CN107108558B - 制备用于制备四氢喹啉衍生物的合成中间体的方法 - Google Patents
制备用于制备四氢喹啉衍生物的合成中间体的方法 Download PDFInfo
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- CN107108558B CN107108558B CN201580046606.1A CN201580046606A CN107108558B CN 107108558 B CN107108558 B CN 107108558B CN 201580046606 A CN201580046606 A CN 201580046606A CN 107108558 B CN107108558 B CN 107108558B
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
本发明涉及一种用于制备合成中间体的方法,所述合成中间体可用于制备四氢喹啉衍生物,所述衍生物具有对胆固醇酯转运蛋白(CETP)的抑制活性、显示出增加HDL胆固醇水平而降低LDL胆固醇水平的作用并且可用于治疗和/或预防诸如动脉硬化性疾病、高脂血症、血脂异常等疾病。
Description
发明技术领域
本发明涉及一种用于制备合成中间体的方法,所述合成中间体可用于制备四氢喹啉衍生物,所述衍生物具有对胆固醇酯转运蛋白(CETP)的抑制活性、显示出增加HDL胆固醇水平而降低LDL胆固醇水平的作用并且可用于治疗和/或预防诸如动脉硬化性疾病、高脂血症、血脂异常等疾病。
发明背景
前瞻性流行病学研究已经显示了低密度脂蛋白-胆固醇(LDL-C)水平与心血管疾病(CVD)风险之间的强烈关联性[1]。以他汀类疗法降低这些导致动脉粥样硬化的LDL-C水平的后续应用已使得CVD相关发病率和死亡率显著下降:每1mmol/L的LDL-C降低使得CVD事件估计减少22%以及全因死亡率(all-cause mortality)下降10%[2]。尽管有这些令人印象深刻的益处,但剩余的疾病负担依然很大,该负担对个体患者以及对全球保健成本来说都有着重大的影响[3]。需要新型的疗法来进一步降低患者的该剩余CVD风险。
降低LDL-C以及提高高密度脂蛋白胆固醇(HDL-C)水平的一种新方法是抑制胆固醇酯转运蛋白(CETP)。CETP是主要由肝脏和脂肪组织分泌的血浆蛋白。CETP调节胆固醇酯以甘油三酯作交换从HDL向含载脂蛋白B(Apo B)的颗粒(主要是LDL和极低密度脂蛋白VLDL)的转运,从而降低HDL中的胆固醇含量,而有利于(V)LDL中的胆固醇含量。因此,已猜测CETP抑制将使得胆固醇酯保持在HDL-C中,并降低导致动脉粥样硬化的Apo B部分的胆固醇含量。
尽管有证据支持CETP抑制在降低心血管发病率中的潜力,但CETP抑制剂的临床开发却未见明朗。进入III期临床试验的第一个化合物是托彻普(torcetrapib),虽然托彻普显示出疗效,但是其随后却因安全方面的顾虑(包括未预见到的与阿托伐他汀(atorvastatin)联用时较之阿托伐他汀单独使用而言心血管事件和死亡的增加)中止了开发[4]。
进入了IIb期临床试验的另一CETP抑制剂达塞曲匹(dalcetrapib)显示为弱抑制剂,其使HDL-C增加30-40%,对LDL-C浓度的影响极低,但似乎未表现出托彻普的脱靶效应(off-target effect)[11-13]。近来,对达塞曲匹的开发也因在使用该化合物开展的III期研究中没有效果而已终止。
还有两种CETP抑制剂安塞曲匹(anacetrapib)和依塞曲匹(evacetrapib)目前正处于III期临床试验中。然而,使用这些CETP抑制剂的缺点在于:由于为了获得CETP抑制必须使用相对高的剂量,因此可能会发生更多且更强烈的副作用。这可能对患者的身体健康以及对患者顺从性均有负面影响。
本发明人通过提供强效且耐受良好的CETP抑制剂及其药物组合物而成功地克服了上述缺点。该CETP抑制剂为称为化合物A的四氢喹啉衍生物并具有以下结构式:
临床研究已显示化合物A(或其盐)是一种强效CETP抑制剂。与其他已知的CETP抑制剂相比,仅需要相对低剂量的化合物A即可达到几乎完全的CETP抑制。一般来讲,已证实,每日重复一次低至2.5mg剂量的化合物A已足以达到几乎完全的CETP抑制。与其他CETP抑制剂必须用到的剂量相比,这些剂量相当低。此外,临床研究还已显示化合物A耐受良好并且不会导致严重的副作用。
对于诸如化合物A的四氢喹啉衍生物的制备,已用到根据式I的中间体
虽然这些种类的中间体通过用于制备这些种类的中间体的当前方法(诸如在WO2007/116922中所述)在制备诸如化合物A的四氢喹啉衍生物中非常有用,但是总体产率相对较低。此外,必须使用相对昂贵的原料和催化剂,诸如分别是(R)-3-氨基戊酸和钯。另外,在当前的制造方法中,存在残余的氟腐蚀制造设备的问题。
因此,需要一种用于制备根据式I的中间体的高效且具有成本效益的方法,该中间体可用于进一步制备具有CETP抑制性质的四氢喹啉衍生物,诸如化合物A。
发明内容
本发明的第一方面涉及一种用于制备式I的化合物或其盐的方法:
包括以下步骤:
(a)使根据式II的4-氨基-1-三氟甲基苯
与根据式III的醛
以及与根据式IV的化合物
在存在溶剂以及任选地一种或多种催化剂的情况下反应以形成式V的化合物
其中
R1为H或C1-C3烷基,优选地CH2CH3;
R2为H、C1-C3烷基或
(b)使式V的化合物水解以形成式I的化合物。
通过本发明的方法,现在可能以相对便宜的原料、以较少的副产物以及以良好的产率高效地制备根据式I的中间体化合物。如上文所提及,这些化合物可用于进一步制备四氢喹啉衍生物,诸如化合物A。
在根据本发明的方法中,利用所谓的三组分波瓦罗夫(Povarov)反应。该方法中的关键步骤是形成所谓的根据式V的波瓦罗夫产物:
该中间体可用相对便宜的原料制备,并且可高效地水解形成根据式I的化合物。
因此,本发明的第二方面涉及根据式V的中间体,因为之前无人制备这样的中间体。
本发明的第三方面涉及根据式V的中间体在制备根据式I的化合物尤其是在制备根据式I-a的其2R,4S对映体中的用途,所述对映体可用于制备化合物A。
因此,本发明的最后方面涉及根据式V的化合物在制备化合物A中的用途。
定义
如本文所用的术语“药学上可接受的”具有其常规含义,并指下述化合物、材料、组合物和/或剂型,其在经充分医学判断为适于与哺乳动物(尤其是人)的组织接触的范围内,没有与合理利益/风险比相称的过度毒性、刺激、过敏反应和其他问题并发症。
如本文所用的术语“盐”具有其常规含义,并包括酸加成盐和碱盐。
如本文所用的术语“治疗”具有其常规含义,并指治愈性、姑息性和预防性治疗。
术语“心血管疾病”具有其常规含义,并包括动脉硬化、外周血管疾病、高脂血症、混合型血脂异常β-脂蛋白血症(betalipoproteinemia)、低α-脂蛋白血症(hypoalphalipoproteinemia)、高胆固醇血症、高甘油三酯血症、家族性高胆固醇血症(familial-hypercholesteremia)、心绞痛、缺血、心肌缺血、中风、心肌梗塞、再灌注损伤、血管成形术后再狭窄、高血压、脑梗及脑中风。
术语“卤代”、“卤素原子”或“卤素”是指氟、氯、溴或碘。
如本文所用的术语“烷基”或“烷基基团”具有其常规含义,并指具有1至10个碳原子的直链或支链饱和烃链和具有3至10个碳原子的环状饱和烃链。
如本文所用的术语“C1-C3烷基”具有其常规含义,并指具有1至3个碳原子的烷基基团。此类烷基基团的实例为甲基、乙基、丙基和异丙基。
发明详述
用于制备四氢喹啉衍生物的方法已在WO 2007/116922中进行了描述。虽然可通过上述方法制备诸如化合物A的四氢喹啉衍生物,但该方法是低产率的并生成高水平的不希望的副产物。此外,该方法中使用昂贵的原料,诸如(R)-3-氨基戊酸。据发现,尤其是根据式I的化合物(诸如在以上方法中的DIAM)的制备麻烦而又昂贵。
为了解决这些问题,本发明人开发了一种用于制备根据式I的化合物的改良方法。已令人惊讶地发现,使用所谓的三组分波瓦罗夫反应,可以制备根据式I的化合物。
波瓦罗夫反应是一种3组分反应,其中由苯胺、醛和烯胺在一个立体选择性步骤中形成顺式-2-烷基-4-氨基-1,2,3,4-四氢喹啉(Tetrahedron 2009,65,2721)。该反应的用途已在文献中有所报道,但是其在制备药学活性成分中的应用因对储存稳定性和产物纯度的顾虑而受限。
因此,本发明的第一方面涉及一种用于制备式I的化合物或其盐的方法:
包括以下步骤:
(a)使根据式II的4-氨基-1-三氟甲基苯
与根据式III的醛
以及与根据式IV的化合物
在存在溶剂以及任选地一种或多种催化剂的情况下反应以形成式V的化合物
其中
R1为H或C1-C3烷基,优选地CH2CH3;
R2为H、C1-C3烷基或
(b)使式V的化合物水解以形成式I的化合物。
通过本发明的方法,现在可能以相对便宜的原料以及以良好的产率高效地制备根据式I的化合物,而没有许多不希望的副产物。
对于化合物A的制备,优选的是在本发明的方法中使用其中R1为CH2CH3并且R2为H的化合物。在这样的情况下,根据式III的醛为丙醛并且根据式IV的化合物为N-乙烯基甲酰胺。
在执行本发明的方法的步骤a)和b)之后,得到根据式I的关键中间体,该中间体可用于进一步制备四氢喹啉衍生物,诸如化合物A。
由于根据式I的化合物是手性的,因此可能希望至少部分地分离或纯化式I的化合物的不同对映体。这样的分离或纯化是本领域熟知的,并且技术人员可容易地使用若干方法来执行这样的分离或纯化。
至少部分地分离或纯化不同对映体的一种优选方式是使用手性拆分剂,诸如L-酒石酸或其衍生物,诸如二对甲苯甲酰-L-酒石酸。
对于具有CETP抑制性质的四氢喹啉衍生物诸如化合物A的制备,最通常需要使用根据式I的化合物的2R,4S对映体。因此,在本发明的方法的进一步步骤c)中,优选地将根据式I-a的2R,4S-对映体
与其他对映体分离。
至于化合物A的制备,优选的是从其他对映体中分离化合物B(在WO2007/116922中也称为(2R,4S)-2-乙基-6-三氟甲基-1,2,3,4-四氢喹啉-4-基胺)):
优选地,根据式I的化合物的分离或纯化使得以至少99%对映体过量(e.e.),优选地至少99.6%e.e.,更优选地至少99.7%e.e.的纯度获得根据式I-a的化合物或化合物B。
在已获得这些化合物之后,可通过使用已在WO2007/116922中描述的相同方法,使这些化合物反应形成具有CETP抑制性质的四氢喹啉衍生物,诸如化合物A。
在本发明的一个优选实施方案中,在具有式III的醛化合物、具有式IV酰胺化合物与式II的4-氨基-1-三氟甲基苯之间的反应的化学计量分别在0.5-5(:)1(:)0.5-1的范围内。
根据式I的化合物的产率还可取决于步骤a)中所用的溶剂。优选地,所用的溶剂为二氯甲烷、乙腈、乙酸乙酯、甲苯或其混合物。如果R1为CH2CH3并且R2为H,则步骤a)的反应优选地在二氯甲烷、乙腈或在甲苯与二氯甲烷的混合物中进行。
在本发明的优选实施方案中,本发明的步骤a)中所用的催化剂为酸,优选地布朗斯台德酸( acid)或路易斯酸(Lewis acid)。
在根据本发明的甚至更优选的实施方案中,在具有式III的醛化合物、具有式IV的化合物与具有式II的4-氨基-1-三氟甲基苯之间的反应在存在酸催化剂4-甲苯磺酸的情况下进行。存在多种可成功产生所需产物的添加模式。同时添加模式是优选的,以便防止形成难以移除的产物相关杂质。
优选地,在本发明的方法的步骤a)中,将根据式II的4-氨基-1-三氟甲基苯和催化剂的混合物同时添加到根据式IV的化合物和根据式III的醛的添加中。
或者,首先在根据本发明的溶剂中混合根据式III的醛、根据式IV的化合物和根据式II的4-氨基-1-三氟甲基苯,然后将这些化合物与催化剂接触。
或者,首先在根据本发明的溶剂中溶解根据式III的醛和根据式II的4-氨基-1-三氟甲基苯,然后将它们与根据式IV的化合物和根据本发明的催化剂接触。
为了进一步提高根据式I的化合物的产率和纯度,本发明人发现,有益的是将步骤(a)中形成的式V的化合物(即波瓦罗夫产物)从反应混合物中分离,再执行后续步骤(b)。
优选地,在步骤(b)之前通过沉淀和/或过滤工序分离式V的化合物。式V的化合物从反应产物中沉淀可通过向所述反应混合物添加非极性溶剂而进行。优选的非极性溶剂为庚烷、环己烷或其混合物。
如果需要,通过两步沉淀工艺实现式V的化合物的纯化。为此,具有式V的化合物优选地在第一步骤中用庚烷或环己烷或其混合物沉淀,随后用丙酮、异丙醇、乙酸乙酯、甲基叔丁基醚在第二沉淀步骤中重结晶。可执行进一步的沉淀和/或重结晶以进一步增加具有式V的化合物的纯度。
在本发明的方法的步骤b)中,使具有式V的化合物水解形成式I的化合物。优选地,这样的水解通过将包含化合物V的混合物在45至80℃的温度在存在含水酸(优选盐酸)的情况下温热1至3小时而进行。
在本发明的方法的优选实施方案中,使根据式V的化合物在存在醇(优选乙醇)和含水酸的情况下水解。
根据式I-a的化合物并且尤其是化合物B优选地通过使用已在WO2007/116922中描述的相同种类的方法进一步用于制备具有CETP抑制性质的四氢喹啉衍生物,诸如化合物A。
本发明的第二方面涉及根据式V的化合物
其中R2为H、C1-C3烷基或
式V的化合物为所谓的波瓦罗夫产物,所述化合物之前无人合成。其中R1为CH2CH3并且R2为H的根据式V的化合物是尤其优选的,原因是该化合物可非常高效地用于制备化合物A。
本发明的第三方面涉及这些化合物在制备根据式I-a的化合物尤其是在制备化合物B中的用途。
本发明的最后方面涉及式V的化合物在制备化合物A中的用途。
将通过以下非限制性实施例进一步阐述本发明。
实施例
实施例1:制备外消旋顺式-N-(2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基)甲酰胺(波瓦罗夫产物)
实施例1a)使用同时添加(50g规模)而进行的3mol%甲苯磺酸(TsOH)催化的3组分
波瓦罗夫反应
向反应器A中添加丙醛(90g,5当量)和乙腈(50ml),向反应器B中添加对甲苯磺酸(1.77g,3%mol)、4-三氟甲基苯胺(50g,1当量)和乙腈(100ml),并向反应器C中添加N-乙烯基甲酰胺(26.5g,1.2当量)和乙腈(100mL,2倍体积)。
经约4小时将反应器B和反应器C的内容物同时添加到反应器A,同时将反应器A的内容物的温度保持在20-30℃。在添加后,将反应器A中的反应混合物在20-25℃下搅拌16小时。然后将混合物冷却到0-5℃,并搅拌3小时。将沉淀滤除,并用冷乙腈(100ml)洗涤。然后将固体在真空下在40℃干燥16小时,得到31g波瓦罗夫产物(37%收率)。
实施例1b)在二氯甲烷中过夜而进行的2mol%对甲苯磺酸(TsOH)催化的3组分波
瓦罗夫反应(100g规模)
将4-氨基-1-三氟甲基苯(100g,78mL,0.62mol)在室温下溶于CH2Cl2(200mL)。添加丙醛(44.7mL,0.62mol),然后添加CH2Cl2(200mL)。将透明溶液在室温下搅拌1小时,得到浅黄色亚胺溶液。将反应混合物进一步用CH2Cl2(300mL)稀释,并在冰上冷却。一次性添加N-乙烯基甲酰胺(86.8mL,1.24mol,2.0当量),以原位制备亚胺溶液,如上所述。将TsOH(2.36g,12.4mmol,2mol%)加入反应混合物中,在冰上在0℃至室温下将反应混合物搅拌过夜。将庚烷(700mL)加入悬浮液中。5分钟后,将浆液在抽吸下经玻璃过滤器过滤。将灰白色晶体在过滤器上用庚烷(2x 200mL)在抽吸下洗涤。所得的固体在50℃下用旋转蒸发仪在减压下干燥,得到为灰白色固体的产物(99g,59%产率)。液相色谱–质谱(LCMS)和1H-核磁共振(NMR)确认产物。接下来,将粗固体从热丙酮中重结晶。将未溶解的固体从热丙酮溶液中通过过滤而移除。将所得的透明溶液在5℃下储存过夜。将所得的浓稠的泥状物(slush)用玻璃过滤器过滤,并用庚烷(2x 200mL)洗涤。这得到52.5g白色固体(32%产率)。蒸发母液,从异丙醇(IPA)(±100mL)中重结晶,得到13.5g白色固体。两批合并得到66g的产量(39%产率)。1HNMR(300MHz,CDCl3)δ8.40(s,1H),7.34(t,1H),7.26(d,J=7.7Hz,1H),6.52(d,J=8.4Hz,1H),5.88–5.54(m,J=26.6Hz,1H),5.52–5.36(m,1H),4.85–4.67(m,J=16.3,10.8Hz,1H),4.14(s,1H),3.58–3.31(m,1H),2.45–2.30(m,1H),1.80–1.36(m,4H),1.03(t,3H)。
实施例2:化合物B的制备
实施例2a)外消旋2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-胺(外消旋化合物
B)
将波瓦罗夫产物(20g,73.5mmol)、浓盐酸(22.3mL)和乙醇(60mL)的混合物在50℃下加热5小时。在冷却到30-40℃后,将混合物蒸发到60ml的总体积。然后将混合物冷却,添加二氯甲烷(160ml),再用6MNaOH(60mL)碱化到pH12-13。分离各层,并将水相用二氯甲烷(40mL)萃取。将合并的有机层用水(40mL)洗涤,经硫酸钠干燥,并蒸发至干得到17.6g外消旋化合物B(95%产率)。
实施例2b)外消旋2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-胺(外消旋化合物
B(在乙腈中,然后是硫酸水解)
将4-氨基-1-三氟甲基苯(6.3mL,50.0mmol)在室温下溶于CH3CN(40mL)。一次性添加丙醛(4.3mL,60mmol,1.2当量;储存在4℃下)。温度升至25℃。将透明溶液在室温下(在水浴中进行冷却)搅拌5分钟,得到浅黄色亚胺溶液。将N-乙烯基甲酰胺(4.4mL,63mmol,1.25当量;储存在4℃下)一次性添加至以原位制备的亚胺溶液,然后添加TsOH(160mg,0.017当量)。温度升至27℃。5分钟后,形成沉淀。将混合物在氮气氛下在室温搅拌过夜。NMR分析显示组分完全转化成波瓦罗夫产物。向混合物中添加水(140mL),然后添加H2SO4(14mL),并将混合物在60℃下温热。0.5小时后,NMR揭示波瓦罗夫产物完全转化成外消旋化合物B。将混合物用甲苯(50mL)萃取。将含水层用浓NaOH水溶液碱化至pH 10。将碱性水层用甲苯(200mL)萃取,并将甲苯层干燥(Na2SO4)且浓缩,得到7.3g(60%)为棕色固体的粗2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-胺(外消旋化合物B),NMR表明纯度为80-90%。1H NMR(300MHz,CDCl3)δ7.62(s,1H),7.28(d,1H),6.45(d,J=8.4Hz,1H),4.03(s,2H),4.00(s,1H),3.48–3.28(m,J=2.8Hz,1H),2.27–2.08(m,1H),1.67–1.32(m,6H),1.00(t,3H)。
实施例2c)拆分对映纯(2R,4S)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-胺
(化合物B)
将二对甲苯甲酰-L-酒石酸一水合物(134.7g,0.33mol,0.75当量)加入粗外消旋化合物B(108.4g)的甲醇(1L,9V)溶液,并搅拌直至形成晶体。将所得的泥状物加热至回流,使之冷却至室温,然后在冰上冷却。形成晶体,其通过过滤而收集并干燥(99.9g固体)。将该材料从甲醇(750mL,7V)中再次结晶,并用甲基叔丁基醚(TBME)(200mL,2V)洗涤,得到81.6g99.5%e.e.的化合物B二对甲基苯甲酰酒石酸(B-DTTA)盐(27%产率)。
实施例2d)将化合物B二对甲苯甲酰-L-酒石酸盐转化成甲磺酸盐
向10g化合物B-DTTA盐(94%e.e.)中添加甲苯(100mL)和2N NaOH(100mL)。将混合物搅拌10分钟,之后,分离各层。将水相用甲苯(2x 100mL)萃取。接下来,将合并的甲苯层用盐水洗涤,经Na2SO4干燥并蒸发至干。这得到棕色油,向其中添加3倍体积的异丙醇。将甲磺酸(MsOH)(1mL)逐滴加入所得的悬浮液中。最先,悬浮液变成透明混合物。几分钟后,开始形成固体。收集这些固体,用TBME(2x)洗涤并干燥。这得到4g(从富集的化合物B-TA盐,产率为75%)98.6%e.e.的化合物B MsOH盐。
添加10倍体积的异丙醇(IPA)(40mL),并将所得的悬浮液加热至回流保持5分钟,之后,使之冷却到室温。形成固体,其通过过滤而收集,并用TBME洗涤。这得到2.58g(48%产率)99.7%e.e.的化合物B MsOH盐。
实施例2e)将化合物B甲磺酸盐转化成化合物A
对于化合物B甲磺酸盐向化合物A的转化,使用了如WO2007/116922中所述的类似方法。
化合物A的化学名称和化学式
{4-[(2-{[3,5-双(三氟甲基)苄基][(2R,4S)-1-(乙氧基羰基)-2-乙基-6-(三氟甲基)-1,2,3,4-四氢喹啉-4-基]氨基}嘧啶-5-基)氧基]丁酸}
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Claims (18)
1.一种用于制备式I的化合物或其盐的方法:
包括以下步骤:
(a) 使根据式II的4-氨基-1-三氟甲基苯
与根据式III的醛
以及与根据式IV的化合物
在存在溶剂以及任选地一种或多种催化剂的情况下反应以形成式V的化合物
其中
R1为H或C1-C3烷基;
R2为H、C1-C3烷基或
(b) 使式V的所述化合物水解以形成式(I)的化合物,其中步骤a)中所用的所述催化剂为布朗斯台德酸。
2.根据权利要求1所述的方法,其中R1为CH2CH3并且R2为H。
3.根据权利要求1所述的方法,其中R1为CH2CH3。
4.根据权利要求1或2所述的方法,其中所用的所述溶剂为二氯甲烷、乙腈、乙酸乙酯、甲苯或其混合物。
5.根据权利要求1所述的方法,其中所述催化剂为4-甲苯磺酸。
6.根据权利要求1或2所述的方法,其中在步骤(b)前,将式V的所述化合物从步骤(a)的所述反应混合物中分离。
7.根据权利要求6所述的方法,其中通过沉淀和/或过滤将式V的所述化合物从步骤(a)的所述反应混合物中分离,其中所述沉淀通过向所述反应混合物中添加非极性溶剂而进行。
8.根据权利要求7所述的方法,其中所述非极性溶剂为庚烷、环己烷或其混合物。
9.根据权利要求1或2所述的方法,其中在步骤(b)中,通过将包含式V的所述化合物的混合物在45℃至80℃的温度下在存在含水酸的情况下温热1至3小时而使所述化合物水解。
10.根据权利要求9所述的方法,其中式V的所述化合物在存在含水酸和醇的情况下水解。
11.根据权利要求9所述的方法,其中所述酸为盐酸。
12.根据权利要求10所述的方法,其中所述醇为乙醇。
13.根据权利要求1或2所述的方法,其中在进一步的步骤c)中,将根据式I-a的2R,4S-对映体分离
其中R1为H或C1-C3烷基。
14.根据权利要求13所述的方法,其中根据式I-a的所述对映体的所述分离通过用手性拆分剂拆分而进行。
15.根据权利要求14所述的方法,其中所述手性拆分剂为L-酒石酸或其衍生物。
16.根据权利要求14所述的方法,其中所述手性拆分剂为二对甲苯甲酰-L-酒石酸。
17.根据权利要求13所述的方法,其中R1为CH2CH3。
18.根据权利要求13所述的方法,其中将根据式I-a的所述化合物或其盐用于制备根据下式的所述化合物A
。
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