CN103130708A - Preparing method of N-t-butyloxycarboryl-4-nitro piperidine - Google Patents
Preparing method of N-t-butyloxycarboryl-4-nitro piperidine Download PDFInfo
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- CN103130708A CN103130708A CN2011103907233A CN201110390723A CN103130708A CN 103130708 A CN103130708 A CN 103130708A CN 2011103907233 A CN2011103907233 A CN 2011103907233A CN 201110390723 A CN201110390723 A CN 201110390723A CN 103130708 A CN103130708 A CN 103130708A
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- tertbutyloxycarbonyl
- piperidines
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Abstract
The invention relates to a preparing method of N-t-butyloxycarboryl-4-nitro piperidine. The method mainly solves the technical problems that in an existing synthetic process, the route is long, yield is low, reaction is not easy to control, experimental operation is inconvenient, and the like. According to the method, N-t-butyloxycarboryl-4-hydroxy piperidine is used as raw material to prepare N-t-butyloxycarboryl-4-iodine piperidine, and further the target product is obtained through the substitution reaction. The N-t-butyloxycarboryl-4-nitro piperidine obtained with the method is a useful intermediate or product used for synthesis of various kinds of drugs.
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 useful intermediate of a class in organic synthesis, all relate at patent WO2009126515, JP2008273847 and WO2007055514, be widely used in Michael addition, as WO2007052843, US20060217417 and WO2003048124.Recently also be used to synthetic anti-HIV class medicine, as WO9744037.At present, the synthetic method about this compounds mainly contains two kinds: the first is first synthetic oxime of raw material by N-tertbutyloxycarbonyl-piperidone, reoxidizes and obtains N-tertbutyloxycarbonyl-4-nitro piperidone.The method operation is comparatively complicated, and productive rate is not high.The second directly obtains product by N-tertbutyloxycarbonyl-4-anilinic piperidines oxidation of ketones.Although step is few, simple to operate, only have 22% productive rate.In addition, also have by being first synthetic oxime of raw material by N-tertbutyloxycarbonyl-piperidone, restore, amide condensed, oxidation obtains N-tertbutyloxycarbonyl-4-nitro piperidines, but reactions steps is long, and operation is too complicated, is unfavorable for a large amount of synthetic.Concrete reaction formula is as follows:
Therefore, need raw material of exploitation to be easy to get, easy to operate, reaction is easy to control, the synthetic method that overall yield is high.
Summary of the invention
The objective of the invention is to develop and a kind ofly have raw material and be easy to get, easy to operate, reaction is easy to control, the synthetic method of the N-tertbutyloxycarbonyl of high yield-4-nitro piperidines.Mainly solve present synthesis yield low, reactions steps is long, and operation is too complicated, is unfavorable for a large amount of technical problems such as synthetic.
Thinking of the present invention: the iodo thing is organic intermediate commonly used in organic synthesis, because its replacement and leave away all very convenient.Therefore, our imagination is the synthetic N-tertbutyloxycarbonyl of raw material-4-iodine piperidines by N-tertbutyloxycarbonyl-4-hydroxy piperidine, then obtains target product by substitution reaction.By test, we find: the method is not only simple to operate, and has obtained yield preferably.
Technical scheme of the present invention: 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; With 4 hydroxyl tertiary butyloxycarbonyl phenylpiperidines, triphenyl phosphorus and imidazoles are dissolved in anhydrous tetrahydro furan, then drip the tetrahydrofuran solution of iodine, reaction solution ambient temperature overnight (12-16 hour, rear same) reacts complete to raw material reaction, cooling, outstanding doing filtered, washing, refilter, obtain target product N-tertbutyloxycarbonyl-4-iodine piperidines after filtrate is concentrated;
(2): the preparation process of N-tertbutyloxycarbonyl-4-nitro piperidines; With N-tertbutyloxycarbonyl-4-iodine piperidines, Sodium Nitrite and Phloroglucinol are dissolved in dimethyl sulfoxide (DMSO), then the lower 45 ℃ of stirrings of nitrogen protection spend the night complete to raw material reaction, cooling, extraction, outstanding doing crossed post and obtained target product N-tertbutyloxycarbonyl-4-nitro piperidines.
Reaction formula is as follows:
Beneficial effect of the present invention: the invention solves in the synthesis technique of both having known at present route long, yield is low, and reaction is not easy to control, the shortcomings such as experimental implementation inconvenience.When synthetic N-tertbutyloxycarbonyl-4-iodine piperidines, we do not adopt the method for column chromatography to carry out purifying.By crystallization, washing, not only simple to operate, and also productive rate is higher.The crude product that obtains can be directly used in subsequent reactions.When synthetic N-tertbutyloxycarbonyl-4-nitro piperidines, adopt dimethyl sulfoxide (DMSO) to make solvent, greatly shortened the reaction times, improved productive rate.
Embodiment
Synthesizing of compound 2:
Embodiment 1: add raw material 1 (100 g in reaction flask, 0.496mol), triphenyl phosphorus (156g, 0.596mol) and imidazoles (405 g, 0.596mol) be dissolved in anhydrous tetrahydro furan (400ml), keep 2-3 ℃ of temperature, then with iodine (151g, 0.596mol) be dissolved in and splash into reaction solution in anhydrous tetrahydro furan, drip process control temp not over 12 ℃.After adding material, recover room temperature and stir and spend the night.Take sherwood oil: ethyl acetate (volume ratio)=5:1 is as developping agent, and product Rf value is in 0.5 left and right.After detection reaction is complete, add the NaHSO of 10% massfraction when being cooled to 8 ℃
3(80mL).Then outstanding dried solution add normal hexane (350mL), and suction filtration first inclines the upper strata stillness of night, and then filter the bottom solid, and filter residue washs with a large amount of normal hexanes.The upper strata stillness of night removes to be washed till neutrality, water then with 1mol/L hydrochloric acid, saturated NaCl washing respectively, dried over sodium sulfate, filtration, the outstanding dried crude product that obtains.Crude product is dissolved in 310mL ethanol. then be cooled to-5 ℃, divided the water that adds 270mL for 3 times under stirring in 20 minutes, guarantee that simultaneously temperature all the time-5 ℃ of left and right, has a large amount of solids to separate out.After water injection continue afterwards to stir 1 hour, suction filtration obtains white solid 96 g.
Embodiment 2: add raw material 1 (1000 g in reaction flask, 4.96mol), triphenyl phosphorus (1560g, 5.96mol) and imidazoles (4050 g, 5.96mol) be dissolved in anhydrous tetrahydro furan (4000ml), keep 2-3 ℃ of temperature, then with iodine (1510g, 5.96mol) be dissolved in and splash into reaction solution in anhydrous tetrahydro furan, drip process control temp not over 12 ℃.After adding material, recover room temperature and stir and spend the night.Take sherwood oil: ethyl acetate (volume ratio)=5:1 is as developping agent, and product Rf value is in 0.5 left and right.After detection reaction is complete, add the NaHSO of 10% massfraction when being cooled to 8 ℃
3(800mL).Then outstanding dried solution add normal hexane (4000mL), and suction filtration first inclines the upper strata stillness of night, and then filter the bottom solid, and filter residue washs with a large amount of normal hexanes.The upper strata stillness of night removes to be washed till neutrality, water then with 1mol/L hydrochloric acid, saturated NaCl washing respectively, dried over sodium sulfate, filtration, the outstanding dried crude product that obtains.Crude product is dissolved in 3017mL ethanol. then be cooled to-5 ℃, divided the water that adds 2700mL for 3 times under stirring in 20 minutes, guarantee that simultaneously temperature all the time-5 ℃ of left and right, has a large amount of solids to separate out.After water injection continue afterwards to stir 1 hour, suction filtration obtains white solid 1000 g.
Synthesizing of compound 3:
。
Embodiment 1: in reaction flask with raw material 2(100g, 0.267mol), Sodium Nitrite (36.8g, 0.533mol) and Phloroglucinol (53.8g, 0.427mol) are dissolved in DMSO (400ML), then the lower 45 ℃ of stirrings of nitrogen protection are spent the night.Product is at sherwood oil: in the developping agent of ethyl acetate (volume ratio)=5:1, the rf value is 0.3 left and right.After having reacted, add the water of 1.5L and stirred 15 minutes, then using sherwood oil: the mixed extractant solvent of ethyl acetate (volume ratio)=5:1, some plate detect whether extract (developing the color with triketohydrindene hydrate) fully.Organic phase is washed with saturated NaCl, dried over sodium sulfate, the concentrated crude product that obtains.Crude product obtains oily matter product 30 g by column chromatography.
Embodiment 2: in reaction flask with raw material 2(1000g, 2.67mol), Sodium Nitrite (368g, 5.33mol) and Phloroglucinol (538g, 4.27mol) are dissolved in DMSO (4L), then the lower 45 ℃ of stirrings of nitrogen protection are spent the night.Product is at sherwood oil: in the developping agent of ethyl acetate (volume ratio)=5:1, the rf value is 0.3 left and right.After having reacted, add the water of 20L and stirred 30 minutes, then using sherwood oil: the mixed extractant solvent of ethyl acetate (volume ratio)=5:1, some plate detect whether extract (developing the color with triketohydrindene hydrate) fully.Organic phase is washed with saturated NaCl, dried over sodium sulfate, the concentrated crude product that obtains.Crude product obtains oily matter product 290 g by column chromatography.
Claims (4)
1. the preparation method of N-tertbutyloxycarbonyl-4-nitro piperidines comprises the following steps:
(1): the preparation process of N-tertbutyloxycarbonyl-4-iodine piperidines; 4 hydroxyl tertiary butyloxycarbonyl phenylpiperidines, triphenyl phosphorus and imidazoles are dissolved in anhydrous tetrahydro furan, then drip the tetrahydrofuran solution of iodine, react complete to raw material reaction, cooling, outstanding doing filtered, washing refilters, and obtains N-tertbutyloxycarbonyl-4-iodine piperidines after filtrate is concentrated;
(2): the preparation process of N-tertbutyloxycarbonyl-4-nitro piperidines; N-tertbutyloxycarbonyl-4-iodine piperidines, Sodium Nitrite and Phloroglucinol are dissolved in dimethyl sulfoxide (DMSO), and then nitrogen protection is complete down to raw material reaction, and is cooling, extraction, and outstanding doing crossed post and obtained target product N-tertbutyloxycarbonyl-4-nitro piperidines.
2. the preparation method of a kind of N-tertbutyloxycarbonyl according to claim 1-4-nitro piperidines, it is characterized in that: step (1) room temperature reaction spends the night.
3. the preparation method of a kind of N-tertbutyloxycarbonyl according to claim 1-4-nitro piperidines is characterized in that: need add massfraction after step (1) reaction is cooling is 10% NaHSO
3Outstanding doing, wash with normal hexane before filtering again.
4. the preparation method of a kind of N-tertbutyloxycarbonyl according to claim 1-4-nitro piperidines is characterized in that: (2) 45 ℃ of reactions of step are stirred and are spent the night.
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Cited By (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 |
Citations (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 |
| EP0511001A2 (en) * | 1991-04-25 | 1992-10-28 | 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 |
| CN102070633A (en) * | 2009-11-24 | 2011-05-25 | 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 |
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2011
- 2011-12-01 CN CN201110390723.3A patent/CN103130708B/en active Active
Patent Citations (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 |
| EP0511001A2 (en) * | 1991-04-25 | 1992-10-28 | 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 |
| CN102070633A (en) * | 2009-11-24 | 2011-05-25 | 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 |
Cited By (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 |
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