SEQ ID NO 1)，并将反应在室温搅拌19h。反应通过HPLC监测并显示出53％酸形成。将所得反应混合物在减压(30-120mbar,45℃)下浓缩至约500g并随后冷却至20-23℃(冰冷却)，之后历经30min添加浓(37％)HCl水溶液(190mL,2.28mol,2.8eq.)，以沉淀出(S)-哌嗪甲酸二盐酸盐。进一步搅拌4.5h确保在室温完成产物沉淀。
将所得的晶体过滤出并用HCl(3N,120mL,360mmol)洗涤，并在高真空下干燥过夜，从而以41％产率(69g)得到期望的产物，其纯度为98a％并且>99％ee。
实例3
a)(2S)-4-叔丁氧基羰基哌嗪-2-甲酸的制备
(S)-哌嗪-2-甲酸二盐酸盐(10.8g；50mmol)和碳酸钾(7.3g；53mmol)在丙酮水溶液(17g丙酮和85g水)中合并。所得溶液经硅藻土(1g)过滤，以除去从上一步剩余的任何酶残留物。将Boc-酸酐(12g)的丙酮(17g)溶液历经4h给予至该溶液，期间产物逐渐结晶。在给予结束后，用碳酸氢钾(0.42g)的水(2g)溶液将反应混合物的pH从pH 6调节回至pH 7。继续搅拌过夜，以确保产物沉淀完成。将残余物过滤，用乙酮水溶液(11g乙酮和1g水)和乙酮(12g)洗涤，并将湿饼以45℃/12mbar干燥过夜以得到8.8g标题化合物。
(2S)-4-叔丁氧基羰基哌嗪-2-甲酸的NMR和MS数据。
1H NMR(600MHz,D2O)δppm：4.30(ddd,J＝14.6,4.1,1.0Hz,1H),4.04(br s,1H),3.78(dd,J＝10.0,4.0Hz,1H),3.45(br d,J＝12.8Hz,1H),3.33(ddd,J＝14.5,10.9,3.3Hz,1H),3.39(br s,1H),3.15(ddd,J＝12.9,10.7,3.8Hz,1H),1.48(s,9H)
MS[M-H]-，m/z＝229.1。
b)(2S)-4-叔丁氧基羰基哌嗪-2-甲酸的制备
向(S)-哌嗪甲酸二盐酸盐(50g；246mmol)、乙酮(77.9g)和水(347g)的混合物缓慢添加碳酸钾(34g；246mmol)的水(47.2g)溶液。所得溶液用硅藻土(5g)搅拌10min并过滤以除去从上一步剩余的任何酶残留物。过滤残余物用乙酮水溶液(13g乙酮和34g水)洗涤。在20℃，将Boc-酸酐(56.4g,259mmol)的丙酮(77.9g)溶液历经4h给予至该溶液，期间产物逐渐结晶。在给予结束后，用由碳酸氢钾(12.3g)和水(50g)组成的15ml制备溶液将反应混合物的pH从pH 5.5调节至pH 7。继续搅拌过夜，以确保产物沉淀完成。将残余物过滤，用乙酮水溶液(44g乙酮和4g水)和乙酮(40g)洗涤，并将湿饼以43℃/5mbar/6h干燥以得到38.25g标题化合物。
1H NMR(600MHz,D2O)δppm：4.30(ddd,J＝14.6,4.1,1.0Hz,1H),4.04(br s,1H),3.78(dd,J＝10.0,4.0Hz,1H),3.45(br d,J＝12.8Hz,1H),3.33(ddd,J＝14.5,10.9,3.3Hz,1H),3.39(br s,1H),3.15(ddd,J＝12.9,10.7,3.8Hz,1H),1.48(s,9H)
MS[M-H]-，m/z＝229.1。
序列表
<110> 豪夫迈·罗氏有限公司
<120> 用于制备手性哌嗪-2-甲酸的方法
<130> P36021-WO
<150> ep20171689.1
<151> 2020-04-28
<160> 1
<170> PatentIn 版本 3.5
<210> 1
<211> 496
<212> PRT
<213> 米曲霉
<400> 1
Met Arg Ser Leu Leu Trp Ala Ser Leu Leu Ser Gly Val Leu Ala Gly
1 5 10 15
Arg Ala Leu Val Ser Pro Asp Glu Phe Pro Glu Asp Ile Gln Leu Glu
20 25 30
Asp Leu Leu Glu Gly Ser Gln Gln Leu Glu Asp Phe Ala Tyr Ala Tyr
35 40 45
Pro Glu Arg Asn Arg Val Phe Gly Gly Lys Ala His Asp Asp Thr Val
50 55 60
Asn Tyr Leu Tyr Glu Glu Leu Lys Lys Thr Gly Tyr Tyr Asp Val Tyr
65 70 75 80
Lys Gln Pro Gln Val His Leu Trp Ser Asn Ala Asp Gln Thr Leu Lys
85 90 95
Val Gly Asp Glu Glu Ile Glu Ala Lys Thr Met Thr Tyr Ser Pro Ser
100 105 110
Val Glu Val Thr Ala Asp Val Ala Val Val Lys Asn Leu Gly Cys Ser
115 120 125
Glu Ala Asp Tyr Pro Ser Asp Val Glu Gly Lys Val Ala Leu Ile Lys
130 135 140
Arg Gly Glu Cys Pro Phe Gly Asp Lys Ser Val Leu Ala Ala Lys Ala
145 150 155 160
Lys Ala Ala Ala Ser Ile Val Tyr Asn Asn Val Ala Gly Ser Met Ala
165 170 175
Gly Thr Leu Gly Ala Ala Gln Ser Asp Lys Gly Pro Tyr Ser Ala Ile
180 185 190
Val Gly Ile Ser Leu Glu Asp Gly Gln Lys Leu Ile Lys Leu Ala Glu
195 200 205
Ala Gly Ser Val Ser Val Asp Leu Trp Val Asp Ser Lys Gln Glu Asn
210 215 220
Arg Thr Thr Tyr Asn Val Val Ala Gln Thr Lys Gly Gly Asp Pro Asn
225 230 235 240
Asn Val Val Ala Leu Gly Gly His Thr Asp Ser Val Glu Ala Gly Pro
245 250 255
Gly Ile Asn Asp Asp Gly Ser Gly Ile Ile Ser Asn Leu Val Ile Ala
260 265 270
Lys Ala Leu Thr Gln Tyr Ser Val Lys Asn Ala Val Arg Phe Leu Phe
275 280 285
Trp Thr Ala Glu Glu Phe Gly Leu Leu Gly Ser Asn Tyr Tyr Val Ser
290 295 300
His Leu Asn Ala Thr Glu Leu Asn Lys Ile Arg Leu Tyr Leu Asn Phe
305 310 315 320
Asp Met Ile Ala Ser Pro Asn Tyr Ala Leu Met Ile Tyr Asp Gly Asp
325 330 335
Gly Ser Ala Phe Asn Gln Ser Gly Pro Ala Gly Ser Ala Gln Ile Glu
340 345 350
Lys Leu Phe Glu Asp Tyr Tyr Asp Ser Ile Asp Leu Pro His Ile Pro
355 360 365
Thr Gln Phe Asp Gly Arg Ser Asp Tyr Glu Ala Phe Ile Leu Asn Gly
370 375 380
Ile Pro Ser Gly Gly Leu Phe Thr Gly Ala Glu Gly Ile Met Ser Glu
385 390 395 400
Glu Asn Ala Ser Arg Trp Gly Gly Gln Ala Gly Val Ala Tyr Asp Ala
405 410 415
Asn Tyr His Ala Ala Gly Asp Asn Met Thr Asn Leu Asn His Glu Ala
420 425 430
Phe Leu Ile Asn Ser Lys Ala Thr Ala Phe Ala Val Ala Thr Tyr Ala
435 440 445
Asn Asp Leu Ser Ser Ile Pro Lys Arg Asn Thr Thr Ser Ser Leu His
450 455 460
Arg Arg Ala Arg Thr Met Arg Pro Phe Gly Lys Arg Ala Pro Lys Thr
465 470 475 480
His Ala His Val Ser Gly Ser Gly Cys Trp His Ser Gln Val Glu Ala
485 490 495
Claims (18)
1.一种用于制备式I的手性哌嗪-2-甲酸或其盐的方法，
所述方法包括以下步骤：
a)将式II的吡嗪-2-甲酰胺进行催化氢化
以形成式III的哌嗪-2-甲酰胺
以及
b)将式III的哌嗪-2-甲酰胺用水解酶进行酶促转化，以形成所述式I的手性哌嗪-2-甲酸或其盐。
2.根据权利要求1所述的方法，其中键
3.根据权利要求1或2所述的方法，其中所述催化氢化在金属氢化催化剂和溶剂的存在下用氢气进行。
4.根据权利要求3所述的方法，其中所述金属氢化催化剂为Pd或Pt，优选Pd，其中支持物上的金属负载为0.5％w/w至20％w/w，优选3％w/w至15％，更优选8％w/w至12％w/w，并且惰性支持物选自碳或氧化铝，更优选碳。
5.根据权利要求3或4所述的方法，其中所述溶剂为有机溶剂，所述有机溶剂选自脂肪醇诸如甲醇或乙醇、或水、或它们的混合物，但优选水。
6.根据权利要求3至5中任一项所述的方法，其中所述催化氢化在20℃至所述溶剂的沸腾温度、优选30℃至60℃的反应温度下在5bar至50bar、优选15bar至25bar的氢气压力下进行。
7.根据权利要求1至6中任一项所述的方法，其中步骤a)中获得的式III的哌嗪-2-甲酰胺未被分离并且在步骤b)中在原位进一步被处理。
8.根据权利要求1至7中任一项所述的方法，其中所述氢化催化剂被重复使用。
9.根据权利要求1所述的方法，其中步骤b)的所述酶促转化中使用的所述水解酶为肽酶或酰胺酶或它们的混合物。
10.根据权利要求9所述的方法，其中所述水解酶有潜力形成具有至少90％的对映体过量的式Ia的(S)-哌嗪-2-甲酸
11.根据权利要求9或10所述的方法，其中所述水解酶具有的氨基酸序列与SEQ ID NO1的氨基酸序列有至少80％、至少85％、至少90％或至少95％的同一性。
12.根据权利要求9或10所述的方法，其中所述水解酶为酶混合物
或含有SEQ ID NO 1的水解酶的酶制剂。
13.根据权利要求9至12中任一项所述的方法，其中所述酶促转化在10℃至50℃、优选20℃至30℃的反应温度下在氢化步骤a)中使用的所述溶剂中、优选在水中进行。
14.根据权利要求9至13中任一项所述的方法，其中在所述酶促转化之后，以将反应温度保持在-15℃至30℃的范围内的方式，向反应混合物中加入盐酸水溶液，从而将式I的手性哌嗪-2-甲酸转化为其盐酸盐。
15.根据权利要求1所述的方法，其中所述方法进一步包括以下步骤：
c)引入氨基保护基团PG以形成式IV的手性哌嗪-2-甲酸，
其中PG代表氨基保护基团。
16.根据权利要求15所述的方法，其中PG为Boc(叔丁氧基羰基)并且式IV的手性哌嗪-2-甲酸为式IVa的(2S)-4-叔丁氧基羰基哌嗪-2-甲酸
17.根据权利要求15或16所述的方法，其中所述方法进一步包括式IX化合物或其对映体或立体异构体的形成，
其中
R7为C1-6-烷基、C3-7-环烷基、-CmH2m-COOH、-CmH2m-C3-7-环烷基-COOH或羧基苯基；
所述形成包括以下步骤：
d)将式IV的手性哌嗪-2-甲酸或其盐，
其中PG为氨基保护基团，与胺R7-NH2，其中R7如上所述，在偶联剂和碱的存在下进行转化，以形成式V的混合脲或其盐，
其中PG和R7如上所述；
e)将式V的混合脲进行环化，以形成式VI的乙内酰脲，
其中PG和R7如上所述；
f)将式VI的乙内酰脲进行还原，以形成式VII的环脲，
其中PG和R7如上所述；以及
g)脱保护并形成式IX化合物。
18.根据权利要求1至17所述的方法用于制备式X化合物或其药用盐、或对映体或非对映体的用途，
其中
R1为卤素或C1-6-烷基；
R2为氢或卤素；
R3为氢或卤素；
R4为C1-6-烷基；
R5为氢或羧基；
R6为氢；
R7为C1-6-烷基、C3-7-环烷基、-CmH2m-COOH、-CmH2m-C3-7-环烷基-COOH或羧基苯基；
m为1-6。
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| US6214604B1 (en) * | 1995-05-08 | 2001-04-10 | Lonza Ag | Biotechnical production process of piperazine R-α-carboxylic acids and piperazine S-α-carboxylic acid amide |
| CN108718527A (zh) * | 2016-02-19 | 2018-10-30 | 豪夫迈·罗氏有限公司 | 用于制备4-苯基-5-烷氧羰基-2-噻唑-2-基-1，4-二氢嘧啶-6-基]甲基]-3-氧代-5，6，8，8a-四氢-1H-咪唑并[1，5-a]吡嗪-2-基]-甲酸的方法 |
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| EA030115B9 (ru) | 2014-03-07 | 2018-09-28 | Ф. Хоффманн-Ля Рош Аг | Новые 6-конденсированные гетероарилдигидропиримидины для лечения и профилактики заражения вирусом гепатита b |
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2021
- 2021-04-26 US US17/997,337 patent/US20230175026A1/en active Pending
- 2021-04-26 EP EP21720759.6A patent/EP4143173A1/en active Pending
- 2021-04-26 JP JP2022565589A patent/JP2023523961A/ja active Pending
- 2021-04-26 AU AU2021266084A patent/AU2021266084A1/en active Pending
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- 2021-04-26 CN CN202180031458.1A patent/CN115461333A/zh active Pending
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- 2021-04-26 BR BR112022021928A patent/BR112022021928A2/pt unknown
- 2021-04-26 KR KR1020227041188A patent/KR20230005290A/ko active Search and Examination
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| US6214604B1 (en) * | 1995-05-08 | 2001-04-10 | Lonza Ag | Biotechnical production process of piperazine R-α-carboxylic acids and piperazine S-α-carboxylic acid amide |
| CN108718527A (zh) * | 2016-02-19 | 2018-10-30 | 豪夫迈·罗氏有限公司 | 用于制备4-苯基-5-烷氧羰基-2-噻唑-2-基-1，4-二氢嘧啶-6-基]甲基]-3-氧代-5，6，8，8a-四氢-1H-咪唑并[1，5-a]吡嗪-2-基]-甲酸的方法 |
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| HIDENOBU KOMEDA等: "S -Stereoselective piperazine-2-tert-butylcarboxamide hydrolase from Pseudomonas azotoformans IAM 1603 is a novel L-amino acid amidase", 《EUR.J.BIOCHEM.》, vol. 271, pages 1466 * |
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Also Published As
| Publication number | Publication date |
|---|---|
| WO2021219523A1 (en) | 2021-11-04 |
| CA3179165A1 (en) | 2021-11-04 |
| AU2021266084A1 (en) | 2022-10-20 |
| US20230175026A1 (en) | 2023-06-08 |
| JP2023523961A (ja) | 2023-06-08 |
| BR112022021928A2 (pt) | 2022-12-13 |
| KR20230005290A (ko) | 2023-01-09 |
| EP4143173A1 (en) | 2023-03-08 |
| MX2022013205A (es) | 2022-11-14 |
| IL297595A (en) | 2022-12-01 |
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