CN104447511A - Synthetic method of N-t-butyloxycarboryl-3-piperidone - Google Patents
Synthetic method of N-t-butyloxycarboryl-3-piperidone Download PDFInfo
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- CN104447511A CN104447511A CN201410638184.4A CN201410638184A CN104447511A CN 104447511 A CN104447511 A CN 104447511A CN 201410638184 A CN201410638184 A CN 201410638184A CN 104447511 A CN104447511 A CN 104447511A
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- China
- Prior art keywords
- tertbutyloxycarbonyl
- synthetic method
- piperidone
- hydroxy piperidine
- butyloxycarboryl
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- 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
- C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—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 one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
Abstract
The invention discloses a synthetic method of N-t-butyloxycarboryl-3-piperidone. The method comprises the following steps: carrying out reaction on 3-hydroxypiperidine and di-tert-butyl dicarbonate ester to obtain N-t-butyloxycarboryl-3-hydroxypiperidine; and oxidizing N-t-butyloxycarboryl-3-hydroxypiperidine by sodium hypochlorite under the effect of a tetramethylpiperidine oxide to obtain N-t-butyloxycarboryl-3-piperidone. Compared with the existing method, the synthetic method is shorter in route and milder in reaction condition, the product is easier to separate and purify, the cost and energy consumption are lowered, the environmental pollution is reduced, and the N-t-butyloxycarboryl is high in total yield and purity, so that the synthetic method is more suitable for industrial production.
Description
Technical field
The invention belongs to chemical industry and field of medicaments, relate to a kind of synthetic method of N-tertbutyloxycarbonyl-3-piperidone.
Background technology
N-tertbutyloxycarbonyl-3-piperidone is a kind of important agricultural chemicals, and be also the intermediate of medicine intermediate and other chemical additives, existing synthetic method has multiple:
(1) take gamma-butyrolactone as raw material, through benzylamine aminolysis, hydrolysis, esterification, give birth to 1-benzyl-3-piperidone hydrochloride with ethyl bromoacetate condensation, cyclization, hydrolysis decarboxylation six-step process, then on debenzylation, tertbutyloxycarbonyl obtains N-tertbutyloxycarbonyl-3-piperidone (US0053565).This method synthesis route is long, and raw materials cost is high, and energy consumption is high, low yield, and the N-tertbutyloxycarbonyl-3-piperidone purity of synthesis is low, seriously polluted, is not suitable for suitability for industrialized production.
(2) with 3-pyridone for raw material, react with bromobenzyl and generate tertbutyloxycarbonyl on quaternary ammonium salt, sodium borohydride reduction, palladium carbon debenzylation, through oxalyl chloride, dimethyl sulfoxide (DMSO) low-temperature oxidation obtains N-tertbutyloxycarbonyl-3-piperidone (CN103204801).This method synthesis route is long, and oxidizing condition is harsh, and energy consumption is high, low yield, is not suitable for suitability for industrialized production.
Summary of the invention
In order to overcome the series of problems of N-tertbutyloxycarbonyl-3-piperidone synthesis in prior art, the invention provides a kind of method of synthesis N-tertbutyloxycarbonyl-3-piperidone newly.Compared with existing N-tertbutyloxycarbonyl-3-piperidone synthetic method, synthetic route of the present invention is shorter, and oxidation reaction condition is gentleer, and product is easier to isolation andpurification, reduces cost and energy consumption, decreases environmental pollution.N-tertbutyloxycarbonyl-3-piperidone overall yield reach more than 67%, purity is greater than 98%.
To achieve these goals, the present invention is achieved through the following technical solutions:
The synthetic method of N-tertbutyloxycarbonyl-3-piperidone, comprises the steps:
(1) 3-hydroxy piperidine is under mineral alkali condition, is obtained by reacting N-tertbutyloxycarbonyl-3-hydroxy piperidine with tert-Butyl dicarbonate.
(2) N-tertbutyloxycarbonyl-3-hydroxy piperidine is under tetramethyl piperidine oxide compound (TEMPO), bromide catalysis, and the oxidation of hypohalous acid sodium obtains N-tertbutyloxycarbonyl-3-piperidone.
Further, the mol ratio of described N-tertbutyloxycarbonyl-3-hydroxy piperidine and tetramethyl piperidine oxide compound is 1:0.005 ~ 0.05; Be preferably 1:0.01 ~ 0.02.
Further, described bromide is Potassium Bromide, Sodium Bromide; Be preferably Potassium Bromide.
Further, the mol ratio of described N-tertbutyloxycarbonyl-3-hydroxy piperidine and bromide is 1:0.005 ~ 0.05; Be preferably 1:0.01 ~ 0.02.
Further, described hypohalous acid sodium is sodium hypobromite, clorox; Be preferably the clorox of brand-new.
Further, the whole temperature of reaction 0 DEG C ~ 30 DEG C of described N-tertbutyloxycarbonyl-3-hydroxy piperidine; Be preferably 20 DEG C ~ 25 DEG C, condition of normal pressure.Described mineral alkali is preferably sodium carbonate, sodium bicarbonate.
The method that the present invention isolates reaction product from the reaction solution of each step is as follows respectively:
Step (1) reaction terminates, reaction solution separatory, water layer washed with dichloromethane, and merge organic layer, anhydrous sodium sulfate drying, rotary evaporation falls organic solvent, obtains N-tertbutyloxycarbonyl-3-hydroxy piperidine.
Step (2) reaction terminates, reaction solution separatory, and water layer washed with dichloromethane merges organic layer, and with sodium thiosulfate solution washing, anhydrous sodium sulfate drying, rotary evaporation falls organic solution, obtains N-tertbutyloxycarbonyl-3-piperidone.
Compared with the prior art, the present invention adopts more cheap oxygenant, and oxidation reaction condition is gentleer, and product is easier to isolation andpurification, reduces cost and energy consumption, decreases environmental pollution.
Concrete embodiment
The present invention is further described for the following examples, but do not thereby limit the invention.
Embodiment 1
The first step:
101 grams of 3-hydroxy piperidines (1mol) are dissolved in 400 milliliters of methylene dichloride, add 400 ml waters, 252 grams of sodium bicarbonates (3mol), temperature control 0 DEG C drips tert-Butyl dicarbonate 240 grams (1.1mol), after GC detection reaction is complete, directly add 400 ml waters and methylene dichloride, separatory, use washed with dichloromethane water layer, merge organic phase, anhydrous sodium sulfate drying, rotary evaporation falls organic solvent and obtains oily N-tertbutyloxycarbonyl-3-hydroxy piperidine, with normal hexane 0-5 DEG C recrystallization, obtain colorless solid (173 grams, 0.86mol), productive rate 86%.
Second step:
100 grams of N-tertbutyloxycarbonyl-3-hydroxy piperidine (0.5mol) are dissolved in 500 milliliters of methylene dichloride, add 1.56 grams of tetramethyl piperidine oxide compounds, 0.6 gram of Potassium Bromide, temperature control 25 DEG C drips freshly prepd aqueous sodium hypochlorite solution 600 milliliters (effective concentration 10%).After GC detection reaction is complete, direct separatory, water layer washed with dichloromethane, merges organic phase, wash with sodium thiosulfate solution, anhydrous sodium sulfate drying, rotary evaporation falls organic solvent and obtains oily crude product, normal hexane 0-5 DEG C recrystallization, obtain white N-tertbutyloxycarbonyl-3-piperidone (78 grams, 0.39mol, purity is more than 98%), productive rate 78%.
Embodiment 2
The first step:
101 grams of 3-hydroxy piperidines (1mol) are dissolved in 400 milliliters of methylene dichloride, add 400 ml waters, 252 grams of sodium bicarbonates (3mol), temperature control 0 DEG C drips tert-Butyl dicarbonate 240 grams (1.1mol), after GC detection reaction is complete, directly add 400 ml waters and methylene dichloride, separatory, use washed with dichloromethane water layer, merge organic phase, anhydrous sodium sulfate drying, rotary evaporation falls organic solvent and obtains oily N-tertbutyloxycarbonyl-3-hydroxy piperidine, with normal hexane 0-5 DEG C recrystallization, obtain colorless solid (173 grams, 0.86mol), productive rate 86%.
Second step:
100 grams of N-tertbutyloxycarbonyl-3-hydroxy piperidine (0.5mol) are dissolved in 500 milliliters of methylene dichloride, add 3.12 grams of tetramethyl piperidine oxide compounds, 1.03 grams of Sodium Bromides, temperature control 25 DEG C drips the freshly prepd sodium hypobromite aqueous solution 600 milliliters (effective concentration 10%).After GC detection reaction is complete, direct separatory, water layer washed with dichloromethane, merges organic phase, wash with sodium thiosulfate solution, anhydrous sodium sulfate drying, rotary evaporation falls organic solvent and obtains oily crude product, normal hexane 0-5 DEG C recrystallization, obtain white N-tertbutyloxycarbonyl-3-piperidone (76 grams, 0.38mol, purity is more than 98%), productive rate 76%.
Claims (10)
1. the synthetic method of a N-tertbutyloxycarbonyl-3-piperidone, it is characterized in that, under mineral alkali, 3-hydroxy piperidine and tert-Butyl dicarbonate are obtained by reacting N-tertbutyloxycarbonyl-3-hydroxy piperidine, N-tertbutyloxycarbonyl-3-hydroxy piperidine is under tetramethyl piperidine oxide compound and bromide catalysis, and the oxidation of hypohalous acid sodium obtains N-tertbutyloxycarbonyl-3-piperidone.
2. synthetic method according to claim 1, is characterized in that: the mol ratio of described N-tertbutyloxycarbonyl-3-hydroxy piperidine and tetramethyl piperidine oxide compound is 1:0.005 ~ 0.05.
3. synthetic method according to claim 2, is characterized in that: the mol ratio of described N-tertbutyloxycarbonyl-3-hydroxy piperidine and tetramethyl piperidine oxide compound is 1:0.01 ~ 0.02.
4. synthetic method according to claim 1, is characterized in that: described bromide is Potassium Bromide, Sodium Bromide.
5. synthetic method according to claim 1, is characterized in that: described N-tertbutyloxycarbonyl-3-hydroxy piperidine and the mol ratio of bromide are 1:0.005 ~ 0.05.
6. synthetic method according to claim 2, is characterized in that: described N-tertbutyloxycarbonyl-3-hydroxy piperidine and the mol ratio of bromide are 1:0.01 ~ 0.02.
7. synthetic method according to claim 1, is characterized in that: described hypohalous acid sodium is sodium hypobromite or clorox.
8. synthetic method according to claim 1, is characterized in that: the temperature of reaction 0 DEG C ~ 30 DEG C of described N-tertbutyloxycarbonyl-3-hydroxy piperidine.
9. synthetic method according to claim 1, is characterized in that: the temperature of reaction 20 DEG C ~ 25 DEG C of described N-tertbutyloxycarbonyl-3-hydroxy piperidine.
10. synthetic method according to claim 1, is characterized in that: described mineral alkali is sodium carbonate, sodium bicarbonate.
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| CN201410638184.4A CN104447511A (en) | 2014-11-12 | 2014-11-12 | Synthetic method of N-t-butyloxycarboryl-3-piperidone |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107573278A (en) * | 2017-09-14 | 2018-01-12 | 深圳市宏辉浩医药科技有限公司 | A kind of preparation method of the piperidones of pharmaceutical intermediate N BOC 3 |
| CN111393356A (en) * | 2020-04-03 | 2020-07-10 | 东莞市东阳光生物合成药有限公司 | Preparation method of N-tert-butyloxycarbonyl-3-piperidone and derivatives thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101903386A (en) * | 2007-12-21 | 2010-12-01 | 株式会社Lg生命科学 | Dipeptidyl peptidase-IV inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as active agent |
| CN103204801A (en) * | 2013-04-12 | 2013-07-17 | 兰州远辉生物科技有限公司 | Synthesis method for N-Boc-3-piperidone |
| 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 |
-
2014
- 2014-11-12 CN CN201410638184.4A patent/CN104447511A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101903386A (en) * | 2007-12-21 | 2010-12-01 | 株式会社Lg生命科学 | Dipeptidyl peptidase-IV inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as active agent |
| CN103204801A (en) * | 2013-04-12 | 2013-07-17 | 兰州远辉生物科技有限公司 | Synthesis method for N-Boc-3-piperidone |
| 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 |
Non-Patent Citations (2)
| Title |
|---|
| MENG-YANG CHANG: "Synthesis of 1,2,4-trisubstituted-1,2,5,6-tetrahydropyridines", 《TETRAHEDRON LETTERS》, vol. 52, 3 December 2010 (2010-12-03), pages 588 - 591 * |
| 姚其正主编: "《药物合成反应》", 30 September 2012, article "8.2.1.4 TEMPO催化氧化" * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107573278A (en) * | 2017-09-14 | 2018-01-12 | 深圳市宏辉浩医药科技有限公司 | A kind of preparation method of the piperidones of pharmaceutical intermediate N BOC 3 |
| CN111393356A (en) * | 2020-04-03 | 2020-07-10 | 东莞市东阳光生物合成药有限公司 | Preparation method of N-tert-butyloxycarbonyl-3-piperidone and derivatives thereof |
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