CN107652226B - 一种N-Boc-4-哌啶甲醛的制备方法 - Google Patents
一种N-Boc-4-哌啶甲醛的制备方法 Download PDFInfo
- Publication number
- CN107652226B CN107652226B CN201711133696.5A CN201711133696A CN107652226B CN 107652226 B CN107652226 B CN 107652226B CN 201711133696 A CN201711133696 A CN 201711133696A CN 107652226 B CN107652226 B CN 107652226B
- Authority
- CN
- China
- Prior art keywords
- boc
- reaction
- piperidinecarboxaldehyde
- formyl
- dihydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- JJRBNKQELFDHOG-UHFFFAOYSA-N tert-butyl 4-formyl-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C=O)=CC1 JJRBNKQELFDHOG-UHFFFAOYSA-N 0.000 claims abstract description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 14
- JYUQEWCJWDGCRX-UHFFFAOYSA-N tert-butyl 4-formylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C=O)CC1 JYUQEWCJWDGCRX-UHFFFAOYSA-N 0.000 claims abstract description 12
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 claims abstract description 11
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims abstract description 11
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 230000022244 formylation Effects 0.000 claims abstract description 8
- 238000006170 formylation reaction Methods 0.000 claims abstract description 8
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 16
- FEWLNYSYJNLUOO-UHFFFAOYSA-N 1-Piperidinecarboxaldehyde Chemical compound O=CN1CCCCC1 FEWLNYSYJNLUOO-UHFFFAOYSA-N 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- FDSBVQSWIOHAIJ-UHFFFAOYSA-N bis-(4-methylphenyl)sulfonylmethylidenehydrazine Chemical compound C1(=CC=C(C=C1)S(=O)(=O)C(=NN)S(=O)(=O)C1=CC=C(C=C1)C)C FDSBVQSWIOHAIJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 150000007857 hydrazones Chemical class 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 4
- -1 ketone hydrazone Chemical class 0.000 abstract description 2
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- ANUZKYYBDVLEEI-UHFFFAOYSA-N butane;hexane;lithium Chemical compound [Li]CCCC.CCCCCC ANUZKYYBDVLEEI-UHFFFAOYSA-N 0.000 description 4
- 235000011089 carbon dioxide Nutrition 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000010907 mechanical stirring Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 101001050886 Homo sapiens Lysine-specific histone demethylase 1A Proteins 0.000 description 2
- 102100024985 Lysine-specific histone demethylase 1A Human genes 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- CTEDVGRUGMPBHE-UHFFFAOYSA-N tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CO)CC1 CTEDVGRUGMPBHE-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 239000013037 reversible inhibitor Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
本发明公开了一种N‑Boc‑4‑哌啶甲醛的制备方法，属于有机化学技术领域。从N‑Boc‑4‑哌啶酮出发，与对甲苯磺酰肼反应生成酮腙，接着加入丁基锂/四甲基乙二胺/甲酰化试剂反应得到1‑Boc‑4‑甲酰基‑3,6‑二氢‑2H‑吡啶，随后钯碳催化氢化得到N‑Boc‑4‑哌啶甲醛。本发明具有操作简便，收率较高，使用的起始原料廉价易得，是制备N‑Boc‑4‑哌啶甲醛的适宜方法。
Description
技术领域：
本发明属于有机化学领域，具体涉及一种N-Boc-4-哌啶甲醛的制备方法。
背景技术：
N-Boc-4-哌啶甲醛,英文名：N-Boc-4-piperidine arboxyaldehyde，CAS：137076-22-3，类白色固体，可以用来合成治疗JAK相关的疾病，KDM1A/LSD1可逆抑制剂等潜在药物分子。因此，作为是重要的医药化工中间体，N-Boc-4-哌啶甲醛的制备方法被广泛研究，目前最常用的方法主要有两种：
1)第一种氧化合成方法
采用N-Boc-4-哌啶甲醇为原料，有机碱作用下，与二甲基亚砜和草酰氯或DCC混合氧化剂发生Swern oxidation反应得到N-Boc-4-哌啶甲醛。
合成路线如下所示：
但这一种合成方法具有操作麻烦、成生的硫醚很臭等缺点。
2)第二种还原合成方法
以酰胺、酯为原料，经铝氢化物还原得到N-Boc-4-哌啶甲醛；或以羧酸或酯为原料先被还原成N-Boc-4-哌啶甲醇，在进行氧化反应最后得到N-Boc-4-哌啶甲醛。
合成路线如下所示：
由于该类方法用到铝氢化物，存在易发生安全事故，并且污染环境，极易产生杂质，产品的纯度较低等缺点。
发明内容：
为克服以上缺点，本发明目的是提供一种N-Boc-4-哌啶甲醛的制备方法，从N-Boc-4-哌啶酮出发，与对甲苯磺酰肼反应生成酮腙，接着加入丁基锂/四甲基乙二胺/甲酰化试剂反应得到1-Boc-4-甲酰基-3,6-二氢-2H-吡啶，随后钯碳催化氢化得到N-Boc-4-哌啶甲醛。
一种N-Boc-4-哌啶甲醛的制备方法，其技术特征在于，包括如下步骤：
第一步，N-Boc-4-哌啶酮和对甲苯磺酰肼在醇类溶剂中回流制得对甲苯磺酰酮腙；
第二步，对甲苯磺酰酮腙与丁基锂、四甲基乙二胺混合，在低温下加入甲酰化试剂，反应结束后酸淬灭处理，得到1-Boc-4-甲酰基-3,6-二氢-2H-吡啶；
第三步，1-Boc-4-甲酰基-3,6-二氢-2H-吡啶经钯碳催化氢化，经后处理得到N-Boc-4-哌啶甲醛。
反应路线如下：
进一步地，所述第一步中，醇类溶剂为甲醇、乙醇或异丙醇。
进一步地，所述第一步中，N-Boc-4-哌啶酮和对甲苯磺酰肼的摩尔比为1：0.95-1，反应后得到的腙为白色晶状固体。
进一步地，所述第二步中，甲酰化试剂选自DMF或N-甲酰基哌啶。其中，对甲苯磺酰酮腙、丁基锂、四甲基乙二胺、甲酰化试剂的摩尔比为1：3-6：3-10：1.1-4，研究中发现四种物料不同的摩尔比，反应结果不同，优先1：4-5：4-5：1.5-2，以甲酰化试剂以DMF为例，反应结果如下：
进一步地，所述第二步中，萃取溶剂为乙酸乙酯、甲基叔丁基醚、甲苯、二氯甲烷等溶剂。
进一步地，所述第三步中，钯碳的催化量为1-Boc-4-甲酰基-3,6-二氢-2H-吡啶重量的5％-10％。
本发明的有益成果：
本发明应用了新颖的合成路线，和传统的氧化或还原工艺相比，反应条件温和，反应操作简便，同时避免了过度氧化或还原等副反应的发生，产品的收率和纯度高。本发明可以进行工业放大生产。
具体实施例
实施例1：
1、向磁力搅拌的250mL单口瓶中，加入18.62g对甲苯磺酰肼(0.10mol，1.0eq)，19.92gN-Boc-4-哌啶酮(0.10mol，1.0eq)，100mL甲醇，加热回流3小时，降至室温，过滤，干燥得白色固体对甲苯磺酰酮腙32.78g，HPLC含量99.0％，收率89.23％。
2、氮气保护下，体系用干冰/乙醇外浴降温至-70℃，向带有机械搅拌的500mL四口瓶中加入178mL正丁基锂的正己烷溶液(2.5mol/L，0.445mol，5eq)和95mL四氢呋喃，滴加滴液漏斗内用51.71g四甲基乙二胺(0.445mol，5eq)溶解的32.78g对甲苯磺酰酮腙(0.089mol，1eq)溶液，滴毕，自然升值室温保温3小时。继续降温至-70℃以下，滴加13.01gDMF(0.178mol，2.0eq)，滴毕，保温1小时，自然升至室温搅拌过夜，0～10℃下滴加1M盐酸至溶液pH值为6～7，分层，水层用乙酸乙酯萃取(50mL×3)，合并有机层浓缩后，得粗品黄色油液体1-Boc-4-甲酰基-3,6-二氢-2H-吡啶17.95g，不经纯化直接投下步，GC/MS(M/Z)211.12。
3、向250mL高压反应釜中，加入上步所得粗品17.95g 1-Boc-4-甲酰基-3,6-二氢-2H-吡啶和120mL甲醇，加入0.89g 10％Pd/C，体系用氮气置换三次，通入氢气，控制压力0.1-0.2MPa，30-40℃下保温2小时，过滤，滤液浓缩后，进行减压蒸馏得浅黄色油状物N-Boc-4-哌啶甲醛12.3g，GC：98.9％，1H-NMR(400MHz,CDCl3):9.67(1H,s),4.00-3.95(2H,m),2.96-2.90(2H,m),2.45-2.37(1H,m),1.91-1.87(2H,m),1.62-1.53(2H,m),1.46(9H,s)。
第二步和第三步总收率64.70％。
实施例2：
1、向磁力搅拌的250mL单口瓶中，加入18.62g对甲苯磺酰肼(0.10mol，1.0eq)，19.92gN-Boc-4-哌啶酮(0.10mol，1.0eq)，100mL乙醇，加热回流3小时，降至室温，过滤，干燥得白色固体对甲苯磺酰酮腙33.42g，HPLC含量98.5％，收率90.96％。
2、氮气保护下，体系用干冰/乙醇外浴降温至-70℃，向带有机械搅拌的500mL四口瓶中加入146mL正丁基锂的正己烷溶液(2.5mol/L，0.364mol，4eq)和65mL四氢呋喃，滴加滴液漏斗内用42.28g四甲基乙二胺(0.364mol，4eq)溶解的33.42g对甲苯磺酰酮腙(0.091mol，1eq)溶液，滴毕，自然升值室温保温3小时。继续降温至-70℃以下，滴加20.60gN-甲酰哌啶(0.182mol，2.0eq)，滴毕，保温1小时，自然升至室温搅拌过夜，0～10℃下滴加1M盐酸至溶液pH值为6～7，分层，水层用甲苯萃取(50mL×3)，合并有机层浓缩后，得粗品黄色油液体1-Boc-4-甲酰基-3,6-二氢-2H-吡啶18.18g，不经纯化直接投下步。
3、向250mL高压反应釜中，加入上步所得粗品18.18g 1-Boc-4-甲酰基-3,6-二氢-2H-吡啶和120mL甲醇，加入1.82g 10％Pd/C，体系用氮气置换三次，通入氢气，控制压力0.1-0.2MPa，30-40℃下保温2小时，过滤，滤液浓缩后，进行减压蒸馏得浅黄色油状物N-Boc-4-哌啶甲醛11.9g，GC：99.1％，第二步和第三步总收率61.45％。
实施例3：
1、向磁力搅拌的500mL单口瓶中，加入35.38g对甲苯磺酰肼(0.19mol，0.95eq)，39.85gN-Boc-4-哌啶酮(0.20mol，1.0eq)，100mL异丙醇，加热回流3小时，降至室温，过滤，干燥得白色固体对甲苯磺酰酮腙65.78g，HPLC含量98.3％，收率89.52％。
2、氮气保护下，体系用干冰/乙醇外浴降温至-40℃，向带有机械搅拌的1L四口瓶中加入358mL正丁基锂的正己烷溶液(2.5mol/L，0.896mol，5eq)和80mL四氢呋喃，滴加滴液漏斗内用104.06g四甲基乙二胺(0.896mol，5eq)溶解的65.78g对甲苯磺酰酮腙(0.179mol，1eq)溶液，滴毕，自然升值室温保温3小时。继续降温至-40℃以下，滴加19.62gDMF(0.268mol，1.5eq)，滴毕，保温1小时，自然升至室温搅拌过夜，0～10℃下滴加1M盐酸至溶液pH值为6～7，分层，水层用甲基叔丁基醚萃取(50mL×3)，合并有机层浓缩后，得粗品黄色油液体1-Boc-4-甲酰基-3,6-二氢-2H-吡啶34.62g，不经纯化直接投下步。
3、向500mL高压反应釜中，加入上步所得粗品34.62g 1-Boc-4-甲酰基-3,6-二氢-2H-吡啶和240mL甲醇，加入1.73g 10％Pd/C，体系用氮气置换三次，通入氢气，控制压力0.1-0.2MPa，30-40℃下保温2小时，过滤，滤液浓缩后，进行减压蒸馏得浅黄色油状物N-Boc-4-哌啶甲醛23.72g，GC：99.0％，第二步和第三步总收率62.12％。
实施例4：
1、向磁力搅拌的500mL单口瓶中，加入35.38g对甲苯磺酰肼(0.190mol，0.95eq)，39.85gN-Boc-4-哌啶酮(0.200mol，1.0eq)，200mL无水乙醇，加热回流3小时，降至室温，过滤，干燥得白色固体对甲苯磺酰酮腙66.15g，HPLC含量98.9％，收率90.02％。
2、氮气保护下，体系用干冰/乙醇外浴降温至-40℃，向带有机械搅拌的1L四口瓶中加入288mL正丁基锂的正己烷溶液(2.5mol/L，0.72mol，4eq)和130mL四氢呋喃，滴加滴液漏斗内用83.67g四甲基乙二胺(0.72mol，4eq)溶解的66.15g对甲苯磺酰酮腙(0.180mol，1eq)溶液，滴毕，自然升值室温保温3小时。继续降温至-50℃以下，滴加30.55gN-甲酰哌啶(0.27mol，1.5eq)，滴毕，保温1小时，自然升至室温搅拌过夜，0～10℃下滴加1M盐酸至溶液pH值为6～7，分层，水层用乙酸乙酯萃取(100mL×3)，合并有机层浓缩后，得粗品黄色油液体1-Boc-4-甲酰基-3,6-二氢-2H-吡啶36.28g，不经纯化直接投下步。
3、向500mL高压反应釜中，加入上步所得粗品36.28g 1-Boc-4-甲酰基-3,6-二氢-2H-吡啶和240mL甲醇，加入1.81g 10％Pd/C，体系用氮气置换三次，通入氢气，控制压力0.1-0.2MPa，30-40℃下保温2小时，过滤，滤液浓缩后，进行减压蒸馏得浅黄色油状物N-Boc-4-哌啶甲醛23.18g，GC：98.6％，第二步和第三步总收率60.38％。
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 (5)
1.一种N-Boc-4-哌啶甲醛的制备方法，其特征在于：N-Boc-4-哌啶酮与对甲苯磺酰肼制得对甲苯磺酰酮腙，接着与丁基锂、四甲基乙二胺/甲酰化试剂反应得到1-Boc-4-甲酰基-3,6-二氢-2H-吡啶，经钯碳氢化后得到N-Boc-4-哌啶甲醛；具体步骤如下：第一步，N-Boc-4-哌啶酮和对甲苯磺酰肼在醇类溶剂中回流制得对甲苯磺酰酮腙；第二步，对甲苯磺酰酮腙与丁基锂、四甲基乙二胺，在-40℃或-70℃反应后，加入甲酰化试剂，反应结束酸淬灭，得到1-Boc-4-甲酰基-3,6-二氢-2H-吡啶；第三步，1-Boc-4-甲酰基-3,6-二氢-2H-吡啶钯碳加压下催化氢化，经后处理得到N-Boc-4-哌啶甲醛；其中，所述对甲苯磺酰酮腙、丁基锂、四甲基乙二胺、甲酰化试剂摩尔比为1：4-5：4-5：1.5-2。
2.根据权利要求1所述的一种N-Boc-4-哌啶甲醛的制备方法，其特征在于：所述第一步中，醇类溶剂为甲醇、乙醇或异丙醇。
3.根据权利要求1所述的一种N-Boc-4-哌啶甲醛的制备方法，其特征在于：所述第一步中，N-Boc-4-哌啶酮和对甲苯磺酰肼的摩尔比为1：0.95-1，反应后得到的腙为白色晶状固体。
4.根据权利要求1所述的一种N-Boc-4-哌啶甲醛的制备方法，其特征在于：所述第二步中，甲酰化试剂选自DMF或N-甲酰基哌啶。
5.根据权利要求1所述的一种N-Boc-4-哌啶甲醛的制备方法，其特征在于：所述第三步中，钯碳的催化量为1-Boc-4-甲酰基-3,6-二氢-2H-吡啶重量的5％-10％。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711133696.5A CN107652226B (zh) | 2017-11-15 | 2017-11-15 | 一种N-Boc-4-哌啶甲醛的制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711133696.5A CN107652226B (zh) | 2017-11-15 | 2017-11-15 | 一种N-Boc-4-哌啶甲醛的制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107652226A CN107652226A (zh) | 2018-02-02 |
| CN107652226B true CN107652226B (zh) | 2020-03-31 |
Family
ID=61121580
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711133696.5A Active CN107652226B (zh) | 2017-11-15 | 2017-11-15 | 一种N-Boc-4-哌啶甲醛的制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107652226B (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110540535B (zh) * | 2019-10-23 | 2020-07-31 | 上海再启生物技术有限公司 | 适合放大制备4-(6-氨基吡啶-3-基)取代哌啶的工艺方法 |
| CN111423360A (zh) * | 2020-04-27 | 2020-07-17 | 暨南大学 | 一种丙烯醛-丝氨酸加合物及其制备方法与应用 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503869A (zh) * | 2011-08-10 | 2016-04-20 | 爱尔兰詹森科学公司 | 抗细菌的哌啶基取代的3,4-二氢-1h-[1,8]萘啶酮 |
| WO2017147328A1 (en) * | 2016-02-23 | 2017-08-31 | Portola Pharmaceuticals, Inc. | Compounds for binding proprotein convertase subtilisin/kexin type 9 (pcsk9) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB201308736D0 (en) * | 2013-05-15 | 2013-06-26 | Univ Aberdeen | Compounds and their therapeutic use |
-
2017
- 2017-11-15 CN CN201711133696.5A patent/CN107652226B/zh active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503869A (zh) * | 2011-08-10 | 2016-04-20 | 爱尔兰詹森科学公司 | 抗细菌的哌啶基取代的3,4-二氢-1h-[1,8]萘啶酮 |
| WO2017147328A1 (en) * | 2016-02-23 | 2017-08-31 | Portola Pharmaceuticals, Inc. | Compounds for binding proprotein convertase subtilisin/kexin type 9 (pcsk9) |
Non-Patent Citations (1)
| Title |
|---|
| Min-Ruei Tsai，等.New Approach to N-substituted-1,2,3,6-tetrahydro-pyridine-4-carbaldehyde, a Precursor for Synthesizing Aricep®, Isoguvacine, and Deethylibophyllidine.《Journal of the Chinese Chemical Society》.2004,第51卷(第3期),613-617. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107652226A (zh) | 2018-02-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR20090045920A (ko) | 방향족 시클로프로판 에스테르 및 아미드의 화학적 제조 방법 | |
| WO2012102247A1 (ja) | ルテニウム錯体を含む水素移動反応用触媒及び水素移動反応物の製造方法 | |
| CN107652226B (zh) | 一种N-Boc-4-哌啶甲醛的制备方法 | |
| CN112142694A (zh) | 一种多取代四氢呋喃与四氢吡喃双烯体类化合物及其制备方法 | |
| CN112500361B (zh) | 一种(s)-4-苯基-2-恶唑烷酮的制备方法 | |
| CN111793016B (zh) | 一种拉罗替尼中间体的制备方法以及中间体化合物 | |
| CN112724064A (zh) | 一种利用改性有序介孔碳负载金属催化剂制备5,6-二羟基吲哚的方法 | |
| CN107286070A (zh) | (r)‑2‑(2,5‑二氟苯基)吡咯烷的合成方法及中间体 | |
| CN114702402B (zh) | 一种氟代苯基氨基酸盐酸盐的合成方法 | |
| EP3904333A1 (en) | Method for preparing (2s,3s)-3-amino-bicyclo[2.2.2]octane-2-carboxylate | |
| JP5448572B2 (ja) | アセチル化合物、該アセチル化合物の製造方法、および該アセチル化合物を使用したナフトール化合物の製造方法 | |
| CN112159336B (zh) | 一种高纯度的芳炔取代的腈类化合物的制备方法 | |
| CA2502360C (en) | Process for producing acetylene compound | |
| CN113620761B (zh) | 苯硅烷还原芳基仲酰胺或芳基仲酰胺衍生物合成芳基醛类化合物的制备方法 | |
| CN115872887B (zh) | 一种阿戈美拉汀的制备方法 | |
| CN117682980B (zh) | 一种2-乙酰基四氢吡啶的制备方法 | |
| KR100477048B1 (ko) | 피페리딘 화합물의 새로운 제조방법 | |
| JP4759722B2 (ja) | 置換基を有する芳香族カルボン酸エステルの製造方法 | |
| JPH0641012A (ja) | 光学活性３−フェニル−３−ヒドロキシプロピオン酸エステルの製造方法 | |
| JP4896539B2 (ja) | ３−アルキル−４，４’−ビフェノールの製造方法及び３−アルキル−４，４’−ビフェノールと３，３’−ジアルキル−４，４’−ビフェノールとの混合物の製造方法 | |
| JP4212466B2 (ja) | アラルキルアミン誘導体の製造方法 | |
| TW202334100A (zh) | 芳香族硝基化合物之催化氫化 | |
| JP2002512210A (ja) | ２−ヒドロキシアルキルハロフェノンの製造方法 | |
| CN116003305A (zh) | 一种5-乙基-2-吡咯甲酸的制备方法 | |
| CN117486730A (zh) | 一种二环已基甲胺的制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20231121 Address after: 034406 guomaoshan Park, donghenan Town, Lingqiu County, Datong City, Shanxi Province (guomaoshan road section, 120km away from the original Daling highway) Patentee after: Shanxi Kubang Biomedical Technology Co.,Ltd. Address before: 201611 room 2207, building 6, 1378 Xingxian Road, Jiading District, Shanghai Patentee before: SHANGHAI HOBOR CHEMICAL Co.,Ltd. |