CN112778193B - 一种(s)-3-(4-氯苯基)-哌啶的合成方法 - Google Patents
一种(s)-3-(4-氯苯基)-哌啶的合成方法 Download PDFInfo
- Publication number
- CN112778193B CN112778193B CN202110305836.2A CN202110305836A CN112778193B CN 112778193 B CN112778193 B CN 112778193B CN 202110305836 A CN202110305836 A CN 202110305836A CN 112778193 B CN112778193 B CN 112778193B
- Authority
- CN
- China
- Prior art keywords
- chlorophenyl
- piperidine
- chloro
- steps
- acid
- 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
- GLXKIKPTKUQMAP-SNVBAGLBSA-N (3s)-3-(4-chlorophenyl)piperidine Chemical compound C1=CC(Cl)=CC=C1[C@H]1CNCCC1 GLXKIKPTKUQMAP-SNVBAGLBSA-N 0.000 title claims abstract description 18
- 238000001308 synthesis method Methods 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 12
- GLXKIKPTKUQMAP-UHFFFAOYSA-N 3-(4-chlorophenyl)piperidine Chemical compound C1=CC(Cl)=CC=C1C1CNCCC1 GLXKIKPTKUQMAP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims abstract description 8
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- YPBFNHGCMSEQHJ-UHFFFAOYSA-N ClCCCC(C1=CC=C(C=C1)Cl)C#N Chemical compound ClCCCC(C1=CC=C(C=C1)Cl)C#N YPBFNHGCMSEQHJ-UHFFFAOYSA-N 0.000 claims description 5
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 5
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 claims description 3
- 229960001270 d- tartaric acid Drugs 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- IVYMIRMKXZAHRV-UHFFFAOYSA-N 4-chlorophenylacetonitrile Chemical compound ClC1=CC=C(CC#N)C=C1 IVYMIRMKXZAHRV-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 3
- 239000000047 product Substances 0.000 abstract description 3
- GJNGXPDXRVXSEH-UHFFFAOYSA-N 4-chlorobenzonitrile Chemical group ClC1=CC=C(C#N)C=C1 GJNGXPDXRVXSEH-UHFFFAOYSA-N 0.000 abstract description 2
- 230000029936 alkylation Effects 0.000 abstract description 2
- 238000005804 alkylation reaction Methods 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 230000003287 optical effect Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 4
- 229910003446 platinum oxide Inorganic materials 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- -1 5-chloro-2- (4-chlorophenyl) pentan-1-amine Chemical compound 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- CBDGLHGPNJMCQK-UHFFFAOYSA-N 2-bromo-2-methylhexanoic acid Chemical compound CCCCC(C)(Br)C(O)=O CBDGLHGPNJMCQK-UHFFFAOYSA-N 0.000 description 1
- XDELKSRGBLWMBA-UHFFFAOYSA-N 3-iodopyridine Chemical compound IC1=CC=CN=C1 XDELKSRGBLWMBA-UHFFFAOYSA-N 0.000 description 1
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- INPLXZPZQSLHBR-UHFFFAOYSA-N cobalt(2+);sulfide Chemical compound [S-2].[Co+2] INPLXZPZQSLHBR-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 150000004687 hexahydrates Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000009987 spinning Methods 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
-
- 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
Abstract
本发明涉及一种(S)‑3‑(4‑氯苯基)‑哌啶的合成方法。主要解决通过氢化吡啶环，然后利用手性SFC制备获得光学纯(S)‑3‑(4‑氯苯基)‑哌啶，存在的反应条件苛刻，催化剂昂贵，成本高昂等等不适合放大生产的技术问题。本发明合成通过四个步骤，（1）4‑氯苯乙腈的a位烷基化；（2）5‑氯‑2‑(4‑氯苯基)戊氰的还原；（3）5‑氯‑2‑(4‑氯苯基)戊‑1‑胺环化得到(RS)‑3‑(4‑氯苯基)‑哌啶；（4）(RS)‑3‑(4‑氯苯基)‑哌啶经过化学拆分得最终产物。通过四步反应得到光学纯度达到98%以上的目标产物。本发明具有高收率，低成本，操作及纯化简便、经济效益好，更适合工业化生产。
Description
技术领域
本发明涉及一种(S)-3-(4-氯苯基)-哌啶的合成方法。(S)-3-(4-氯苯基)-哌啶是一种用于合成治疗神经性疾病药物的中间体，属于药物合成化工技术领域。
背景技术
哌啶类结构化合物属于含氮类六元杂环化合物相关的衍生物，它们具有广泛的生物活性。哌啶环是众多镇痛类药物药效的靶点，具有广泛的科研和药用价值，特别是手性的哌啶类结构化合物更是成为许多科研工作者的研究热点。
专利WO2015019103A1公开了一种合成(S)-3-(4-氯苯基)-哌啶的合成方法，该方法是以3-碘吡啶为原料经过与4-氯苯硼酸的Suzuki反应，然后再经过氧化铂催化氢化得到消旋的3-(4-氯苯基)-哌啶，最后用手性SFC分离得到(S)-3-(4-氯苯基)-哌啶。由于这个催化剂氧化铂非常的昂贵，以及手性SFC分离放大困难，成本很高，不适宜工业化生产。
合成线路如下:
。
发明内容
本发明的目的是公开一种简洁，高效，条件温和适合工业化生产的用于合成(S)-3-(4-氯苯基)-哌啶的方法。主要解决催化剂氧化铂非常的昂贵，以及手性SFC分离放大困难，成本很高，不适宜工业化生产的技术问题。
本发明的技术方案为：一种(S)-3-(4-氯苯基)-哌啶的合成方法，其特征是：包括以下步骤：
步骤1：4-氯苯乙腈在碱的存在下，加入1-溴-3-氯丙烷，经反应得到5-氯-2-(4-氯苯基)戊氰；
步骤2：将步骤1得到的5-氯-2-(4-氯苯基)戊氰在甲醇溶液中，用硼氢化钠配氯化钴还原，得到5-氯-2-(4-氯苯基)戊-1-胺；
步骤3：将步骤2得到的5-氯-2-(4-氯苯基)戊-1-胺在碳酸钾的存在下环化得到(RS)-3-(4-氯苯基)-哌啶；
步骤4：将步骤3得到的(RS)-3-(4-氯苯基)-哌啶用手性酸拆分得到(S)-3-(4-氯苯基)-哌啶；
反应式如下：
。
上述反应中，第一步所述的碱为钠氢或叔丁醇钾，优选碱为钠氢；第四步所述的手性酸为右旋樟脑磺酸或D-酒石酸，优选手性酸为右旋樟脑磺酸。
本发明的有益效果：本发明以4-氯苯乙腈为原料经过a位烷基化，硼氢化钠配氯化钴还原，碱性条件下环化随后化学拆分，制备得到高光学纯度的手性(S)-3-(4-氯苯基)-哌啶。此方法原料便宜易得，反应条件温和，方法简洁，高效，且质量、产率较高，经济有效，适于工业大生产。
具体实施方式
实施例1：
第一步，4-氯苯乙腈的a位烷基化
向10 L三口烧瓶中加入溶剂THF (6500 mL)，置换氮气。冰浴冷却，分批加入钠氢(质量百分浓度60%, 145.1 g, 3.6 mol)。然后分批加入4-氯苯乙腈 (500 g, 3.3 mol)，加毕，冰浴下搅拌1小时。然后滴加3-氯-1溴丙烷 (524.7 g, 3.3 mol)，加毕，冰浴下搅拌0.5小时。在冰浴下用水(3000 mL)淬灭反应。用乙酸乙酯萃取(2 x 3000 mL)，有机相用无水硫酸镁干燥。过滤，滤液直接旋干。油状物用减压蒸馏纯化得到5-氯-2-(4-氯苯基)戊氰(311 g, 产率41%)。
第二步，5-氯-2-(4-氯苯基)戊氰的还原
向10 L三口烧瓶中加入2-溴-2-甲基己酸 (300 g，1.31 mmol)，甲醇 (3500 mL)和六水和硫化钴 (375 g, 1.58 mol)，搅拌，冷却至-30摄氏度。分批加入硼氢化钠 (149g, 3.94 mol)，反应1小时。加入1000 mL的水，过滤，滤饼用乙酸乙酯萃取(1000 mL)，滤液直接旋干。得到5-氯-2-（4-氯苯基）戊-1-胺 (241 g, 产率79%)。
第三步，5-氯-2-(4-氯苯基)戊-1-胺的环化
向5 L三口烧瓶中加入5-氯-2-(4-氯苯基)戊-1-胺酸 (240, 1.03 mol)和乙腈(2500 mL)。搅拌，加入碳酸钾 (69 g, 0.5 mol), 室温搅拌过夜。次日，浓缩，加入2L水，然后用DCM (1 L x 2) 萃取。有机相用盐水洗涤，无水硫酸钠干燥，蒸干。剩余物用甲叔醚打浆，过滤，干燥后得到产物(RS)-3-(4-氯苯基)-哌啶 (108.3 g，产率54%)。
第四步，(RS)-3-(4-氯苯基)-哌啶的化学拆分
向5 L三口烧瓶中加入(RS)-3-(4-氯苯基)-哌啶 (103.1 g，0.52 mol)和乙腈(2000 mL)，加入右旋樟脑磺酸(69.7 g, 0.3 mol)。加热至50摄氏度，搅拌过夜。次日冷却至25摄氏度后过滤收集析出的固体，并用50mL的乙腈洗涤，干燥后得到(S)-3-(4-氯苯基)-哌啶的樟脑磺酸盐(93.6 g, 0.22 mol)。
将上述固体加入350 mL的0.5M的氢氧化钠水溶液中，搅拌过夜。次日过滤收集固体，并用100 mL水洗涤，干燥后得到产物(S)-3-(4-氯苯基)-哌啶 (38.2 g，产率74%)。
1H NMR (DMSO-d 6): δ7.33 (d, J = 8.4 Hz, 2 H), 7.26 (d, J = 8.4 Hz, 2H), 2.95-2.93 (m, 2H), 2.61-2.59 (m, 1H), 2.49-2.45 (m, 2H), 1.85-1.82 (m,1H), 1.66-1.62 (m, 1H), 1.55-1.48 (m, 2H)。
实施例2，第一步用的碱为叔丁醇钾，其余同实施例1。
实施例3，第三步手性酸为D-酒石酸，其余同实施例1。
Claims (3)
1.一种(S)-3-(4-氯苯基)-哌啶的合成方法，其特征是：包括下步骤：
步骤1：4-氯苯乙腈在碱：叔丁醇钾或钠氢的存在下，加入1-溴-3-氯丙烷，经反应得到5-氯-2-(4-氯苯基)戊氰；
步骤2：将步骤1得到的5-氯-2-(4-氯苯基)戊氰在甲醇溶液中，用硼氢化钠配氯化钴还原，得到5-氯-2-(4-氯苯基)戊-1-胺；
步骤3：将步骤2得到的5-氯-2-(4-氯苯基)戊-1-胺在碳酸钾的存在下环化得到(RS)-3-(4-氯苯基)-哌啶；
步骤4：将步骤3得到的(RS)-3-(4-氯苯基)-哌啶用手性酸：右旋樟脑磺酸或D-酒石酸化学拆分，然后用氢氧化钠游离得到(S)-3-(4-氯苯基)-哌啶。
2.根据权利要求1所述的一种(S)-3-(4-氯苯基)-哌啶的合成方法，其特征是：所述步骤1的碱为钠氢。
3.根据权利要求1所述的一种(S)-3-(4-氯苯基)-哌啶的合成方法，其特征是：所述步骤4的手性酸是右旋樟脑磺酸。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110305836.2A CN112778193B (zh) | 2021-03-23 | 2021-03-23 | 一种(s)-3-(4-氯苯基)-哌啶的合成方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110305836.2A CN112778193B (zh) | 2021-03-23 | 2021-03-23 | 一种(s)-3-(4-氯苯基)-哌啶的合成方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112778193A CN112778193A (zh) | 2021-05-11 |
| CN112778193B true CN112778193B (zh) | 2024-03-12 |
Family
ID=75762812
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110305836.2A Active CN112778193B (zh) | 2021-03-23 | 2021-03-23 | 一种(s)-3-(4-氯苯基)-哌啶的合成方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112778193B (zh) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432059A (zh) * | 2015-08-04 | 2017-02-22 | 上海朴颐化学科技有限公司 | 一种3-羟基哌啶和其衍生物的制备方法及其中间体 |
| CN106854176A (zh) * | 2016-12-21 | 2017-06-16 | 南京艾德凯腾生物医药有限责任公司 | 一种制备尼拉帕尼对甲苯磺酸盐一水合物的方法 |
| CN109134351A (zh) * | 2018-09-21 | 2019-01-04 | 武汉理工大学 | S-3-（4-氨基苯基）哌啶的合成方法 |
| CN110759853A (zh) * | 2019-11-11 | 2020-02-07 | 上海科利生物医药有限公司 | 一种(s)-n-boc-3-羟基哌啶的制备方法 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2011232675A1 (en) * | 2010-03-25 | 2012-09-27 | Merck Sharp & Dohme Corp. | Novel spiro imidazolones as glucagon receptor antagonists, compositions, and methods for their use |
| WO2018005801A2 (en) * | 2016-07-01 | 2018-01-04 | Venenum Biodesign Llc | Novel non-systemic tgr5 agonists |
-
2021
- 2021-03-23 CN CN202110305836.2A patent/CN112778193B/zh active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432059A (zh) * | 2015-08-04 | 2017-02-22 | 上海朴颐化学科技有限公司 | 一种3-羟基哌啶和其衍生物的制备方法及其中间体 |
| CN106854176A (zh) * | 2016-12-21 | 2017-06-16 | 南京艾德凯腾生物医药有限责任公司 | 一种制备尼拉帕尼对甲苯磺酸盐一水合物的方法 |
| CN109134351A (zh) * | 2018-09-21 | 2019-01-04 | 武汉理工大学 | S-3-（4-氨基苯基）哌啶的合成方法 |
| CN110759853A (zh) * | 2019-11-11 | 2020-02-07 | 上海科利生物医药有限公司 | 一种(s)-n-boc-3-羟基哌啶的制备方法 |
Non-Patent Citations (3)
| Title |
|---|
| Dual-Functional Chiral Cu-Catalyst-Induced Photoredox Asymmetric Cyanofluoroalkylation of Alkenes;Quanping Guo，等;《ACS Catalysis》;第9卷;4470-4476 * |
| 沈大冬 ; 朱锦桃 ; .(R)-3-氯-1,2-丙二醇及镇咳药左羟丙哌嗪的合成.中国药物化学杂志.2007,(第01期),29-32. * |
| 王李平，等.（3S,4R）-３-甲基-４-苯基哌啶-４-羧酸乙酯的合成.《精细石油化工》.2019,第36卷(第3期),1-4. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112778193A (zh) | 2021-05-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2014339136C1 (en) | Process for the preparation of a PDE4 inhibitor | |
| MX2007008499A (es) | Metodo para la preparacion de 10,11-dihidro-10-hidroxi-5h-dibenz/ b, f/azepina-5-carboxamida. | |
| CN110590635A (zh) | 左乙拉西坦及其中间体的制备方法 | |
| CN107337676A (zh) | 一种托法替布起始原料的制备方法 | |
| CN112062712A (zh) | 一种2-（5-溴-3-甲基吡啶-2-基）乙酸盐酸盐的制备方法 | |
| CN1613848A (zh) | 合成多奈哌齐及其衍生物的新方法 | |
| CN112778193B (zh) | 一种(s)-3-(4-氯苯基)-哌啶的合成方法 | |
| EP2914574B1 (en) | New process | |
| CN105820174A (zh) | 一种多取代噻吩并吲哚衍生物的制备方法 | |
| CN105884746B (zh) | 氟马替尼的合成方法 | |
| CN114315609B (zh) | 一种制备顺式2-氨基环己醇的工艺方法 | |
| CN101654416A (zh) | N-[3-硝基-4-甲基-苯基]-4-醛基-苯甲酰胺及其制备方法以及其衍生物的制备方法 | |
| CN110092726B (zh) | 一种Bictegravir中间体的合成方法 | |
| CN109134351B (zh) | S-3-(4-氨基苯基)哌啶的合成方法 | |
| CN113105335A (zh) | 一种稳定氘标记的美利曲辛盐酸盐的合成方法 | |
| CN101088999A (zh) | 3－氨基奎宁二盐酸盐的合成方法 | |
| CN111606924A (zh) | 手性噻喃并吲哚并苯并噻吩砜类衍生物及其制备方法 | |
| CN111675710B (zh) | 度维尼西的制备方法 | |
| CN111635404B (zh) | 一种度维尼西的制备方法 | |
| CN115368234B (zh) | 一种索马鲁肽侧链及其中间体的合成方法 | |
| CN110467558B (zh) | 一种镍催化合成3-胺基异吲哚啉酮的反应方法 | |
| CN115286504B (zh) | 一种合成（r）-2-（2-（叔丁氧基）-2-氧乙基）戊酸的方法 | |
| CN115181047B (zh) | 手性3 -(二甲氨基)吡咯烷的制备方法 | |
| CN102827152A (zh) | 噻加宾的制备方法及其前体化合物 | |
| CN102863370A (zh) | 一种抗癫痫药左乙拉西坦的新合成方法 |
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 |