CN105237496A - A new method for synthesizing N-tert-butoxycarbonylpiperazine - Google Patents
A new method for synthesizing N-tert-butoxycarbonylpiperazine Download PDFInfo
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- CN105237496A CN105237496A CN201510706046.XA CN201510706046A CN105237496A CN 105237496 A CN105237496 A CN 105237496A CN 201510706046 A CN201510706046 A CN 201510706046A CN 105237496 A CN105237496 A CN 105237496A
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- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title claims abstract description 13
- 230000002194 synthesizing effect Effects 0.000 title description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 82
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 23
- CVVIJWRCGSYCMB-UHFFFAOYSA-N hydron;piperazine;dichloride Chemical compound Cl.Cl.C1CNCCN1 CVVIJWRCGSYCMB-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 7
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 6
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 claims 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- 229960004756 ethanol Drugs 0.000 claims 3
- 229960000935 dehydrated alcohol Drugs 0.000 claims 2
- 238000010992 reflux Methods 0.000 claims 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 1
- 238000004090 dissolution Methods 0.000 claims 1
- 238000009413 insulation Methods 0.000 claims 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 abstract description 22
- MSQACBWWAIBWIC-UHFFFAOYSA-N hydron;piperazine;chloride Chemical compound Cl.C1CNCCN1 MSQACBWWAIBWIC-UHFFFAOYSA-N 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 9
- 238000001816 cooling Methods 0.000 description 4
- -1 filtered Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 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
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域：Technical field:
本发明属于药物中间体合成领域，涉及了一种N-叔丁氧羰基哌嗪的合成方法。 The invention belongs to the field of synthesis of pharmaceutical intermediates, and relates to a synthesis method of N -tert-butoxycarbonylpiperazine.
背景技术：Background technique:
N-叔丁氧羰基哌嗪属于哌嗪类单取代化合物，哌嗪单取代化合物由于其特殊的结构成为众多药物合成中的关键中间体，广泛应用于镇咳药、抗过敏药、抗精神病类药物、抗菌药物等领域。因此，合成哌嗪类单取代化合物具有非常重要的药学价值及经济价值。 N -tert-butoxycarbonylpiperazine belongs to piperazine monosubstituted compounds. Due to its special structure, piperazine monosubstituted compounds have become key intermediates in the synthesis of many drugs, and are widely used in antitussives, antiallergics, and antipsychotics. Drugs, antibacterial drugs and other fields. Therefore, the synthesis of piperazine monosubstituted compounds has very important pharmaceutical and economic value.
目前合成N-叔丁氧羰基哌嗪的方法较多，其中专利WO2012048894介绍了一种将二碳酸二叔丁酯滴加在过量的无水哌嗪中，反应结束后浓缩溶剂，水洗、过滤、萃取、干燥、浓缩得产品N-叔丁氧羰基哌嗪，这样不可避免的有部分哌嗪两端都被叔丁氧羰基保护起来，不仅N-叔丁氧羰基哌嗪的收率低，还降低了原料无水哌嗪的利用率。同时专利CN20101059535报道了以乙二醇胺为原料，用氯化苄先保护胺，再将经取代、氨解、成环得到单保护的哌嗪，再与二碳酸二叔丁酯反应，再脱苄基得产品。这种方法虽然提高了哌嗪N上的选择性，但是反应步骤多，合成工艺复杂，增加了成本，并且使用了有毒性的氯化亚砜，不利于大规模工业化生产。因此开发一种合成方法简单，选择性好的工艺是本发明的关键问题。 At present, there are many methods for synthesizing N -tert-butoxycarbonylpiperazine, wherein patent WO2012048894 introduces a method of adding di-tert-butyl dicarbonate dropwise in excess anhydrous piperazine, and after the reaction is finished, the solvent is concentrated, washed with water, filtered, Extract, dry, concentrate to get product N -tert-butoxycarbonyl piperazine, so inevitably some piperazine two ends are all protected by tert-butoxycarbonyl, not only the yield of N -tert-butoxycarbonyl piperazine is low, but also Reduced the utilization rate of raw material anhydrous piperazine. At the same time, patent CN20101059535 reported that ethylene glycol amine was used as a raw material, and benzyl chloride was used to protect the amine first, and then the monoprotected piperazine was obtained through substitution, ammonolysis, and ring formation, and then reacted with di-tert-butyl dicarbonate, and then removed Benzyl products. Although this method improves the selectivity on piperazine N, there are many reaction steps, the synthesis process is complicated, the cost is increased, and toxic thionyl chloride is used, which is not conducive to large-scale industrial production. Therefore developing a kind of synthesis method is simple, and the technique with good selectivity is the key problem of the present invention.
本发明针对哌嗪两端N上都被叔丁氧羰基保护这一问题，提供了一种N-叔丁氧羰基哌嗪合成的新方法，将无水哌嗪先做成哌嗪二盐酸盐的形式，之后将哌嗪二盐酸盐与无水哌嗪混合做成哌嗪单盐酸盐，再与二碳酸二叔丁酯反应，得到产品N-叔丁氧羰基哌嗪。此合成路线提高了哌嗪N上的选择性，同时又避免了原料无水哌嗪的浪费，未反应的哌嗪盐酸盐还可以回收，该合成路线产品收率高，纯度好，为实施大规模化工业生产提供了技术支持。 Aiming at the problem that the N at both ends of piperazine is protected by tert-butoxycarbonyl groups, the present invention provides a new method for the synthesis of N -tert-butoxycarbonylpiperazine, in which anhydrous piperazine is first made into piperazine dihydrochloride In the form of salt, piperazine dihydrochloride and anhydrous piperazine are mixed to make piperazine monohydrochloride, and then reacted with di-tert-butyl dicarbonate to obtain the product N -tert-butoxycarbonyl piperazine. This synthetic route improves the selectivity on piperazine N, avoids the waste of raw material anhydrous piperazine at the same time, unreacted piperazine hydrochloride can also be recovered, and the product yield of this synthetic route is high, and purity is good, for implementation Large-scale industrial production provides technical support.
发明内容：Invention content:
本发明的目的是针对现有技术上的不足提供了一种N-叔丁氧羰基哌嗪合成方法，可通过如下技术方案实现： The purpose of the present invention is to provide a kind of N -tert-butoxycarbonylpiperazine synthetic method at the deficiencies in the prior art, can realize by following technical scheme:
具体步骤为：The specific steps are:
第一步向无水哌嗪的乙醇溶液加浓盐酸得哌嗪二盐酸盐。 The first step is to add concentrated hydrochloric acid to the ethanol solution of anhydrous piperazine to obtain piperazine dihydrochloride.
冰浴下，向无水哌嗪（1当量）的乙醇溶液中慢慢滴加浓盐酸（2当量），析出固体，过滤得哌嗪二盐酸盐，产率定量。 Under ice-cooling, slowly add concentrated hydrochloric acid (2 equivalents) dropwise to anhydrous piperazine (1 equivalent) in ethanol to precipitate a solid, which was filtered to obtain piperazine dihydrochloride in quantitative yield.
第二步将哌嗪二盐酸盐与无水哌嗪在无水乙醇中回流，得哌嗪单盐酸盐。 In the second step, piperazine dihydrochloride and anhydrous piperazine are refluxed in absolute ethanol to obtain piperazine monohydrochloride.
将哌嗪二盐酸盐（1当量）与无水哌嗪（1当量）在无水乙醇中回流1h，固体溶解，得哌嗪单盐酸盐。 Piperazine dihydrochloride (1 equivalent) and anhydrous piperazine (1 equivalent) were refluxed in absolute ethanol for 1 hour, and the solid was dissolved to obtain piperazine monohydrochloride.
第三步哌嗪单盐酸盐与二碳酸二叔丁酯反应得N-叔丁氧羰基哌嗪。 The third step is to react piperazine monohydrochloride with di-tert-butyl dicarbonate to obtain N -tert-butoxycarbonyl piperazine.
50℃水浴条件下，向哌嗪单盐酸盐的乙醇中慢慢滴加的二碳酸二叔丁酯（2当量），保温反应5h，冷却至室温，过滤回收盐酸盐，真空浓缩滤液，水洗，过滤，滤液用二氯甲烷萃取两次，合并有机相，无水MgSO4干燥，浓缩得N-叔丁氧羰基哌嗪，产率76.0%。 Under the condition of 50°C water bath, slowly add di-tert-butyl dicarbonate (2 equivalents) dropwise to the ethanol of piperazine monohydrochloride, keep the temperature for 5 hours, cool to room temperature, filter and recover the hydrochloride, and concentrate the filtrate in vacuo, Wash with water, filter, and extract the filtrate twice with dichloromethane, combine the organic phases, dry over anhydrous MgSO 4 , and concentrate to obtain N -tert-butoxycarbonylpiperazine with a yield of 76.0%.
本发明的有益效果： Beneficial effects of the present invention:
由于哌嗪上有两个活性相同的氨基，降低了酰化反应的选择性，所以本专利将无水哌嗪先做成哌嗪二盐酸盐的形式，之后将哌嗪二盐酸盐与无水哌嗪混合做成哌嗪单盐酸盐，再与二碳酸二叔丁酯反应，较之现有技术，提高了反应的选择性，使用了廉价易得的乙醇做溶剂，反应步骤少，反应时间短，产品收率高、纯度好，后处理简单，同时又可回收哌嗪盐酸盐，并且溶剂可多次回收套用，降低了生产成本，适用于大规模工业化生产。 Since there are two amino groups with the same activity on piperazine, which reduces the selectivity of the acylation reaction, this patent first makes piperazine dihydrochloride from anhydrous piperazine, and then combines piperazine dihydrochloride with Anhydrous piperazine is mixed to make piperazine monohydrochloride, and then reacted with di-tert-butyl dicarbonate. Compared with the prior art, the selectivity of the reaction is improved, and cheap and easy-to-get ethanol is used as a solvent, and the reaction steps are less , the reaction time is short, the product yield is high, the purity is good, the post-treatment is simple, and piperazine hydrochloride can be recovered at the same time, and the solvent can be recycled for many times, which reduces the production cost and is suitable for large-scale industrial production.
具体实施方式：detailed description:
实施例1： Example 1:
冰浴下，向无水哌嗪（1eq）的乙醇溶液中慢慢滴加浓盐酸（2eq），析出白色固体，过滤得哌嗪二盐酸盐，滤液套用。将哌嗪二盐酸盐（2.5g，1eq）与无水哌嗪（1.3g，1eq）在无水乙醇中回流1h，固体溶解。50℃水浴条件下慢慢滴加的二碳酸二叔丁酯（6.8g，2eq）保温反应5h，冷却至室温，过滤回收盐酸盐，真空蒸发溶剂，向体系中加入50mL水处理，过滤，滤液进一步用二氯甲烷（50+30）mL萃取，水相浓缩回收原料哌嗪，合并有机相，用无水MgSO4干燥，真空浓缩得无色油状物，得产品4.4g，收率76.0%。 Slowly add concentrated hydrochloric acid (2eq) dropwise to the ethanol solution of anhydrous piperazine (1eq) under ice-cooling, and a white solid precipitates, which is filtered to obtain piperazine dihydrochloride, and the filtrate is used mechanically. Piperazine dihydrochloride (2.5g, 1eq) and anhydrous piperazine (1.3g, 1eq) were refluxed in absolute ethanol for 1h, and the solid dissolved. Slowly add di-tert-butyl dicarbonate (6.8g, 2eq) dropwise in a water bath at 50°C for 5 hours, cool to room temperature, recover the hydrochloride by filtration, evaporate the solvent in vacuo, add 50mL of water to the system, filter, The filtrate was further extracted with dichloromethane (50+30) mL, the aqueous phase was concentrated to recover the raw material piperazine, the organic phases were combined, dried with anhydrous MgSO 4 , and concentrated in vacuo to obtain a colorless oil, 4.4 g of the product, yield 76.0% .
实施例2： Example 2:
冰浴下，向无水哌嗪（1eq）的乙醇溶液中慢慢滴加浓盐酸（2eq），析出白色固体，过滤得哌嗪二盐酸盐，滤液套用。将哌嗪二盐酸盐（10g，1eq）与无水哌嗪（5.3g，1eq）在无水乙醇中回流1h，固体溶解。50℃水浴条件下慢慢滴加的二碳酸二叔丁酯（27.2g，2eq）保温反应5h，冷却至室温，过滤回收盐酸盐，真空蒸发滤液，向体系中加入200mL水处理，过滤，滤液进一步用二氯甲烷（100+50）mL萃取，水相浓缩回收原料哌嗪，合并有机相，用无水MgSO4干燥，真空浓缩得无色油状物，得产品18.1g，收率76.9%。 Slowly add concentrated hydrochloric acid (2eq) dropwise to the ethanol solution of anhydrous piperazine (1eq) under ice-cooling, and a white solid precipitates, which is filtered to obtain piperazine dihydrochloride, and the filtrate is used mechanically. Piperazine dihydrochloride (10g, 1eq) and anhydrous piperazine (5.3g, 1eq) were refluxed in absolute ethanol for 1h, and the solid dissolved. Slowly add di-tert-butyl dicarbonate (27.2g, 2eq) dropwise in a water bath at 50°C for 5 hours, cool to room temperature, filter to recover the hydrochloride, evaporate the filtrate in a vacuum, add 200mL of water to the system, filter, The filtrate was further extracted with dichloromethane (100+50) mL, the aqueous phase was concentrated to recover the raw material piperazine, the organic phase was combined, dried with anhydrous MgSO 4 , and concentrated in vacuo to obtain a colorless oily product, 18.1 g of the product, yield 76.9% .
实施例3： Example 3:
冰浴下，向无水哌嗪（1eq）的乙醇溶液中慢慢滴加浓盐酸（2eq），析出白色固体，过滤得哌嗪二盐酸盐，滤液套用。将哌嗪二盐酸盐（30.0g，1eq）与无水哌嗪（15.8g，1eq）在无水乙醇中回流1h，固体溶解。50℃水浴条件下慢慢滴加的二碳酸二叔丁酯（81.6g，2eq）保温反应5h，真空蒸发滤液，向体系中加入600mL水处理，过滤，滤液进一步用二氯甲烷（300+150）mL萃取，水相浓缩回收原料哌嗪，合并有机相，用无水MgSO4干燥，真空浓缩得无色油状物，得产品50.1g，收率72.0%。 Slowly add concentrated hydrochloric acid (2eq) dropwise to the ethanol solution of anhydrous piperazine (1eq) under ice-cooling, and a white solid precipitates, which is filtered to obtain piperazine dihydrochloride, and the filtrate is used mechanically. Piperazine dihydrochloride (30.0g, 1eq) and anhydrous piperazine (15.8g, 1eq) were refluxed in absolute ethanol for 1h, and the solid dissolved. Slowly add di-tert-butyl dicarbonate (81.6g, 2eq) dropwise in a water bath at 50°C for 5 hours, evaporate the filtrate in vacuo, add 600mL of water to the system, filter, and further dichloromethane (300+150 ) mL extraction, the aqueous phase was concentrated to recover the raw material piperazine, the organic phases were combined, dried with anhydrous MgSO 4 , and concentrated in vacuo to obtain a colorless oily product, 50.1 g of the product, with a yield of 72.0%.
上述虽然对本发明的具体实施方式进行了描述，但并非对本发明保护范围的限制，所属领域技术人员应该明白，在本发明的技术方案的基础上，本领域技术人员不需要付出创造性劳动即可做出的各种修改或变形仍在本发明的保护范围以内。 Although the specific implementation of the present invention has been described above, it is not a limitation to the protection scope of the present invention. Those skilled in the art should understand that on the basis of the technical solution of the present invention, those skilled in the art can do it without creative work. Various modifications or deformations are still within the protection scope of the present invention.
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Cited By (6)
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|---|---|---|---|---|
| CN106045941A (en) * | 2016-06-16 | 2016-10-26 | 盐城工学院 | Method for preparing piperazine hydrochloride |
| CN106083761A (en) * | 2016-06-16 | 2016-11-09 | 盐城工学院 | The preparation method of the monosubstituted piperazine compounds of a kind of N and application |
| CN113773279A (en) * | 2021-09-16 | 2021-12-10 | 安徽德信佳生物医药有限公司 | A method for preparing N-tert-butoxycarbonylpiperazine using microchannel reactor |
| CN114349711A (en) * | 2022-02-28 | 2022-04-15 | 四川恒康科技发展有限公司 | Synthesis method of (R) -1-Boc-3-hydroxymethyl piperazine |
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Cited By (7)
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| CN106045941A (en) * | 2016-06-16 | 2016-10-26 | 盐城工学院 | Method for preparing piperazine hydrochloride |
| CN106083761A (en) * | 2016-06-16 | 2016-11-09 | 盐城工学院 | The preparation method of the monosubstituted piperazine compounds of a kind of N and application |
| CN113773279A (en) * | 2021-09-16 | 2021-12-10 | 安徽德信佳生物医药有限公司 | A method for preparing N-tert-butoxycarbonylpiperazine using microchannel reactor |
| CN114349711A (en) * | 2022-02-28 | 2022-04-15 | 四川恒康科技发展有限公司 | Synthesis method of (R) -1-Boc-3-hydroxymethyl piperazine |
| CN114349711B (en) * | 2022-02-28 | 2023-08-15 | 四川依维欣医药科技有限公司 | Synthesis method of (R) -1-Boc-3-hydroxymethyl piperazine |
| CN116120260A (en) * | 2023-01-06 | 2023-05-16 | 中国科学院宁波材料技术与工程研究所 | Preparation method and application of piperazine monohalogen salt |
| CN116143724A (en) * | 2023-01-06 | 2023-05-23 | 中国科学院宁波材料技术与工程研究所 | A kind of preparation method and application of piperazine chloride |
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