CN107805218B - 一种制备4-Boc-氨基哌啶的方法 - Google Patents
一种制备4-Boc-氨基哌啶的方法 Download PDFInfo
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- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 22
- SJZKULRDWHPHGG-UHFFFAOYSA-N 1-benzylpiperidin-4-one Chemical compound C1CC(=O)CCN1CC1=CC=CC=C1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 claims abstract description 13
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- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical group COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
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- 238000001816 cooling Methods 0.000 description 6
- 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 6
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- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
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- QSQFAQYEUFYKEM-UHFFFAOYSA-N 1-benzylpiperidine-4-carbohydrazide Chemical compound C1CC(C(=O)NN)CCN1CC1=CC=CC=C1 QSQFAQYEUFYKEM-UHFFFAOYSA-N 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229940122694 Muscarinic M3 receptor antagonist Drugs 0.000 description 1
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- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
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- DBWGQUNBMXDISE-UHFFFAOYSA-N tert-butyl 2-amino-1-benzylpiperidine-4-carboxylate Chemical compound NC1CC(C(=O)OC(C)(C)C)CCN1CC1=CC=CC=C1 DBWGQUNBMXDISE-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- C07D211/58—Nitrogen atoms attached in position 4
Abstract
本发明公开了一种制备4‑Boc‑氨基哌啶的方法,包括以下步骤:N‑苄基‑4‑哌啶酮在酸催化下与原甲酸酯在醇溶液中反应形成缩酮,接着与氨基甲酸叔丁酯反应生成亚胺,然后亚胺经Pd/C催化氢化还原得到4‑Boc‑氨基哌啶。该方法合成路线简短、原料易得、价格低廉、操作简便、反应收率高、产物易分离纯化、具有很好的应用前景。
Description
技术领域:
本发明涉及一种制备4-Boc-氨基哌啶的方法,属于有机合成技术领域。
背景技术:
4-Boc-氨基哌啶是合成1,4-二取代哌啶衍生物的重要中间体,该类化合物是毒蕈碱M3受体拮抗剂,可用于治疗或预防呼吸系统疾病如慢性阻塞性肺疾病,慢性支气管炎,哮喘和鼻炎的毒蕈碱;消化系统疾病如肠易激综合征,惊厥性结肠炎,憩室炎和伴随消化系统平滑肌收缩的疼痛;泌尿系统疾病,如尿失禁和神经源性尿频,神经源性膀胱,夜间遗尿,膀胱不稳定,膀胱痉挛和慢性囊肿的频率;晕车等多种疾病,在医药行业具有广泛的用途。
目前该化合物的相关合成方法主要有以下三种:
第一种,以1-苄基-4-哌啶酮为原料与盐酸羟胺反应成肟,再经还原、上Boc、脱苄基共四步反应制得4-Boc-氨基哌啶。该方法存在反应步骤长;第二步肟的还原反应不完全;且使用四氢铝锂或金属钠或镍,存在安全隐患,不适于工业化生产的缺点。
第二种,以1-苄基哌啶-4-甲酰肼为原料,经亚硝酸还原生成1-苄基-4-氨基哌啶,然后与二碳酸二叔丁酯反应,接着经钯碳催化氢化脱苄基共三步反应制得4-Boc-氨基哌啶。该方法第一步还原反应收率只有43%,限制了其应用。
第三种,以4-氨基哌啶为原料,与溴苄或氯苄或苯甲醛反应制得1-苄基-4-氨基哌啶,然后与二碳酸二叔丁酯反应,接着经钯碳催化氢化脱苄基反应制得4-Boc-氨基哌啶;或以4-氨基哌啶为原料,先与二碳酸二叔丁酯反应,然后再与溴苄或氯苄或苯甲醛反应制得1-苄基-4-Boc-氨基哌啶,接着经钯碳催化氢化脱苄基反应制得4-Boc-氨基哌啶。该方法所用原料4-氨基哌啶价格昂贵,难于进行工业化批量生产。
综上所述,研究4-Boc-氨基哌啶的制备方法,探索其合适的合成路线,完成工业化生产工艺的途径探索,还是有很大的必要。
发明内容:
为克服以上缺点,本发明目的是提供一种制备4-Boc-氨基哌啶的方法,N-苄基-4-哌啶酮在酸催化下与原甲酸酯在醇溶液中反应形成缩酮,接着与氨基甲酸叔丁酯反应生成亚胺,然后亚胺经Pd/C催化氢化还原得到4-Boc-氨基哌啶。该方法合成路线简短、原料易得、价格低廉、操作简便、反应收率高、产物易分离纯化、具有很好的应用前景。
一种制备4-Boc-氨基哌啶的方法:经过两步反应后得到,采用的技术方案为:
第一步,N-苄基-4-哌啶酮在酸催化下与原甲酸酯在醇溶液中反应形成缩酮,接着与氨基甲酸叔丁酯反应生成亚胺。
第二步,亚胺经Pd/C催化氢化还原得到4-Boc-氨基哌啶。
反应路线如下:
所述第一步中,原甲酸三酯选自原甲酸三甲酯或原甲酸三乙酯,醇溶液为甲醇或乙醇,即HC(OR)3和ROH中“R”选自甲基或乙基。
所述第一步中,N-苄基-4-哌啶酮、原甲酸酯和氨基甲酸叔丁酯的摩尔比为1:1-2:1-1.2。
所述第一步中,酸选自氯化铵或对甲苯磺酸;酸用量为N-苄基-4-哌啶酮摩尔量的1-5%。
所述第一步中,亚胺的生成采用边反应边蒸出缩酮与氨基甲酸叔丁酯反应中生成的醇,促进反应平衡向产物进行,大大节省了反应时间和提高反应收率。
所述第二步中,Pd/C含量为5%或10%,所用量为亚胺重量的5-10%。
所述第二步中,Pd/C催化氢化还原反应为加压反应,反应压力为0.8MPa-1.0MPa,反应温度为60-80℃。
本发明的有益成果是:
(1)设计路线简短,省略了1-苄基-4-氨基哌啶的合成步骤,直接经两步反应即可制得产品,大大缩短了生产周期。
(2)所用原料都为常见试剂,来源方便,价格低廉,避免了金属还原剂的使用。
(3)操作简便、反应收率高、产物易分离纯化、适合工业化生产。
具体实施方式
实施例1
第一步:向1L三口瓶内,加入N-苄基-4-哌啶酮189.2g(1.00mol),对甲苯磺酸1.72g(10mmol),原甲酸三甲酯159.2g(1.50mol)和甲醇400mL,加热回流2小时,常压蒸出甲醇后,加入氨基甲酸叔丁酯117.1g(1.00mol)和甲苯600mL,加热至80-100℃,边反应边蒸出反应生成的甲醇加速反应,反应3小时,GC中控原料剩余<1%,降温,减压浓缩出溶剂,加入乙醇,降温至0℃搅拌1小时,析出白色固体,过滤,得到240.5g白色固体产品,收率83.4%,纯度99.1%,LCMS(ESI)m/z:[M+H]+289.18.
第二步:向5L高压釜中,加入上步所得产品240.5g(0.834mol)和2.4L甲醇,加入24.0g5%Pd/C,体系用氮气置换三次,通入氢气,控制压力0.8-1.0MPa,缓慢升温至60℃,保温5小时,GC中控原料反应完全,降温,过滤,滤液浓缩得粗品,加入正庚烷打浆得白色固体产品4-Boc-氨基哌啶150.7g,收率90.2%,GC含量99.1%,mp:161.3-162.8℃。1H-NMR(400MHz,DMSO-d6):δ6.73(d,J=7.5Hz,1H),3.21(m,1H),2.86-2.82(m,2H),2.40-2.32(m,2H),1.83(brs,1H),1.61-1.57(m,2H),1.35(s,9H),1.23-1.09(m,2H).
实施例2
第一步:向1L三口瓶内,加入N-苄基-4-哌啶酮189.2g(1.00mol),氯化铵0.53g(10mmol),原甲酸三甲酯106.1g(1.00mol)和甲醇400mL,加热回流2小时,常压蒸出甲醇后,加入氨基甲酸叔丁酯140.6g(1.20mol)和甲苯600mL,加热至80-100℃,边反应边蒸出反应生成的甲醇加速反应,反应3小时,GC中控原料剩余<1%,降温,减压浓缩出溶剂,加入乙醇,降温至0℃搅拌1小时,析出白色固体,过滤,得到235.3g白色固体产品,收率81.6%,纯度99.0%。
第二步:向5L高压釜中,加入上步所得产品235.3g(0.816mol)和2.3L甲醇,加入11.8g5%Pd/C,体系用氮气置换三次,通入氢气,控制压力0.8-1.0MPa,缓慢升温至80℃,保温8小时,GC中控原料反应完全,降温,过滤,滤液浓缩得粗品,加入正庚烷打浆得白色固体产品4-Boc-氨基哌啶145.0g,收率88.7%,GC含量99.0%,mp:161.7–163.3℃。
实施例3
第一步:向1L三口瓶内,加入N-苄基-4-哌啶酮189.2g(1.00mol),对甲苯磺酸8.60g(50mmol),原甲酸三乙酯296.4g(2.00mol)和乙醇400mL,加热回流2小时,常压蒸出乙醇后,加入氨基甲酸叔丁酯128.9g(1.10mol)和甲苯600mL,加热至90-110℃,边反应边蒸出反应生成的乙醇加速反应,反应3小时,GC中控原料剩余<1%,降温,减压浓缩出溶剂,加入乙醇,降温至0℃搅拌1小时,析出白色固体,过滤,得到242.0g白色固体产品,收率83.9%,纯度99.2%。
第二步:向5L高压釜中,加入上步所得产品242.0g(0.839mol)和2.4L甲醇,加入12.1g10%Pd/C,体系用氮气置换三次,通入氢气,控制压力0.8-1.0MPa,缓慢升温至60℃,保温7小时,GC中控原料反应完全,降温,过滤,滤液浓缩得粗品,加入正庚烷打浆得白色固体产品4-Boc-氨基哌啶148.0g,收率88.1%,GC含量99.1%,mp:161.0–162.3℃。
实施例4
第一步:向1L三口瓶内,加入N-苄基-4-哌啶酮189.2g(1.00mol),氯化铵2.67g(50mmol),原甲酸三乙酯222.3g(1.50mol)和乙醇400mL,加热回流2小时,常压蒸出乙醇后,加入氨基甲酸叔丁酯140.6g(1.20mol)和甲苯600mL,加热至90-110℃,边反应边蒸出反应生成的乙醇加速反应,反应3小时,GC中控原料剩余<1%,降温,减压浓缩出溶剂,加入乙醇,降温至0℃搅拌1小时,析出白色固体,过滤,得到237.0g白色固体产品,收率82.2%,纯度98.9%。
第二步:向5L高压釜中,加入上步所得产品237.0g(0.822mol)和2.4L甲醇,加入23.7g10%Pd/C,体系用氮气置换三次,通入氢气,控制压力0.8-1.0MPa,缓慢升温至70℃,保温4小时,GC中控原料反应完全,降温,过滤,滤液浓缩得粗品,加入正庚烷打浆得白色固体产品4-Boc-氨基哌啶149.3g,收率90.7%,GC含量99.0%,mp:161.5–163.0℃。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (7)
2.根据权利要求1所述的一种制备4-Boc-氨基哌啶的方法,其特征在于:所述第一步中,酸选自对甲苯磺酸。
3.根据权利要求1所述的一种制备4-Boc-氨基哌啶的方法,其特征在于:所述第一步中,原甲酸三酯选自原甲酸三甲酯或原甲酸三乙酯,醇选自甲醇或乙醇。
4.根据权利要求1所述的一种制备4-Boc-氨基哌啶的方法,其特征在于:所述第一步中,N-苄基-4-哌啶酮、原甲酸三酯和氨基甲酸叔丁酯的摩尔比为1:1-2:1-1.2。
5.根据权利要求1所述的一种制备4-Boc-氨基哌啶的方法,其特征在于:所述第一步中,酸加入量为N-苄基-4-哌啶酮摩尔量的1-5%。
6.根据权利要求1所述的一种制备4-Boc-氨基哌啶的方法,其特征在于:所述第二步中,Pd/C含量为5%或10%,所用量为亚胺重量的5-10%。
7.根据权利要求1所述的一种制备4-Boc-氨基哌啶的方法,其特征在于:所述第二步中,Pd/C催化氢化还原反应为加压反应,反应压力为0.8MPa-1.0MPa,反应温度为60-80℃。
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