CN107663184A - A kind of synthetic method of the hydroxy piperidines of N Boc 4 - Google Patents
A kind of synthetic method of the hydroxy piperidines of N Boc 4 Download PDFInfo
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- CN107663184A CN107663184A CN201711133609.6A CN201711133609A CN107663184A CN 107663184 A CN107663184 A CN 107663184A CN 201711133609 A CN201711133609 A CN 201711133609A CN 107663184 A CN107663184 A CN 107663184A
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- boc
- piperidones
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- hydroxy piperidines
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- 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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- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a kind of synthetic method of the hydroxy piperidines of N Boc 4, belong to technical field of organic chemistry.Using 4 piperidones hydrochloride hydrates and di-tert-butyl dicarbonate as raw material, add the piperidones of alkali reaction generation N Boc 4, then add in organic solvent, the hydroxy piperidines of N Boc 4 are obtained in the presence of aluminium isopropoxide and isopropanol, after temperature reaction.The characteristics of there is this method raw material to be easy to get, reaction yield is high, cost is cheap, environment-friendly, good product quality, is adapted to industrialized production.
Description
Technical field：
The present invention relates to a kind of synthetic method of N-Boc-4- hydroxy piperidines, belong to technical field of organic synthesis.
Background technology：
N-Boc-4- hydroxy piperidines are important intermediate of the synthesis with multiple biological activities, as mineralcorticoid receptor is short of money
The preparation of the dihydrobenzo imidazoles of anti-agent, the preparation for treating Alzheimer's M2 muscarinic receptor antagonists, Trk suppressions
The preparation of the preparation of the fused ring heteroaryl compound of preparation, novel pyrazole and pyridine anti-tumor compounds, has in pharmaceuticals industry
It is widely applied prospect.
The synthetic method of the N-Boc-4- hydroxy piperidines of document report mainly has two kinds at present：(1) with N-Boc-4- piperidines
Ketone is raw material, carbonyl is carried out through sodium borohydride to reduce obtained N-Boc-4- hydroxy piperidines (CN105503865), although this method
High income, but the use of sodium borohydride, make post processing inconvenient and deposit potential safety hazard, be not suitable for industrialized production.(2) with 4-
Hydroxy piperidine is raw material, reacts to obtain N-Boc-4- hydroxy piperidines in organic solvent with di-tert-butyl dicarbonate under alkalescence condition
(JournaloftheAmericanChemicalSociety,138(47),15482-15487；2016), this method produces useless
Water, waste gas, the solvent slop three wastes are more；Raw materials used N-Boc-4- hydroxy piperidines cost is high, and raw material sources are limited, and is not suitable for industry
Change big production.
The content of the invention：
To overcome disadvantage mentioned above, the present invention provides a kind of method of synthesis N-Boc-4- hydroxy piperidines, with 4- piperidones water
It is raw material to close hydrochloride and di-tert-butyl dicarbonate, adds alkali reaction generation N-Boc-4- piperidones, then adds in organic solvent,
N-Boc-4- hydroxy piperidines are obtained in the presence of aluminium isopropoxide and isopropanol, after temperature reaction.
A kind of synthetic method of N-Boc-4- hydroxy piperidines, is obtained after two-step reaction, the technical scheme used for：
The first step, 4- piperidones hydrochloride hydrate and di-tert-butyl dicarbonate, add aqueous alkali reaction generation N-Boc-
4- piperidones.
Second step, N-Boc-4- piperidones is added in organic solvent, in the presence of aluminium isopropoxide and isopropanol, temperature reaction
After obtain N-Boc-4- hydroxy piperidines.
Reaction scheme is as follows：
In the first step, the mol ratio of 4- piperidones hydrochloride hydrate, di-tert-butyl dicarbonate and sodium hydroxide is 1:
1-3：1-5, preferably 1:1.1-1.5：2-3.
In the first step, aqueous alkali is 10-50% sodium hydroxides or potassium hydroxide solution selected from mass fraction, preferably
Mass fraction is 20-30% sodium hydroxide or potassium hydroxide solution, and reaction, which terminates rear alkali lye, to be applied mechanically by adding solid base
Once, wastewater flow rate is reduced.
In the second step, organic solvent is toluene, dimethylbenzene, tetrahydrofuran.
In the second step, the mol ratio of N-Boc-4- piperidones, isopropanol and aluminium isopropoxide is 1：10-15：0.1-
0.6, preferably 1：12：0.3.
In the second step, reaction temperature is 40~100 DEG C, preferably 50-60 DEG C.
Beneficial effects of the present invention：
1) with traditional piperidines ketone compounds compared with di-tert-butyl dicarbonate reacts, producing quantity of three wastes reduces 40-
60%：CO 2 waste gas can directly be absorbed by reaction dissolvent alkali lye, no spent organic solvent, and recyclable apply mechanically of alkali lye makes waste water
Amount is reduced.
2) use of metal hydride species reducing agent is avoided, post-processing operation is facilitated and reduces security risk.
3) it is raw materials used be easy to get, reaction yield is high, cost is cheap, environment-friendly, good product quality, be adapted to industrial metaplasia
Production.
Embodiment
Embodiment 1
The first step：In 1L there-necked flasks, 4- piperidones hydrochloride hydrate 153.6g (1.0mol), water 150.0g, control are added
20% sodium hydroxide solution 400.0g (2.0mol) is added dropwise in temperature at 20-30 DEG C, is added dropwise, and stirs 20 minutes, and two carbon are added dropwise
Sour di tert butyl carbonate ((Boc)2O) 240.0g (1.1mol), drop finishes, after 20-30 DEG C of stirring reaction about 12h, TLC monitoring raw material reactions
Completely, reaction terminates, and cooling filtering, filtrate, which can retain, treats that lower batch is applied mechanically, filtering gained crude product ethyl alcohol recrystallization, after drying
Obtain 180.5g white solid product N-Boc-4- piperidones, G/C content 99.4%, yield 90.6%.
Second step：Under nitrogen protection, N-Boc-4- piperidones 180.5g (0.906mol), toluene are added in 2L there-necked flasks
542g, aluminium isopropoxide 55.5g (0.272mol) and isopropanol 653.0g (10.87mol), 50 DEG C are heated to, after stirring 24 hours,
The reaction of control raw material is complete in GC, and reaction is quenched in cooling, 1NHCl, and toluene extracts, and one is washed with saturated sodium-chloride after merging organic layer
Secondary, be concentrated under reduced pressure solvent, and crude product is recrystallized with normal heptane, is dried in vacuo to obtain 156.3g white solid product N-Boc-4- hydroxyl piperazines
Pyridine, G/C content 99.1%, yield 85.7%, 65.2-66.4 DEG C of fusing point,1H-NMR(CDCl3,400MHz):δ3.75-3.85(m,
CHOHandCH2,3H),2.95-3.05(m,CH2,2H),1.79-1.85(m,CH2,2H),1.66(br,OH,1H),1.39-
1.49(m,CH2,2H),1.42(s,tBu,9H)ppm。
Embodiment 2
The first step：In 1L there-necked flasks, 4- piperidones hydrochloride hydrate 122.9g (0.8mol), water 120.0g, control are added
30% potassium hydroxide solution 448.0g (3.0mol) is added dropwise in temperature at 20-30 DEG C, is added dropwise, and stirs 20 minutes, and two carbon are added dropwise
Sour di tert butyl carbonate ((Boc)2O) 261.9g (1.2mol), drop finishes, after 20-30 DEG C of stirring reaction about 12h, TLC monitoring raw material reactions
Completely, reaction terminates, and cooling filtering, filtrate, which can retain, treats that lower batch is applied mechanically, filtering gained crude product ethyl alcohol recrystallization, after drying
Obtain 145.8g white solid product N-Boc-4- piperidones, G/C content 99.2%, yield 91.5%.
Second step：Under nitrogen protection, N-Boc-4- piperidones 145.8g (0.732mol), diformazan are added in 2L there-necked flasks
Benzene 437g, aluminium isopropoxide 29.8g (0.146mol) and isopropanol 440.0g (7.32mol), 60 DEG C are heated to, stirred 24 hours
Afterwards, it is complete that raw material reaction is controlled in GC, reaction is quenched in cooling, 1NHCl, ethyl acetate extraction, saturation chlorination is used after merging organic layer
Sodium is washed once, and be concentrated under reduced pressure solvent, and crude product is recrystallized with normal heptane, is dried in vacuo to obtain 122.6g white solid products N-Boc-4-
Hydroxy piperidine, G/C content 99.0%, yield 83.2%, 65.7-67.0 DEG C of fusing point.
Embodiment 3
The first step：In 1L there-necked flasks, 4- piperidones hydrochloride hydrate 122.9g (0.8mol), water 120.0g, control are added
30% sodium hydroxide solution 400.0g (3.0mol) is added dropwise in temperature at 20-30 DEG C, is added dropwise, and stirs 20 minutes, and two carbon are added dropwise
Sour di tert butyl carbonate ((Boc)2O) 192.1g (0.88mol), drop finishes, and after 20-30 DEG C of stirring reaction about 12h, TLC monitoring raw materials are anti-
Should be complete, reaction terminates, and cooling filtering, filtrate, which can retain, treats that lower batch is applied mechanically, and filtering gained crude product ethyl alcohol recrystallization, dries
144.9g white solid product N-Boc-4- piperidones, G/C content 99.1%, yield 90.9% are obtained afterwards.
Second step：Under nitrogen protection, N-Boc-4- piperidones 144.9g (0.727mol), tetrahydrochysene are added in 2L there-necked flasks
Furans 435g, aluminium isopropoxide 44.5g (0.218mol) and isopropanol 524.0g (8.72mol), 50 DEG C are heated to, stirred 24 hours
Afterwards, it is complete that raw material reaction is controlled in GC, reaction is quenched in cooling, 1NHCl, ethyl acetate extraction, saturation chlorination is used after merging organic layer
Sodium is washed once, and be concentrated under reduced pressure solvent, and crude product is recrystallized with normal heptane, is dried in vacuo to obtain 125.1g white solid products N-Boc-4-
Hydroxy piperidine, G/C content 99.1%, yield 85.5%, 65.4-66.8 DEG C of fusing point.
Embodiment 4
The first step：Into 20L reactors, 4- piperidones hydrochloride hydrate 1.54kg (10mol), water 1.50kg, control are added
20% sodium hydroxide solution 4.0kg (20mol) is added dropwise in temperature at 20-30 DEG C, is added dropwise, and stirs 20 minutes, and two carbonic acid are added dropwise
Di tert butyl carbonate ((Boc)2O) 3.27kg (15mol), drop finishes, and after 20-30 DEG C of stirring reaction about 12h, TLC monitoring raw materials have reacted
Entirely, reaction terminates, cooling filtering, and filtrate, which retains, treats that lower batch is applied mechanically, filtering gained crude product ethyl alcohol recrystallization, after drying
1.81kg white solid product N-Boc-4- piperidones, G/C content 99.3%, yield 90.8%.
Second step：Under nitrogen protection, N-Boc-4- piperidones 1.81kg (9.08mol), toluene are added into 20L reactors
5.42kg, aluminium isopropoxide 0.556kg (2.72mol) and isopropanol 6.54kg (109.0mol), 50 DEG C are heated to, stirred 24 hours
Afterwards, it is complete that raw material reaction is controlled in GC, reaction is quenched in cooling, 1NHCl, toluene extraction, is washed after merging organic layer with saturated sodium-chloride
Once, be concentrated under reduced pressure solvent, and crude product is recrystallized with normal heptane, is dried in vacuo to obtain 1.57kg white solid product N-Boc-4- hydroxyls
Piperidines, G/C content 99.0%, yield 86.0%, 65.6-67.0 DEG C of fusing point.
Embodiment 5
The first step：Into 20L reactors, 4- piperidones hydrochloride hydrate 1.54kg (10mol), water 1.50kg, control are added
The filtrate (adding 800g sodium hydrate solids) that the first step reaction of embodiment 4 retains is added dropwise in temperature at 20-30 DEG C, drips
Finish, stir 20 minutes, di-tert-butyl dicarbonate (Boc) is added dropwise2O (2.40kg, 11mol), drop finish, and 20-30 DEG C of stirring reaction is about
After 12h, TLC monitoring raw material reactions are complete, and reaction terminates, and cooling filtering, filtrate, which can retain, treats that lower batch is applied mechanically, and filtering gained is thick
Product ethyl alcohol recrystallization, 1.80kg white solid product N-Boc-4- piperidones, G/C content 99.1%, yield are obtained after drying
90.3%.
Second step：Under nitrogen protection, N-Boc-4- piperidones 1.80kg (9.03mol), tetrahydrochysene are added into 20L reactors
Furans 5.40kg, aluminium isopropoxide 0.553kg (2.71mol) and isopropanol 6.51kg (108.4mol), 50 DEG C are heated to, stirring 24
It is complete that raw material reaction is controlled after hour, in GC, reaction is quenched in cooling, 1NHCl, ethyl acetate extraction, saturation is used after merging organic layer
Sodium chloride is washed once, and be concentrated under reduced pressure solvent, and crude product is recrystallized with normal heptane, is dried in vacuo to obtain 1.56kg white solid products N-
Boc-4- hydroxy piperidines, G/C content 99.0%, yield 85.6%, 65.2-66.5 DEG C of fusing point.
The general principle and principal character and advantages of the present invention of the present invention has been shown and described above.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the simply explanation described in above-described embodiment and specification is originally
The principle of invention, without departing from the spirit and scope of the present invention, various changes and modifications of the present invention are possible, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent thereof.
Claims (6)
- A kind of 1. synthetic method of N-Boc-4- hydroxy piperidines：Obtained after two-step reaction, reaction scheme is as follows：It is characterised in that it includes following steps：The first step, 4- piperidones hydrochloride hydrate and di-tert-butyl dicarbonate, add aqueous alkali reaction generation N-Boc-4- piperazines Pyridine ketone；Second step, N-Boc-4- piperidones is added in organic solvent, in the presence of aluminium isopropoxide and isopropanol, after temperature reaction To N-Boc-4- hydroxy piperidines.
- 2. a kind of synthetic method of N-Boc-4- hydroxy piperidines according to claim 1, it is characterized in that：The first step In, the mol ratio of 4- piperidones hydrochloride hydrate, di-tert-butyl dicarbonate and sodium hydroxide is 1:1-3：1-5.
- 3. a kind of synthetic method of N-Boc-4- hydroxy piperidines according to claim 1, it is characterized in that：The first step In, aqueous alkali is 10-50% sodium hydroxides or potassium hydroxide solution selected from mass fraction.
- 4. a kind of synthetic method of N-Boc-4- hydroxy piperidines according to claim 1, it is characterized in that：The second step In, organic solvent is toluene, dimethylbenzene or tetrahydrofuran.
- 5. a kind of synthetic method of N-Boc-4- hydroxy piperidines according to claim 1, it is characterized in that：The second step In, the mol ratio of N-Boc-4- piperidones, isopropanol and aluminium isopropoxide is 1：10-15：0.1-0.6.
- 6. a kind of synthetic method of N-Boc-4- hydroxy piperidines according to claim 1, it is characterized in that：The second step In, reaction temperature is 40~100 DEG C.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110759853B (en) * | 2019-11-11 | 2023-06-13 | 上海科利生物医药有限公司 | Preparation method of (S) -N-BOC-3-hydroxy piperidine |
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| CN102036558A (en) * | 2008-03-20 | 2011-04-27 | 森林实验室控股有限公司 | Novel piperidine derivatives as inhibitors of stearoyl-CoA desaturase |
| WO2013160810A2 (en) * | 2012-04-24 | 2013-10-31 | Hetero Research Foundation | Novel betulinic acid derivatives as hiv inhibitors |
| CN104628625A (en) * | 2014-12-23 | 2015-05-20 | 安徽德信佳生物医药有限公司 | Synthesis method of N-boc-4-hydroxypiperidine |
| WO2017017630A1 (en) * | 2015-07-28 | 2017-02-02 | Hetero Research Foundation | Novel betulinic substituted amide derivatives as hiv inhibitors |
-
2017
- 2017-11-15 CN CN201711133609.6A patent/CN107663184A/en active Pending
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| CN102036558A (en) * | 2008-03-20 | 2011-04-27 | 森林实验室控股有限公司 | Novel piperidine derivatives as inhibitors of stearoyl-CoA desaturase |
| WO2013160810A2 (en) * | 2012-04-24 | 2013-10-31 | Hetero Research Foundation | Novel betulinic acid derivatives as hiv inhibitors |
| CN104628625A (en) * | 2014-12-23 | 2015-05-20 | 安徽德信佳生物医药有限公司 | Synthesis method of N-boc-4-hydroxypiperidine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110759853B (en) * | 2019-11-11 | 2023-06-13 | 上海科利生物医药有限公司 | Preparation method of (S) -N-BOC-3-hydroxy piperidine |
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Application publication date: 20180206 |