CN105111134B - 一种制备(r)‑或(s)‑3‑氨基哌啶双盐酸盐的方法 - Google Patents
一种制备(r)‑或(s)‑3‑氨基哌啶双盐酸盐的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 12
- GGPNYXIOFZLNKW-XRIGFGBMSA-N (3s)-piperidin-3-amine;dihydrochloride Chemical compound Cl.Cl.N[C@H]1CCCNC1 GGPNYXIOFZLNKW-XRIGFGBMSA-N 0.000 title claims abstract description 10
- GGPNYXIOFZLNKW-ZJIMSODOSA-N (3r)-piperidin-3-amine;dihydrochloride Chemical compound Cl.Cl.N[C@@H]1CCCNC1 GGPNYXIOFZLNKW-ZJIMSODOSA-N 0.000 title abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 17
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 8
- GWJSQKNYHPYZRN-UHFFFAOYSA-N 2-methylpropane-2-sulfonamide Chemical compound CC(C)(C)S(N)(=O)=O GWJSQKNYHPYZRN-UHFFFAOYSA-N 0.000 claims abstract description 7
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229950002366 nafoxidine Drugs 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- RIFXIGDBUBXKEI-UHFFFAOYSA-N tert-butyl 3-oxopiperidine-1-carboxylate Chemical class CC(C)(C)OC(=O)N1CCCC(=O)C1 RIFXIGDBUBXKEI-UHFFFAOYSA-N 0.000 claims description 9
- PEUGKEHLRUVPAN-RXMQYKEDSA-N (3r)-piperidin-3-amine Chemical compound N[C@@H]1CCCNC1 PEUGKEHLRUVPAN-RXMQYKEDSA-N 0.000 claims description 8
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000002808 molecular sieve Substances 0.000 claims description 6
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 229910020889 NaBH3 Inorganic materials 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000012024 dehydrating agents Substances 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 5
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- 230000003197 catalytic effect Effects 0.000 abstract description 2
- 238000006482 condensation reaction Methods 0.000 abstract description 2
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
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- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 150000003053 piperidines Chemical class 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000000977 initiatory effect Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
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- 238000009740 moulding (composite fabrication) Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- -1 piperidines Hydrochloride Chemical class 0.000 description 2
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- 239000012265 solid product Substances 0.000 description 2
- PEUGKEHLRUVPAN-YFKPBYRVSA-N (3s)-piperidin-3-amine Chemical class N[C@H]1CCCNC1 PEUGKEHLRUVPAN-YFKPBYRVSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 150000003929 3-aminopyridines Chemical class 0.000 description 1
- AHLPHDHHMVZTML-SCSAIBSYSA-N D-Ornithine Chemical compound NCCC[C@@H](N)C(O)=O AHLPHDHHMVZTML-SCSAIBSYSA-N 0.000 description 1
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 206010018473 Glycosuria Diseases 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 description 1
- 229960001667 alogliptin Drugs 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
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- 239000000203 mixture Substances 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- QQWYQAQQADNEIC-RVDMUPIBSA-N tert-butyl [(z)-[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)O\N=C(/C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-RVDMUPIBSA-N 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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- 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
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- 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
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
本发明公开了一种制备(R)‑或(S)‑3‑氨基哌啶双盐酸盐的方法。采用N‑Boc‑3‑哌啶酮为原料,在催化量四氢吡咯存在下,与对映纯的(S)‑或(R)‑叔丁基亚磺酰胺发生缩合反应,随后采用还原剂低温还原,接着乙醇/庚烷重结晶后获得对映纯的中间体,接着在盐酸中同时脱去Boc和叔丁基亚磺酰基保护后得到(R)‑或(S)‑3‑氨基哌啶双盐酸盐。
Description
技术领域
本发明涉及一种制备(R)-或(S)-3-氨基哌啶双盐酸盐的方法,属于医药中间体合成领域。
背景技术
(R)-3-氨基哌啶双盐酸盐作为单一的旋光异构体,在有机合成及医药领域有着广泛的用途,是制备药物的重要原料和中间体。例如:日本武田制药通过结构设计和优化,开发出阿洛列汀(Alogliptin)。该药物作为2-肽基肽酶-IV(DPP-IV)抑制剂,在治疗II型糖尿病中表现出了令人振奋的高活性,2013年已经获准在中国上市。
作为该药物的关键中间体,R-3-氨基哌啶双盐酸盐的合成方法,目前主要有:1)以3-氨基吡啶为起始原料,经过加氢还原、拆分和成盐后得到。2)以烟酰胺为起始原料,通过氢化还原、氨基保护、Hoffman降解、拆分和脱保护成盐后得到。3)以D-鸟氨酸盐酸盐为起始原料,经过酰化、环化、还原、成盐后得到。
以上方法存在不同程度的缺陷,例如:起始原料供应得不到保证,需要自己合成;拆分方法需要用到生物酶,实验室难以实现;或者需要超低温反应和强碱性离子交换树脂。
发明内容
本发明通过采用引入手性助剂叔丁基亚磺酰基,将羰基与助剂缩合还原脱保护后转变成手性氨基。采用N-Boc-3-哌啶酮为原料,在催化量四氢吡咯存在下,与对映纯的(S)-或(R)-叔丁基亚磺酰胺发生缩合反应,随后采用还原剂低温还原,接着乙醇/庚烷重结晶后获得对映纯的中间体,接着在盐酸中同时脱去Boc和叔丁基亚磺酰基保护后得到(R)-或(S)-3-氨基哌啶双盐酸盐。
一种制备(R)-或(S)-3-氨基哌啶双盐酸盐的方法,包括以下步骤:
步骤一、
N-Boc-3-哌啶酮与(S)-或(R)叔丁基亚磺酰胺在溶剂中催化反应得到中间体Ⅰ;反应温度为20-90℃;
N-Boc-3-哌啶酮与(S)-或(R)叔丁基亚磺酰胺的摩尔比为1:1.1-1.5;
所述溶剂选自四氢呋喃、乙醇、乙腈、二氯甲烷或1,2-二氯乙烷中的一种;
反应中有脱水剂,所述脱水剂选自4A分子筛或5A分子筛;
步骤二、
将步骤一得到的中间体Ⅰ与还原剂在醇中反应得到非对映异构体,经过乙醇/庚烷重结晶后,再接着在浓盐酸条件下脱保护得到>99%ee(R)-或(S)-3-氨基哌啶双盐酸盐;
中间体Ⅰ与还原剂的摩尔比为1:1.0-2.0;
所述还原剂选自NaBH4,NaBH(OAc)3或NaBH3CN中的一种;
反应温度为-20-0℃;
中间体Ⅰ与浓盐酸摩尔当量比例为1:2.2-5.0,反应温度为20-80℃。
反应式如下:
其中,步骤一中原料叔丁基亚磺酰胺为R构型时,对应终产物为S型;原料叔丁基亚磺酰胺为S构型时,对应终产物为R型。
进一步地,在上述技术方案中,步骤一中催化剂与N-Boc-3-哌啶酮摩尔比为1:0.05-0.2。
进一步地,在上述技术方案中,步骤一中催化剂为四氢吡咯。
进一步地,在上述技术方案中,步骤二中所述醇选自甲醇、乙醇或异丙醇中的一种。
发明有益效果
本发明利用了叔丁基亚磺酰胺本身的手性,通过手性控制,经过还原后得到非对映异构体混合物,利用两种非对映异构体溶解性的差异,经过乙醇/庚烷混合溶剂重结晶后得到对映纯中间体,随后利用氮上Boc和叔丁基亚磺酰基可以在酸性条件下同时脱去的特性,脱完保护后即得到产物。同时,为了方便第一步中的缩合,经过优化发现采用加入催化量的四氢吡咯后可以达到与传统的需要加入四异丙氧基钛同样的效果,减少了使用金属的环境污染。
具体实施方式
实施例1
N-Boc-3-(R)-叔丁基亚磺酰亚胺哌啶的合成:
氮气保护下,向装有机械搅拌和回流装置的500mL反应瓶内依次加入二氯甲烷220mL,(R)-叔丁基亚磺酰胺(13.3g,0.11mol)和N-Boc-3-哌啶酮(19.9g,0.1mol),搅拌下完全溶清。随后再将4A分子筛100g和四氢吡咯(0.71g,0.01mol),加入后室温搅拌30分钟,随后升温至回流反应8小时,TLC检测反应不再变化,停止反应。冷却后,硅藻土过滤,滤饼再加入50mL二氯甲烷洗涤。滤液水泵旋蒸至干,得到的固体(25.3g,粗品收率84%)正己烷重结晶后得到固体产品,加入甲醇160mL配成溶液直接用于下一步反应中。
(S)-3-胺基哌啶双盐酸盐的合成:
氮气保护下,将上述第一步得到粗品甲醇溶液加入500mL三口瓶内,冷却至-20℃搅拌10分钟。开始分8-10批加入NaBH4固体(3.2g,0.084mol),加入过程中有明显气泡产生,应待前面加入NaBH4后气泡基本消失后,再接着加入下一批次,同时控制反应溶液温度不超过-15℃。加入完毕后,维持-20℃反应1-2小时,TLC检测反应完毕。控制温度在0℃以下,开始缓慢向体系内加入水40mL。淬灭后将反应液旋蒸至干,加入二氯甲烷140mL和水,分层后,饱和食盐水洗涤,有机层旋干后加入乙醇/庚烷重结晶得到dr>50:1单一化合物。随后将该化合物加入带有机械搅拌的三口瓶内,向体系内先加入甲醇,随后缓慢加入浓盐酸22mL,加入过程中反应体系内开始有气泡生成,同时体系开始变浑浊,不断有固体析出。待体系气泡变慢后,升温至回流在继续搅拌反应1小时。冷却后,过滤,甲醇洗涤得到(S)-3-胺基哌啶双盐酸盐8.0g,收率55%,99.2%ee,HNMR纯度:98%。
实施例2
N-Boc-3-(S)-叔丁基亚磺酰亚胺哌啶的合成:
氮气保护下,向装有机械搅拌和回流装置的500mL反应瓶内依次加入四氢呋喃200mL,(S)-叔丁基亚磺酰胺(18.2g,0.15mol)和N-Boc-3-哌啶酮(19.9g,0.1mol),搅拌下完全溶清。随后再将5A分子筛90g和四氢吡咯(0.71g,0.01mol),加入后室温搅拌30分钟,随后升温至回流反应6小时,TLC检测反应反应完全,停止反应。冷却后,硅藻土过滤,滤饼再加入40mL四氢呋喃洗涤。滤液水泵旋蒸至干,得到的固体(27.5g,粗品收率91%)正庚烷重结晶后得到固体产品,加入乙醇180mL配成溶液直接用于下一步反应中。
(R)-3-胺基哌啶双盐酸盐的合成:
氮气保护下,将上述第一步得到粗品乙醇溶液加入500mL三口瓶内,冷却至-10℃搅拌10分钟。开始分8-10批加入NaBH3CN固体(11.4g,0.18mol),加入过程中有明显气泡产生,应待前面加入NaBH3CN后气泡基本消失后,再接着加入下一批次,同时控制反应溶液温度不超过-5℃。加入完毕后,维持-10℃反应1-2小时,TLC检测反应完毕。控制温度在0℃以下,开始缓慢向体系内加入饱和氯化铵水溶液60mL。淬灭后将反应液旋蒸至干,加入二氯甲烷150mL和水,分层后,饱和食盐水洗涤,有机层旋干后加入乙醇/庚烷重结晶得到dr>50:1单一化合物。随后将该化合物加入带有机械搅拌的三口瓶内,向体系内先加入乙醇,随后缓慢加入浓盐酸31mL,加入过程中反应体系内开始有气泡生成,同时体系开始变浑浊,不断有固体析出。待体系气泡变慢后,升温至回流在继续搅拌反应1小时。冷却后,过滤,乙醇洗涤得到(R)-3-胺基哌啶双盐酸盐7.6g,收率48%,99.5%ee,HNMR纯度:98%。。
Claims (2)
1.一种制备(R)-或(S)-3-氨基哌啶双盐酸盐的方法,其特征在于包括以下步骤:
步骤一、
N-Boc-3-哌啶酮与(S)-或(R)叔丁基亚磺酰胺在溶剂中催化反应得到中间体Ⅰ;反应温度为20-90℃;
N-Boc-3-哌啶酮与(S)-或(R)叔丁基亚磺酰胺的摩尔比为1:1.1-1.5;
所述溶剂选自四氢呋喃、乙醇、乙腈、二氯甲烷或1,2-二氯乙烷中的一种;
反应中有脱水剂,所述脱水剂选自4A分子筛或5A分子筛;
步骤二、
将步骤一得到的中间体Ⅰ与还原剂在醇中反应得到非对映异构体,经过乙醇/庚烷重结晶后,再接着在浓盐酸条件下脱保护得到>99%ee(R)-或(S)-3-氨基哌啶双盐酸盐;
中间体Ⅰ与还原剂的摩尔比为1:1.0-2.0;
所述还原剂选自NaBH4,NaBH(OAc)3或NaBH3CN中的一种;
反应温度为-20-0℃;
中间体Ⅰ与浓盐酸摩尔当量比例为1:2.2-5.0,反应温度为20-80℃;
步骤一中催化剂与N-Boc-3-哌啶酮摩尔比为1:0.05-0.2;
步骤一中催化剂为四氢吡咯。
2.根据权利要求1所述制备(R)-或(S)-3-氨基哌啶双盐酸盐的方法,其特征在于:步骤二中所述醇选自甲醇、乙醇或异丙醇中的一种。
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