CN103130708B - A kind of preparation method of N-tertbutyloxycarbonyl-4-nitro piperidines - Google Patents
A kind of preparation method of N-tertbutyloxycarbonyl-4-nitro piperidines Download PDFInfo
- Publication number
- CN103130708B CN103130708B CN201110390723.3A CN201110390723A CN103130708B CN 103130708 B CN103130708 B CN 103130708B CN 201110390723 A CN201110390723 A CN 201110390723A CN 103130708 B CN103130708 B CN 103130708B
- Authority
- CN
- China
- Prior art keywords
- tertbutyloxycarbonyl
- piperidines
- nitro
- iodine
- reaction
- 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
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the preparation method of a kind of N tertbutyloxycarbonyl 4 nitro piperidines, mainly solve existing synthesis technique Road line length, yield is low, reaction is not easy to control, the technical problems such as experimental implementation inconvenience, the present invention, with N tertbutyloxycarbonyl 4 hydroxy piperidine for Material synthesis N tertbutyloxycarbonyl 4 iodine piperidines, then obtains target product by substitution reaction.Reaction equation is as follows:
Description
Technical field
The present invention relates to the synthetic method of N-tertbutyloxycarbonyl-4-nitro piperidines.
Background technology
N-tertbutyloxycarbonyl-4-nitro piperidines is the intermediate that in organic synthesis, a class is useful, all have been directed at patent WO2009126515, JP2008273847 and WO2007055514, it is widely used in Michael's addition, such as WO2007052843, US20060217417 and WO2003048124.The most also it is used for synthesizing AntiHIV1 RT activity class medicine, such as WO9744037.Synthetic method currently, with respect to this compounds mainly has two kinds: the first is that raw material first synthesizes oxime by N-t-butoxycarbonyl-piperidin ketone, reoxidizes and obtains N-tertbutyloxycarbonyl-4-nitro piperidones.The method operation is complex, and productivity is the highest.The second directly obtains product by N-tertbutyloxycarbonyl-4-anilinic piperidines oxidation of ketones.Although step is few, simple to operate, but the productivity of only 22%.In addition, also by being that raw material first synthesizes oxime by N-t-butoxycarbonyl-piperidin ketone, restoring, amide condensed, oxidation obtains N-tertbutyloxycarbonyl-4-nitro piperidines, but reactions steps is long, and operation is excessively complicated, is unfavorable for synthesizing in a large number.Concrete reaction equation is as follows:
Accordingly, it would be desirable to one raw material of exploitation is easy to get, easy to operate, react easily controllable, the synthetic method that overall yield is high.
Summary of the invention
It is an object of the invention to develop one there is raw material be easy to get, easy to operate, react easily controllable, the synthetic method of the N-tertbutyloxycarbonyl-4-nitro piperidines of high yield.Mainly solving current synthesis yield low, reactions steps is long, and operation is excessively complicated, is unfavorable for the technical problems such as a large amount of synthesis.
The thinking of the present invention: iodo thing is organic intermediate conventional in organic synthesis, because it replaces and leaves away the most very convenient.Therefore, it is contemplated that be Material synthesis N-tertbutyloxycarbonyl-4-iodine piperidines by N-tertbutyloxycarbonyl-4-hydroxy piperidine, then target product is obtained by substitution reaction.By test, it has been found that: the method is the most simple to operate, and obtains preferable yield.
Technical scheme: the preparation method of a kind of N-tertbutyloxycarbonyl-4-nitro piperidines, comprises the following steps:
(1): the preparation process of N-tertbutyloxycarbonyl-4-iodine piperidines；By 4-hydroxyl t-butoxycarbonylpiperidin, triphenylphosphine and imidazoles are dissolved in anhydrous tetrahydro furan, then dripping the tetrahydrofuran solution of iodine, reactant liquor ambient temperature overnight (12-16 hour, same afterwards) reaction is complete to raw material reaction, cooling, it is spin-dried for, filters, washing, refiltering, filtrate obtains target product N-tertbutyloxycarbonyl-4-iodine piperidines after concentrating；
(2): the preparation process of N-tertbutyloxycarbonyl-4-nitro piperidines；By N-tertbutyloxycarbonyl-4-iodine piperidines, sodium nitrite and phloroglucinol are dissolved in dimethyl sulfoxide, and then lower 45 DEG C of nitrogen protection is stirred overnight to raw material reaction complete, cooling, and extraction is spin-dried for, crosses post and obtain target product N-tertbutyloxycarbonyl-4-nitro piperidines.
Reaction equation is as follows:
。
Beneficial effects of the present invention: the present invention solves the synthesis technique Road line length both known at present, and yield is low, the shortcomings such as reaction is not easy to control, experimental implementation inconvenience.When synthesizing N-tertbutyloxycarbonyl-4-iodine piperidines, we do not use the method for column chromatography to be purified.By crystallization, wash, the most simple to operate, and also productivity is higher.The crude product obtained can be directly used for subsequent reactions.When synthesizing N-tertbutyloxycarbonyl-4-nitro piperidines, use dimethyl sulfoxide to make solvent, substantially reduce the response time, improve productivity.
Detailed description of the invention
The synthesis of compound 2:
。
Embodiment 1: add raw material 1 (100 g in reaction bulb, 0.496mol), triphenyl phosphorus phosphine (156g, 0.596mol) with imidazoles (405 g, 0.596mol) it is dissolved in anhydrous tetrahydro furan (400ml), keeps temperature 2-3 DEG C, then by iodine (151g, 0.596mol) being dissolved in anhydrous tetrahydro furan instillation reactant liquor, dropping process control temp does not exceeds 12 DEG C.After adding material, recover room temperature and be stirred overnight.With petroleum ether: ethyl acetate (volume ratio)=5:1 is as developing solvent, and product Rf is about 0.5.After detection has been reacted, it is cooled to add when 8 DEG C the NaHSO of 10% mass fraction3(80mL).Being spin-dried for solution, be subsequently adding normal hexane (350mL), sucking filtration, first incline supernatant, filters bottom solid the most again, and filtering residue washs with substantial amounts of normal hexane.Supernatant 1mol/L hydrochloric acid goes to be washed till neutrality, then with water, saturated NaCl washs respectively, sodium sulfate is dried, filter, be spin-dried for obtaining crude product.Crude product is dissolved in 310mL ethanol. then it is cooled to-5 DEG C, in 20 minutes, under stirring, divides 3 times the water adding 270mL, ensure that temperature, all the time at about-5 DEG C, has a large amount of solid to separate out simultaneously.Continue stirring 1 hour, sucking filtration the most afterwards, obtain white solid 96 g.
Embodiment 2: add raw material 1 (1000 g in reaction bulb, 4.96mol), triphenyl phosphorus phosphine (1560g, 5.96mol) with imidazoles (4050 g, 5.96mol) it is dissolved in anhydrous tetrahydro furan (4000ml), keeps temperature 2-3 DEG C, then by iodine (1510g, 5.96mol) being dissolved in anhydrous tetrahydro furan instillation reactant liquor, dropping process control temp does not exceeds 12 DEG C.After adding material, recover room temperature and be stirred overnight.With petroleum ether: ethyl acetate (volume ratio)=5:1 is as developing solvent, and product Rf is about 0.5.After detection has been reacted, it is cooled to add when 8 DEG C the NaHSO of 10% mass fraction3(800mL).Being spin-dried for solution, be subsequently adding normal hexane (4000mL), sucking filtration, first incline supernatant, filters bottom solid the most again, and filtering residue washs with substantial amounts of normal hexane.Supernatant 1mol/L hydrochloric acid goes to be washed till neutrality, then with water, saturated NaCl washs respectively, sodium sulfate is dried, filter, be spin-dried for obtaining crude product.Crude product is dissolved in 3017mL ethanol. then it is cooled to-5 DEG C, in 20 minutes, under stirring, divides 3 times the water adding 2700mL, ensure that temperature, all the time at about-5 DEG C, has a large amount of solid to separate out simultaneously.Continue stirring 1 hour, sucking filtration the most afterwards, obtain white solid 1000 g.
The synthesis of compound 3:
。
Embodiment 1: by raw material 2(100g, 0.267mol in reaction bulb), sodium nitrite (36.8g, 0.533mol) and phloroglucinol (53.8g, 0.427mol) are dissolved in DMSO (400ML), and then lower 45 DEG C of nitrogen protection is stirred overnight.Product is at petroleum ether: in the developing solvent of ethyl acetate (volume ratio)=5:1, rf value is about 0.3.After having reacted, adding the water of 1.5L and stir 15 minutes, then with petroleum ether: the mixed extractant solvent of ethyl acetate (volume ratio)=5:1, some plate detects whether that extraction is completely (developing the color with 1,2,3-indantrione monohydrate).Organic facies is washed with saturated NaCl, and sodium sulfate is dried, and is concentrated to give crude product.Crude product obtains grease product 30 g by column chromatography.
Embodiment 2: by raw material 2(1000g, 2.67mol in reaction bulb), sodium nitrite (368g, 5.33mol) and phloroglucinol (538g, 4.27mol) are dissolved in DMSO (4L), and then lower 45 DEG C of nitrogen protection is stirred overnight.Product is at petroleum ether: in the developing solvent of ethyl acetate (volume ratio)=5:1, rf value is about 0.3.After having reacted, adding the water of 20L and stir 30 minutes, then with petroleum ether: the mixed extractant solvent of ethyl acetate (volume ratio)=5:1, some plate detects whether that extraction is completely (developing the color with 1,2,3-indantrione monohydrate).Organic facies is washed with saturated NaCl, and sodium sulfate is dried, and is concentrated to give crude product.Crude product obtains grease product 290 g by column chromatography.
Claims (2)
1. a preparation method for N-tertbutyloxycarbonyl-4-nitro piperidines, comprises the following steps:
(1): the preparation process of N-tertbutyloxycarbonyl-4-iodine piperidines；4-hydroxyl t-butoxycarbonylpiperidin, triphenylphosphine and imidazoles being dissolved in anhydrous tetrahydro furan, then drip the tetrahydrofuran solution of iodine, the reaction of reactant liquor ambient temperature overnight is complete to raw material reaction, cooling, is spin-dried for, and filters, washing, refilters, and filtrate obtains N-tertbutyloxycarbonyl-4-iodine piperidines after concentrating；
(2): the preparation process of N-tertbutyloxycarbonyl-4-nitro piperidines；N-tertbutyloxycarbonyl-4-iodine piperidines, sodium nitrite and phloroglucinol being dissolved in dimethyl sulfoxide, then lower 45 DEG C of nitrogen protection is stirred overnight to raw material reaction complete, cooling, and extraction is spin-dried for, crosses post and obtain target product N-tertbutyloxycarbonyl-4-nitro piperidines.
The preparation method of a kind of N-tertbutyloxycarbonyl-4-nitro piperidines the most according to claim 1, is characterized in that: needing to add mass fraction after step (1) reaction cooling is 10% NaHSO3It is spin-dried for again, filters front normal hexane and wash.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110390723.3A CN103130708B (en) | 2011-12-01 | 2011-12-01 | A kind of preparation method of N-tertbutyloxycarbonyl-4-nitro piperidines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110390723.3A CN103130708B (en) | 2011-12-01 | 2011-12-01 | A kind of preparation method of N-tertbutyloxycarbonyl-4-nitro piperidines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103130708A CN103130708A (en) | 2013-06-05 |
| CN103130708B true CN103130708B (en) | 2016-08-10 |
Family
ID=48491212
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110390723.3A Active CN103130708B (en) | 2011-12-01 | 2011-12-01 | A kind of preparation method of N-tertbutyloxycarbonyl-4-nitro piperidines |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103130708B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288590A (en) * | 2013-07-01 | 2013-09-11 | 济南大学 | Method for synthesizing 5-iodine-1,8-nonadiene by using ultrasonic method |
| CN103571908A (en) * | 2013-11-22 | 2014-02-12 | 尚科生物医药（上海）有限公司 | Method for preparing chiral N-tert-butyloxycarboryl-3-hydroxypiperidine |
| CN104059952A (en) * | 2014-07-01 | 2014-09-24 | 尚科生物医药（上海）有限公司 | Method for catalyzing immobilized whole-cell compositions to synthesize (S)-N-t-butyloxycarbonyl-3-hydroxypiperidine |
| CN104099383A (en) * | 2014-07-29 | 2014-10-15 | 尚科生物医药（上海）有限公司 | Biological preparation method for (S)-N-t-butyloxycarboryl-3-hydroxide radical piperidine |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH544753A (en) * | 1972-12-21 | 1974-01-15 | Rossier Jean Paul | 2-aminomethyl pyrrolidine prepn - by halogenating 3-hydroxypiperidines, reacting prod with k-phthalimide and soda |
| US4031222A (en) * | 1975-12-22 | 1977-06-21 | Merck & Co., Inc. | Trifluoromethylthio (and sulfonyl) derivatives of cyproheptadine analogs |
| US5089610A (en) * | 1991-04-25 | 1992-02-18 | Eli Lilly And Company | Ring-closure method for 1-carbacephalosporin six-membered ring |
| CN1281850A (en) * | 2000-06-30 | 2001-01-31 | 上海高桥石油化工公司精细化工厂 | Preparation method of 4-chloro-2,2,6,6-tetramethyl piperidine |
| CN102070633B (en) * | 2009-11-24 | 2013-04-10 | 上海药明康德新药开发有限公司 | Method for synthesizing 1,8-diazaspiro[4.5]decane with protective group |
-
2011
- 2011-12-01 CN CN201110390723.3A patent/CN103130708B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN103130708A (en) | 2013-06-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106977572B (en) | A method of using hyodesoxycholic acid as Material synthesis lithocholic acid | |
| CN107001294B (en) | Method for preparing gadobutrol | |
| CN103130708B (en) | A kind of preparation method of N-tertbutyloxycarbonyl-4-nitro piperidines | |
| CN108947881B (en) | Method for preparing optically pure L-type selenium-methyl selenocysteine | |
| CN106365986A (en) | Compounds and preparation methods thereof, and uses of compounds in synthesis of brivaracetam | |
| JP2018532718A (en) | Phosphoramidate compound, production method thereof and crystal | |
| CN109415405A (en) | The method for preparing shellfish cholic acid difficult to understand | |
| CN106632312B (en) | A kind of related substance of Eliquis, intermediate, preparation method and applications | |
| CN110498744B (en) | Preparation method of 1-ethyl-3-nitrobenzene | |
| CN103880745A (en) | Chemical synthesis method of 6-bromo-1,2,3,4-tetrahydroisoquinolyl-1-formic acid | |
| CN103319548A (en) | Purification method for cane sugar-6-acetate | |
| WO2023216317A1 (en) | Method for synthesizing nirmatrelvir intermediate | |
| CN103665084A (en) | Method for preparing abiraterone acetate | |
| CN101805339B (en) | Entecavir compound preparation method | |
| CN101747390B (en) | Synthesis process of edaravone metabolite | |
| CN106905358B (en) | Preparation of vitamin D3Process for preparing analogue intermediates | |
| JP2018030839A (en) | Novel crystal form of vitamin D3 derivative and method for producing the same | |
| CN101492388A (en) | Method for synthesis of Miqujing medicament material | |
| KR20100120558A (en) | Recrystallization process of sarpogrelate hcl | |
| CN111196777A (en) | Synthetic preparation of brivaracetam | |
| CN105131050A (en) | Preparation method of chlorinating agent and method therewith for preparing sucralose | |
| CN102070644B (en) | Method for preparing camptothecin derivatives and intermediates thereof | |
| CN103467270B (en) | Preparation method of 3-oxocyclobutanecarboxylic acid | |
| CN110483360B (en) | Synthesis method of alfaprost alcohol | |
| KR950005737B1 (en) | Separating method of component from gingkolide complex |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20160711 Address after: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Applicant after: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Address before: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Applicant before: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Applicant before: Tianjin Yaoming Kangde New Medicine Development Co., Ltd. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |