CN113165992A - 制备外-n-(3-氮杂双环[3.2.1]辛烷-8-基)氨基甲酸叔丁酯的方法 - Google Patents
制备外-n-(3-氮杂双环[3.2.1]辛烷-8-基)氨基甲酸叔丁酯的方法 Download PDFInfo
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- CN113165992A CN113165992A CN201980077979.3A CN201980077979A CN113165992A CN 113165992 A CN113165992 A CN 113165992A CN 201980077979 A CN201980077979 A CN 201980077979A CN 113165992 A CN113165992 A CN 113165992A
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- acid
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- mandelic
- fumaric
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- 238000010189 synthetic method Methods 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XDDDRCFCDBVFMT-UHFFFAOYSA-N tert-butyl n-(3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1C(C2)CCC1CN2CC1=CC=CC=C1 XDDDRCFCDBVFMT-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Abstract
本发明涉及用于制备化合物(I)或其药用盐的方法,所述化合物或其药用盐可用作合成一类化合物的关键中间体,该类化合物用于预防和治疗与脑中β‑淀粉样蛋白质沉积相关的疾病,特别是阿尔茨海默病,以及其他疾病诸如脑淀粉样血管病、荷兰型遗传性脑出血伴淀粉样变(HCHWA‑D)、多发性梗塞性痴呆、拳击员痴呆和唐氏综合征。
Description
本发明涉及一种用于制备化合物(I)
或其药用盐的方法,该化合物或其药用盐可用作合成一类化合物的关键中间体,该类化合物用于预防和治疗与脑中β-淀粉样蛋白质沉积相关的疾病,特别是阿尔茨海默病,以及其他疾病诸如脑淀粉样血管病、荷兰型遗传性脑出血伴淀粉样变(HCHWA-D)、多发性梗塞性痴呆、拳击员痴呆和唐氏综合征。
背景技术
化合物(I)的合成方法公开于专利WO2018118838和WO2005021536中,然而,由于以下问题,目前的方法不适于大规模生产:
(a)对于以下三种中间体,需要用繁琐的后处理过程进行柱纯化,诸如:3-苄基-3-氮杂双环[3.2.1]辛烷-8-酮肟、3-苄基-3-氮杂双环[3.2.1]辛烷-8-胺、N-(3-苄基-3-氮杂双环[3.2.1]辛烷-8-基)氨基甲酸叔丁酯;
(b)HPLC或SFC手性分离是必要的,这导致大量的成本;
(c)没有关于去除步骤d)中过量Boc2O的报道,这导致步骤e)中的主要副产物。
因此,基于上述问题,本发明的一个目的是找到一种能够解决所有上述问题并在技术规模上应用的有效的合成方法。
本发明的另一方面涉及一种制备化合物(V)和/或化合物(Va)的新方法:
其中该酸选自D-谷氨酸、(R)-(-)-扁桃酸、1-羟基-2-萘甲酸、柠檬酸、4-氨基水杨酸、L-酒石酸、马尿酸、丙二酸、戊二酸、草酸、富马酸、琥珀酸、4-氨基苯甲酸、2,5-二羟基苯甲酸、L-苹果酸、水杨酸、马来酸、(1S,3R)-(-)-樟脑酸、扑酸、粘酸、棕榈酸、油酸和乳糖酸;特别地,该酸为(R)-(-)-扁桃酸。
具体实施方式
定义
术语“药用盐”是指保留式I的化合物的生物学有效性和特性并由合适的无毒有机或无机酸、或有机或无机碱形成的常规酸加成盐或碱加成盐。酸加成盐包括例如衍生自无机酸诸如盐酸、氢溴酸、氢碘酸、硫酸、氨基磺酸、磷酸和硝酸的那些,以及衍生自有机酸诸如对甲苯磺酸、水杨酸、甲磺酸、草酸、琥珀酸、柠檬酸、苹果酸、乳酸、富马酸等的那些。碱加成盐包括衍生自铵、钾、钠和季铵氢氧化物诸如例如四甲基氢氧化铵的那些。将药物化合物化学修饰成盐是药物化学家熟知的技术,以便获得化合物的改善的物理和化学稳定性、吸湿性、流动性和溶解性。该技术例如描述于Bastin R.J.等人,Organic Process Research&Development 2000,4,427-435中;或描述于Ansel,H.等人,Pharmaceutical Dosage Formsand Drug Delivery Systems,第6版(1995),第196页和第1456-1457页中。
缩写
API 活性药物成分
DBU 1,8-二氮杂双环[5.4.0]十一碳-7-烯
DCM 二氯甲烷
DIPEA N,N-二异丙基乙胺
DMF 二甲基甲酰胺
eq 当量
EtOAc或EA乙酸乙酯
IPA 异丙醇
IPAc 乙酸异丙酯
2-MeTHF 2-甲基四氢呋喃
MTBE 甲基叔丁基醚
NMM N-甲基吗啉
NMP N-甲基-2-吡咯烷酮
Pd/C 钯碳
Pd(OH)/C 氢氧化钯碳
雷尼镍雷尼镍
TEA 三乙胺
TFA 三氟乙酸
v/v 体积比
wt.% 重量百分比
本发明提供了一种如方案1中概述的用于制备式(I)的化合物的方法。
方案1
该合成包括以下步骤:
步骤a)化合物(III)的亚胺形成,
步骤b)化合物(VI)的形成,
步骤c)化合物(V)的盐形成,
其由化合物(VI)和酸的反应进行;其中所述酸选自D-谷氨酸、(R)-(-)-扁桃酸、1-羟基-2-萘甲酸、柠檬酸、4-氨基水杨酸、L-酒石酸、马尿酸、丙二酸、戊二酸、草酸、富马酸、琥珀酸、4-氨基苯甲酸、2,5-二羟基苯甲酸、L-苹果酸、水杨酸、马来酸、(1S,3R)-(-)-樟脑酸、扑酸、粘酸、棕榈酸、油酸和乳糖酸;特别地,所述酸为(R)-(-)-扁桃酸;
步骤d)化合物(VI)的形成,
步骤e)化合物(I)的形成,
本发明的方法步骤的详细描述如下:
步骤a)化合物(III)的亚胺形成,
在合适的溶剂存在下用合适的碱合成式(III)的化合物。
合适的溶剂选自MeOH和EtOH;特别地,溶剂为EtOH。
合适的碱选自KOAc和NaOAc;特别地,合适的碱为NaOAc。
就技术规模的生产而言,萃取后将溶剂更换为EtOH对于整个方法是至关重要的。浓缩去除EA直接得到可接受的收率,但由于安全方面的考虑,该方法不适于大规模生产。在本发明中,将溶剂更换为EtOH,可对其进行控制以进行大规模生产。
步骤b)化合物(IV)的形成,
化合物(IV)在合适的溶剂中用合适的还原剂合成。
合适的溶剂选自MeOH、EtOH和IPA;特别地,溶剂为EtOH。
合适的还原剂选自Na、Pd/c和雷尼镍;特别地,还原剂为雷尼镍。
反应在0℃-70℃、特别是在20℃-30℃进行。
就内型/外型选择性而言,温度对于整个方法是至关重要的。在本发明中,步骤a)和b)在没有固体分离的情况下相继进行。在还原反应期间的较高温度(>50℃)和较低温度(<5℃)导致低比率的期望外型产物。本发明的步骤b)中设计的温度系统具有最高的收率和良好的杂质吹清除效果。
进行一系列研究以证明反应温度的影响,其表明20℃-30℃为还原反应的最佳条件:
步骤c)化合物(V)的盐形成,
其由化合物(VI)和酸的反应进行;其中所述酸选自D-谷氨酸、(R)-(-)-扁桃酸、1-羟基-2-萘甲酸、柠檬酸、4-氨基水杨酸、L-酒石酸、马尿酸、丙二酸、戊二酸、草酸、富马酸、琥珀酸、4-氨基苯甲酸、2,5-二羟基苯甲酸、L-苹果酸、水杨酸、马来酸、(1S,3R)-(-)-樟脑酸、扑酸、粘酸、棕榈酸、油酸和乳糖酸;特别地,所述酸为(R)-(-)-扁桃酸。
式(V)的化合物在合适的有机溶剂中在合适量的酸存在下合成。
在该步骤中使用的(R)-(-)-扁桃酸的量为0.1-2.0当量,特别是0.6当量。
合适的溶剂选自MeOH、EtOH、正丙醇、IPA、MeCN、丙酮、THF和甲苯;特别地,溶剂为EtOH。
步骤d)化合物(VI)的形成,
该步骤中的化合物(VI)如下合成:在合适的溶剂中在合适的碱存在下经由解离反应,然后用Boc基团进行保护。化合物(VI)通过在合适的溶剂中进行的重结晶纯化。
在离解反应中使用的合适的碱选自Na2CO3、K2CO3、NaHCO3、KHCO3、NaOH和KOH;特别地,碱为K2CO3。
在离解反应中使用的合适溶剂选自IPAc、EtOAc、MTBE、甲苯、THF和2-MeTHF;特别地,溶剂为THF。
重结晶在合适的溶剂中在20℃-70℃、特别是在20℃-30℃进行2-48小时,特别是16小时;其中合适的溶剂选自正庚烷、己烷和石油醚;特别地,溶剂为正庚烷。
正庚烷中的重结晶对于整个方法用于改善收率、去除过量的Boc2O以及避免在步骤e)中脱保护去除苄基基团后产生二-boc副产物是至关重要的。在本发明中,解离和用Boc基团保护在不分离的情况下相继进行。在本发明的该步骤中设计的重结晶系统具有高收率、对杂质的良好清除效果,并防止在脱保护反应后由于步骤d)中剩余的过量Boc2O而在步骤e)中形成主要副产物
步骤e)化合物(I)的形成,
将式(I)的化合物脱保护,并在合适的溶剂存在下用合适的还原剂合成。
合适的溶剂选自MeOH和EtOH;特别地,溶剂为EtOH。
还原剂选自Pd/C和Pd(OH)/C的氢化;特别地,还原剂为Pd(OH)/C。
反应温度在20℃-100℃、特别是在65℃-75℃进行。
实施例
通过参考以下实施例将更全面地理解本发明。然而,它们不应被解释为限制本发明的范围。
实施例1
3-苄基-3-氮杂双环[3.2.1]辛烷-8-酮肟(化合物III)
在N2保护下,在15℃~25℃向500L玻璃衬里反应器中添加EtOH(150.00kg)和3-苄基-3-氮杂双环[3.2.1]辛烷-8-酮(购自Xinlong Pharmaceutical的化合物(II),27kg,125.41mol,1.00当量)。搅拌30分钟后,向反应混合物中装入盐酸羟胺(15.7kg,225.93mol,1.80当量)并且在15℃~20℃向混合物中分批缓慢添加乙酸钠(15.4kg,187.74mol,1.5当量)。将所得反应混合物加热至40℃~50℃并再搅拌20小时,然后浓缩以去除部分溶剂至约60L~80L。将残余物溶液冷却至0℃~5℃,随后在相同温度范围内在20分钟内添加冰水(108kg)。然后在0℃~20℃,在2小时内将NaHCO3(32.4kg)分批添加到混合物中。将所得反应混合物在20℃~25℃再搅拌一小时,然后用EA(80kg)萃取3次。将合并的有机层用水(54kg)和20重量%NaCl水溶液(40.5kg)洗涤,然后通过Na2SO4(20kg)垫过滤并浓缩,以去除部分溶剂至40L~50L。向混合物中装入EtOH(108kg),然后浓缩至40L~50L。再向残余物中添加EtOH(108kg)并浓缩至50L~60L,得到粗产物,将其直接用于下一步。
实施例2
3-苄基-3-氮杂双环[3.2.1]辛烷-8-胺(化合物(IV))
向1000L玻璃衬里反应器中添加EtOH(270kg)和3-苄基-3-氮杂双环[3.2.1]辛烷-8-酮肟(化合物(III),来自实施例1)。将形成的悬浮液在真空下脱气,并用N2吹扫三次,然后在15℃~25℃添加雷尼镍(32kg,0.8重量%)。将所得的悬浮液在真空下脱气,并用H2吹扫至0.5MPa三次。在0.2MPa~0.3MPa H2下,将反应混合物在搅拌下加热至25℃~30℃,持续14小时,然后通过MCC(微晶纤维素)垫过滤,然后用EtOH(160kg)冲洗以去除催化剂。将母液浓缩至约180L,得到粗化合物(IV),将其用于下一步反应而无需进一步纯化。
实施例3
外-3-苄基-3-氮杂双环[3.2.1]辛烷-8-胺;(R)-(-)-扁桃酸(化合物(Va))
在60℃~70℃,向装有由化合物(IV)(180L)得到的3-苄基-3-氮杂双环[3.2.1]辛烷-8-胺溶液的300L玻璃衬里反应器中装入(R)-(-)-扁桃酸(12kg,78.87mol,0.60当量)。添加后,将反应混合物在该温度再搅拌3小时,然后在4小时内冷却至20℃~25℃,并在相同温度再搅拌7小时。将固体通过离心机分离,并将湿滤饼用EtOH(10kg)洗涤,得到粗产物化合物(Va),为湿滤饼。
在15℃-25℃,向300L玻璃衬里反应器中装入湿滤饼和EtOH(126kg),并在搅拌下加热至80℃~85℃,持续6小时。在该温度下,将溶液在4小时内冷却至20℃~30℃,并再搅拌16小时。将固体通过离心机分离,并且用EtOH(10kg)洗涤,并在真空烘箱(30mmHg,40℃)中干燥32小时,得到化合物(Va)(16kg,34.6%收率(3步,来自化合物II),99.65%手性纯度)。
化合物(Va):1H NMR(400MHz,DMSO-d6)δ=7.37-7.12(m,11H),4.51(s,1H),2.99(s,1H),2.60(dd,J=4.0,10.7Hz,2H),2.16-2.03(m,4H),1.78-1.70(m,2H),1.70-1.60(m,2H)
实施例4
外-N-(3-苄基-3-氮杂双环[3.2.1]辛烷-8-基)氨基甲酸叔丁酯(化合物(VI))
在20℃~30℃,向100L玻璃衬里反应器中分批装入3-苄基-3-氮杂双环[3.2.1]辛烷-8-胺-(R)-(-)-扁桃酸盐(化合物(V),7kg,19.0mol,1.00当量),添加K2CO3(9.17kg,66.35mol,3.49当量)的水(32kg)溶液。将所得反应混合物在20℃~30℃搅拌0.5小时并用THF(35kg)稀释,然后在20℃~30℃在1.5小时内滴加Boc2O(4.97kg,22.77mol,1.2当量)。在20℃~30℃再搅拌16小时后,将反应混合物用EtOAc(25L)萃取三次。将合并的有机层用水(10kg)洗涤三次,经Na2SO4(3.00kg)干燥0.5小时,然后浓缩,以去除几乎所有EtOAc,得到16kg粗固体。将粗残余物悬浮于正庚烷(10.00L)中,并在搅拌下加热至50℃~60℃,持续3小时。冷却至5℃~10℃后,将混合物再搅拌5小时并过滤。将收集的固体用正庚烷(5L)冲洗两次,并在45℃~50℃真空干燥20小时,得到N-(3-苄基-3-氮杂双环[3.2.1]辛烷-8-基)氨基甲酸叔丁酯(化合物(VI),5.60kg,1.26mol,93.5%收率,99.68%纯度),为灰白色固体。
化合物(VI):1H NMR:(400MHz,CDCl3)δppm:7.22-7.32(m,5H),4.43(s,1H),3.49-3.54(d,1H),2.66-2.71(dd,2H),2.19-2.23(d,2H),2.12(s,2H),1.77-1.84(dd,2H),1.64-1.72(dd,2H),1.46(s,9H)。
实施例5
外-N-(3-氮杂双环[3.2.1]辛烷-8-基)氨基甲酸叔丁酯(化合物(I))
在10℃-20℃,向100L高压釜反应器中添加EtOH(35.00L)、Pd(OH)/C(350.00g,10重量%)和N-(3-苄基-3-氮杂双环[3.2.1]辛烷-8-基)氨基甲酸叔丁酯(化合物VI,3.50kg,11.06mol,1.00当量)。将所得悬浮液在真空下脱气,并用H2吹扫三次,然后在H2(0.3MPa~0.4MPa)下搅拌加热至50℃~55℃,持续16小时。将相同的批次大小重复三次,并且在合并后通过MCC垫过滤以去除催化剂。通过与正庚烷(10.00L)共沸,浓缩滤液两次,然后与正庚烷(10.00L)混合。将混合物在搅拌下加热至50℃~55℃,持续16小时,然后冷却至20℃~30℃以形成悬浮液。将固体通过真空过滤收集,并用正庚烷(5L)冲洗两次。将所得湿滤饼在45℃~50℃真空干燥20小时,得到N-(3-氮杂双环[3.2.1]辛烷-8-基)氨基甲酸叔丁酯(化合物(I),6.00kg,26.51mol,80%收率,99.38%纯度),为白色固体。
化合物(I):1H NMR:(400MHz,DMSO)δppm:6.49(s,1H),3.284-3.293(d,1H),2.48-2.57(m,5H),1.89(s,2H),1.66-1.68(m,2H),1.40-1.42(d,2H),1.34(s,9H)。
Claims (8)
1.一种用于制备化合物(I)或其药用盐的方法,
所述方法包括以下步骤:
步骤a)化合物(III)的亚胺形成,
步骤b)化合物(VI)的形成,
步骤c)化合物(V)的盐形成,
其由化合物(VI)和酸形成;其中所述酸选自D-谷氨酸、(R)-(-)-扁桃酸、1-羟基-2-萘甲酸、柠檬酸、4-氨基水杨酸、L-酒石酸、马尿酸、丙二酸、戊二酸、草酸、富马酸、琥珀酸、4-氨基苯甲酸、2,5-二羟基苯甲酸、L-苹果酸、水杨酸、马来酸、(1S,3R)-(-)-樟脑酸、扑酸、粘酸、棕榈酸、油酸和乳糖酸;特别地,所述酸为(R)-(-)-扁桃酸;
步骤d)化合物(VI)的形成,
步骤e)化合物(I)的形成,
2.根据权利要求1所述的方法,其特征在于,步骤b)中的所述化合物(IV)的形成在还原剂存在下在0℃-70℃进行,其中所述还原剂选自Na、Pd/c和雷尼镍;特别地,所述反应在雷尼镍存在下在20℃-30℃进行。
3.根据权利要求1或2所述的方法,其特征在于,在步骤c)中使用的(R)-(-)-扁桃酸的量为0.1-2.0当量,特别是0.6当量。
4.根据权利要求1至3中任一项所述的方法,其特征在于,在步骤d)中合成的所述化合物(VI)通过重结晶而纯化,所述重结晶在溶剂中进行,其中所述溶剂选自正庚烷、己烷和石油醚;特别地,所述溶剂为正庚烷。
5.根据权利要求1至4中任一项所述的方法,其特征在于,在步骤d)中的所述还原反应在20℃-100℃、特别是在65℃-75℃进行。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060014957A1 (en) * | 2004-07-07 | 2006-01-19 | Pfizer Inc | Resolution of an aryl-fused azapolycyclic compound |
CN1845921A (zh) * | 2003-08-29 | 2006-10-11 | 塞诺菲-安万特股份有限公司 | 金刚烷和氮杂双环-辛烷及壬烷衍生物、其制备方法及其作为dpp-iv抑制剂的用途 |
CN103570621A (zh) * | 2013-05-17 | 2014-02-12 | 浙江万邦药业股份有限公司 | 一种(-)-石杉碱甲的制备 |
WO2018118838A1 (en) * | 2016-12-20 | 2018-06-28 | Biomarin Pharmaceutical Inc. | Ceramide galactosyltransferase inhibitors for the treatment of disease |
-
2019
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1845921A (zh) * | 2003-08-29 | 2006-10-11 | 塞诺菲-安万特股份有限公司 | 金刚烷和氮杂双环-辛烷及壬烷衍生物、其制备方法及其作为dpp-iv抑制剂的用途 |
US20060014957A1 (en) * | 2004-07-07 | 2006-01-19 | Pfizer Inc | Resolution of an aryl-fused azapolycyclic compound |
CN103570621A (zh) * | 2013-05-17 | 2014-02-12 | 浙江万邦药业股份有限公司 | 一种(-)-石杉碱甲的制备 |
WO2018118838A1 (en) * | 2016-12-20 | 2018-06-28 | Biomarin Pharmaceutical Inc. | Ceramide galactosyltransferase inhibitors for the treatment of disease |
Non-Patent Citations (1)
Title |
---|
MELANCON, BRUCE J. ET AL: "Continued optimization of the MLPCN probe ML071 into highly potent agonists of the hM1 muscarinic acetylcholine receptor", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, pages 3467 - 3472 * |
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