CN104557674B - The preparation method of the hydroxy piperidines of one kind (S) N Boc 3 - Google Patents
The preparation method of the hydroxy piperidines of one kind (S) N Boc 3 Download PDFInfo
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- OBDLCKJCSDQQCU-UHFFFAOYSA-N C(C1)C11CNCCCC1 Chemical compound C(C1)C11CNCCCC1 OBDLCKJCSDQQCU-UHFFFAOYSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The present invention relates to the preparation method of the hydroxy piperidines of one kind (S) N Boc 3, comprise the following steps：(1) 3 hydroxy piperidine carries out ammonia displacement with L camphorsulfonic acids ammonium；(2) by 3 hydroxy piperidines in step (1), fractionation prepares (S) 3 hydroxy piperidine L camphorsulfonic acids crystalline substance salt (referred to as (S) crystalline substance salt) in ethanol methyl tertbutyl ether (MTBE) system；(3) (S) crystalline substance salt in step (2) is changed into the hydroxy piperidines of (S) N Boc 3 under the catalysis of ammoniacal liquor.Based on the inventive method; 3 hydroxy piperidine chiral resolutions prepare the yield of the hydroxy piperidines of (S) N Boc 3 up to more than 29%; chiral purity is up to more than 99.2%; GC purity is up to more than 99.1%; and during BOC protection groups on S crystalline substance salt; the yield of resolving agent is reclaimed up to more than 95% from S crystalline substance salt, and purity is up to more than 98%.
Description
Technical field
The invention belongs to field of medicine and chemical technology, it is related to the preparation method of (S)-N-Boc-3- hydroxy piperidines.
Background technology
(S)-N-Boc-3- hydroxy piperidines are synthesis non-natural medicine congestion DHF medicine card not Rayleighs
(Bio.Med.Chem.2003,11,581-590), bruton's tyrosine kinase (BKT) inhibitor are different for Buddhist nun, natural materials according to Shandong
White thorn quinoline drenches the important intermediate (Tetrahedron of the medicines such as amine (isonitramine) and nitraria schoberi alkali (sibirine)
Lett.1989,30,2301-2304；J.Org.Chem.1984,49,1688-1691.), it is with a wide range of applications.
(S)-N-Boc-3- hydroxy piperidines can be prepared by two methods of chemical synthesis and living things catalysis at present.Living things catalysis
Method mainly has following approach：(1) with N-Boc-3- piperidones as raw material, chiral centre is reduced and introduced by ketoreductase, should
Although method can maximally utilise substrate, and chiral purity is up to more than 99%, ketoreductase used, coenzyme and
The prices such as the lactic dehydrogenase of its regeneration are high, and easy in inactivation, so approach still rests on laboratory development at present；
(2) selective fractionation is carried out with lipase, can step by step obtains the 3- hydroxy piperidines of (S)-and (R)-type, but lipase splits together
Chemical resolution is the same, and it is 50% to obtain (S) with the theoretical highest yield of (R) -3- piperidine alcohols, and the separation and purifying of product need
Column chromatography, industrialized production is difficult.Enzyme split further disadvantage is that be difficult to racemization initiation material thing to obtain yield higher,
Current raw material racemization also remains high still without feasible short-cut method, thus the fractionation cost of lipase.Chemical method is main
It is divided into two approach：(1) it is anti-through multisteps such as condensation, reduction with the acid of the natural chirals such as L MALIC ACID, L-Glu or L-Asp as raw material
Should, complex procedures, and chiral starting materials and go back original reagent are expensive, it is difficult to industry is amplified；(2) with the 3- hydroxyl piperazines of racemization
Pyridine is raw material, after being split through (2S, 3S)-N- (4- chlorphenyls) -2,3- dihydroxy succinamic acid, L- camphorsulfonic acids etc., by weight
Crystallization obtains chiral alcohol.Chemical resolution method relative ease, realized the industrialized production of (S)-N-Boc-3- hydroxy piperidines already, but
Because resolution yield is low, and resolving agent is expensive, causes product cost of a relatively high.Therefore, work need to be carried out to chemical resolution
Skill optimization to reduce production cost, and effective recovery of resolving agent, split mother liquor comprehensive utilization be currently can be perfect
Improved both direction.
In patent WO2004064730A2,3- hydroxy piperidines are split using L- camphorsulfonic acids, gained (S)-crystalline substance salt exists
NaHCO3In the presence of, (S)-N-Boc-3- hydroxy piperidines are changed into dichloromethane-aqueous systems, due to NaHCO3In this body
Solvent degree is smaller in system, causes system heterogeneous, and the reaction time is relatively long, and post processing when organic solvent and water consumption compared with
Greatly, precipitation high energy consumption is post-processed.Most importantly, resolving agent is changed into L- sodium camphorsulfonates by the method, and the sodium salt is due to tool
There are hydrophilic and hydrophobic both sexes, isolate and purify difficulty, and need to carry out strong acid acidification to it before applying mechanically, cause the rate of recovery and purity
It is relatively low, apply mechanically fractionation effect poor.The work of a kind of method for splitting for being easy to resolving agent to reclaim of selection and upper BOC protection groups is needed for this
Skill route.
The content of the invention
It is an object of the invention to provide a kind of 3- hydroxy piperidines through L- camphorsulfonic acid ammonium chiral resolutions, received ensure that to split
On the premise of rate and chiral purity, resolving agent recovery difficulty is solved, yield and purity are low, apply mechanically the undesirable skill of fractionation effect
Art problem.
To achieve the above object, the present invention uses following technical scheme：
A kind of preparation method of (S)-N-Boc-3- hydroxy piperidines, comprises the following steps：
(1) 3- hydroxy piperidines carry out ammonia displacement with L- camphorsulfonic acids ammonium；
(2) by the 3- hydroxy piperidines in step (1), fractionation prepares (S) -3- hydroxyls in ethanol and methyl tertiary butyl ether(MTBE) system
Phenylpiperidines-L- camphorsulfonic acids crystalline substance salt；
(3) by step (2) (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt changed under the catalysis of ammoniacal liquor (S) -
N-Boc-3- hydroxy piperidines.
Described preparation method is refined also including (S)-N-Boc-3- hydroxy piperidines：Take (the S)-N- in step (3)
Boc-3- hydroxy piperidines, are 1 by the quality of (S)-N-Boc-3- hydroxy piperidines and the volume ratio of normal hexane：2~3 (g/mL) are added
Normal hexane, is heated to reflux a point water 2-4h, is gradually cooled to 0-5 DEG C, micro- stirring and crystallizing, after separation of solid and liquid, using normal hexane drip washing
Solid, drains, in decompression drying under 30 DEG C, -0.1Mpa.
The described preparation method also recovery including resolving agent：The water phase in step (3) is taken, is washed using dichloromethane
Wash, wash Bi Shuixiang in decompression dehydration under 70 DEG C, -0.1Mpa to slurry, then in decompression drying under 70 DEG C, -0.1Mpa to aqueous
Amount is less than 0.5%, obtains final product L- camphorsulfonic acid ammoniums, can directly cover in the middle of step (1).
Used as improvement, backflow solvent used is ether, ethyl acetate, butyl acetate, dichloromethane, three in step (1)
The non-alcohols such as chloromethanes, tetrachloromethane, middle low polar solvent, preferably ethyl acetate, dichloromethane, chloroform；And 3- hydroxyls
The time that phenylpiperidines are heated to reflux replacing ammonia with L- camphorsulfonic acid ammoniums is 0.5-4h, it is therefore preferable to 2-3h.
As improvement, during step (2) fractionation crystallization prepares (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt, institute
Solvent is absolute ethyl alcohol and methyl tertiary butyl ether(MTBE), and its consumption is m (3- hydroxy piperidines):V (ethanol)=1：2, V (ethanol)：V
(methyl tertiary butyl ether(MTBE))=1：5~12, preferably V (ethanol)：V (methyl tertiary butyl ether(MTBE))=2：6~9；The stirring and crystallizing time is
12~60h, preferably 24~48h；
As improvement, during step (2) fractionation crystallization prepares (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt, slightly
(S) -3- hydroxy piperidines-L- camphorsulfonic acids crystalline substance salt recrystallization solvent used is absolute ethyl alcohol, and consumption is m (lump salt):V (second
Alcohol)=1：0.8~2.5 (g/mL), preferably m (lump salt)：V (ethanol)=1：0.8~1.5 (g/mL).
As improvement, BOC blocking groups on (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt in step (3), used is molten
Agent dichloromethane and water, it is m (S- crystalline substances salt) to match:V (dichloromethane)：V (water)=1：3：3(g/mL/mL)；The use of ammoniacal liquor used
It is 1.5~5 times of molar equivalents of (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt to measure, it is therefore preferable to 2~3 times of molar equivalents；Institute
With 1.0~1.2 times of molar equivalents that BOC acid anhydrides consumption is (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt, it is therefore preferable to 1.02
~1.1 times of molar equivalents.
Used as improvement, in step (4) in the subtractive process of (S)-N-Boc-3- hydroxy piperidines, recrystallization solvent used is
Normal hexane, consumption is m [(S)-N-Boc-3- hydroxy piperidines]：V (normal hexane)=1：1~5 (g/mL), it is therefore preferable to m [(S)-N-
Boc-3- hydroxy piperidines]：V (normal hexane)=1：2~3 (g/mL), and increase division box in reflux course.
Used as improvement, in the recovery of step (5) resolving agent, water mutually needs to be washed using dichloromethane, and consumption is V (water
Phase)：V (dichloromethane)=1：2, point 2~4 washings.
3- hydroxy piperidines prepare (S)-N-Boc-3- hydroxy piperidines and reclaim resolving agent through L- camphorsulfonic acid ammonium chiral resolutions
Technique, specifically include following processing step：
(1) 3- hydroxy piperidines carry out ammonia displacement with L- camphorsulfonic acids ammonium：Take the L- of 3- hydroxy piperidines and 0.5 times of molar equivalent
Camphorsulfonic acid ammonium is dissolved in 3 times of organic solvents of volume, is heated to reflux displacement ammonia and with absorption by Hydrochloric Acid；Then vacuum distillation is returned
Organic solvent is received, obtains concentrating grease；
(2) split crystallization and prepare (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt：To the concentrate in step (1) successively
Ethanol, methyl tertiary butyl ether(MTBE) (MTBE) organic solvent are added, in stirring and crystallizing at 15 DEG C, and a small amount of (S) -3- hydroxyl piperazines is added
Used as crystal seed, after stirring and crystallizing, after separation of solid and liquid, solid uses V (ethanol) to pyridine-L- camphorsulfonic acids crystalline substance salt：V (methyl tertbutyls
Ether)=1:2 mixed liquor is washed 2 times, and each wash liquid product is equal with 3- hydroxy piperidine mass numbers, washes complete drying；Then
Lump salt is dissolved using ethanol, and after being heated to reflux 1h, in micro- stirring and crystallizing at 25 DEG C, after separation of solid and liquid, solid uses V (second
Alcohol)：V (methyl tertiary butyl ether(MTBE))=1:2 mixed liquor is washed 2 times, and the overall product of cleaning solution is equal with the mass number of lump salt,
Wash complete drying；
(3) (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt changes into (S)-N-Boc-3- hydroxy piperidines：By step (2)
In (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt be dissolved in dichloromethane-aqueous systems, using 20% ammoniacal liquor as catalysis
Agent, in BOC acid anhydrides is added dropwise at 0-5 DEG C, drop finishes, and is stood after being warmed to room temperature lower stirring 2-4h, after layering, dichloromethane is mutually used etc.
2 washings of the saturation NaCl solution of volume point, obtain final product oil product (S)-N-Boc-3- hydroxy piperidines after precipitation；
(4) (S)-N-Boc-3- hydroxy piperidines is refined：Take oil product (the S)-N-Boc-3- hydroxyl piperazines in step (3)
Pyridine is added in normal hexane, is heated to reflux a point water 2-4h, is gradually cooled to 0-5 DEG C, and micro- stirring and crystallizing after separation of solid and liquid, is used
Normal hexane drip washing solid, drains, in decompression drying under 30 DEG C, -0.1Mpa；
(5) recovery of resolving agent：The water phase in step (3) is taken, is washed using dichloromethane, wash Bi Shuixiang in 70
DEG C, decompression dehydration, to slurry, is then less than 0.5% in decompression drying under 70 DEG C, -0.1Mpa to water content under -0.1Mpa, obtain final product
L- camphorsulfonic acid ammoniums, can directly cover in the middle of step (1).
Beneficial effect：
1st, resolving agent used is L- camphorsulfonic acid ammoniums, and splitting gained (S) -3- hydroxy piperidine-L- camphorsulfonic acid crystalline substance salt is
In the unconventional NaHCO of ammoniacal liquor3, upper BOC blocking groups under the inorganic base catalysis such as NaOH, so can be by resolving agent with L- camphors
The form of ichthyodin is directly reclaimed, and the rate of recovery reaches more than 95%, is returned and has been kept away NaHCO3, in NaOH catalysis during BOC, L- camphors
Sulfonic acid with isolating and purifying for being brought in the presence of its sodium-salt form it is difficult, apply mechanically before need strong acid to be acidified, the rate of recovery and purity is relatively low, set
With drawbacks such as fractionation effect differences, it is ensured that resolution yield and chiral purity.
2nd, in chiral resolution process, the property that make use of the effumability and its solubility in organic solvent of ammonia low
Matter, carries out ammonia displacement, has carried out L- camphorsulfonic acids and 3- hydroxy piperidines into the fractionation salification process of salt.
3rd, the chiral crystalline substance salt of gained (S) -3- hydroxy piperidine-L- camphorsulfonic acids is split, with ammoniacal liquor in dichloromethane-aqueous systems
Used as catalyst, in homogeneously, reaction rate is fast, convenient product separation for system during with BOC anhydride reactions.
Specific embodiment
The present invention is annotated with reference to specific embodiment.(S) -3- hydroxy piperidines-L- camphorsulfonic acids crystalline substance salt referred to as
(S)-brilliant salt
Embodiment 1
(1) 3- hydroxy piperidines carry out ammonia displacement with L- camphorsulfonic acids ammonium：The three-neck flask of 100mL is taken, 3- hydroxyl piperazines are added
Pyridine 10.1g, L- camphorsulfonic acid ammonium 12.47g, butyl acetate 30mL, stirring mixing, are heated to reflux, and the ammonia for displacing is by cold
Solidifying pipe is absorbed using concentrated hydrochloric acid；Backflow 0.5h, is cooled to 50 DEG C, vacuum distillation under -0.1Mpa, reclaims butyl acetate to without cut
Outflow；70 DEG C are then heated to, the butyl acetate of residual is sloughed in vacuum distillation under -0.1Mpa；
(2) split crystallization and prepare (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt：The concentrate in step (1) is taken out, is turned
Move in the middle of the three-neck flask of 250mL, be subsequently adding absolute ethyl alcohol 20.2mL, stirring adds 101mL methyl- terts after being allowed to dissolving
Butyl ether, and 0.5g (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt is added as crystal seed, at 15 DEG C after stirring and crystallizing 12h, Gu
Liquid is separated.Gained solid uses V (ethanol)：V (methyl tertiary butyl ether(MTBE))=1:2 mixed liquor is washed 2 times, each consumption 10mL,
Wash complete, drain and be vacuum dried, obtain thick S- crystalline substance salt 11.57g；The brilliant salt uses 9.3mL anhydrous alcohol solutions, is heated to reflux 1h
Afterwards, in micro- stirring and crystallizing 12h at 25 DEG C, after separation of solid and liquid, gained solid uses V (ethanol)：V (methyl tertiary butyl ether(MTBE))=1:2
Mixed liquor wash 2 times, each 6mL, drying washes complete, drains and is vacuum dried, and obtains S- crystalline substances salt 9.95g；
(3) (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt changes into (S)-N-Boc-3- hydroxy piperidines：By step (2)
In (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt be dissolved in 30mL water, be subsequently adding 30mL dichloromethane, 20% ammoniacal liquor
3.8g, after inserting ice bath stirring 0.5h, is added dropwise BOC acid anhydrides 6.51g；Drop is complete to go to standing after stirring 2h at room temperature, after layering, two
Chloromethanes is mutually washed 2 times using the saturation NaCl solution of 15mL；Oil product (S)-N-Boc-3- hydroxyls are obtained final product after organic phase precipitation
Phenylpiperidines 6.61g, GC purity 98.5%, chiral purity 99.0%.
Embodiment 2
(1) 3- hydroxy piperidines carry out ammonia displacement with L- camphorsulfonic acids ammonium：The three-neck flask of 250mL is taken, 3- hydroxyl piperazines are added
Pyridine 30g, L- camphorsulfonic acid ammonium 36.97g, ethyl acetate 90mL, stirring mixing, are heated to reflux；Backflow 2h after, be cooled to 50 DEG C ,-
Vacuum distillation under 0.1Mpa, reclaims ethyl acetate to flowing out without cut and goes out；70 DEG C are then heated to, in vacuum distillation under -0.1Mpa
Slough the ethyl acetate of residual；
(2) split crystallization and prepare (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt：The concentrate in step (1) is taken out, is turned
Move in the middle of the three-neck flask of 500mL, be subsequently adding absolute ethyl alcohol 60mL, stirring adds 360mL methyl- tert fourths after being allowed to dissolving
Base ether, and 0.5g (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt is added as crystal seed, at 15 DEG C after stirring and crystallizing 24h, solid-liquid
Separate.Gained solid uses V (ethanol)：V (methyl tertiary butyl ether(MTBE))=1:2 mixed liquor is washed 2 times, and each consumption 30mL is washed
Finish, drain and be vacuum dried, obtain thick S- crystalline substance salt 34.68g；The brilliant salt uses 35mL anhydrous alcohol solutions, after being heated to reflux 1h,
In micro- stirring and crystallizing 12h at 25 DEG C, after separation of solid and liquid, gained solid uses V (ethanol)：V (methyl tertiary butyl ether(MTBE))=1:2 it is mixed
Close liquid to wash 2 times, each 17mL, drying washes complete, drains and is vacuum dried, obtain S- crystalline substance salt 29.6g；
(3) (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt changes into (S)-N-Boc-3- hydroxy piperidines：By step (2)
In (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt be dissolved in 90mL water, be subsequently adding 90mL dichloromethane, 20% ammoniacal liquor
15.1g, after inserting ice bath stirring 0.5h, is added dropwise BOC acid anhydrides 19.76g；Drop is complete to go to standing after stirring 2h at room temperature, after layering,
Dichloromethane is mutually washed 2 times using the saturation NaCl solution of 45mL；Oil product (S)-N-Boc-3- is obtained final product after organic phase precipitation
Hydroxy piperidine 18.11g；
(4) (S)-N-Boc-3- hydroxy piperidines is refined：Take oil product (the S)-N-Boc-3- hydroxyl piperazines in step (3)
Pyridine is added in 36mL normal hexanes, after being heated to reflux point water 2h, is gradually cooled to 0-5 DEG C, after micro- stirring and crystallizing 12h, solid-liquid point
From rear, using normal hexane drip washing after, drain, in decompression drying under 30 DEG C, -0.1Mpa, obtain (S)-N-Boc-3- hydroxy piperidines white
Color crystal 17.4g, GC purity 99.5%, chiral purity 99.4%；
(5) recovery of resolving agent：The water phase in step (3) is taken, is washed 2 times using dichloromethane, each consumption
45mL, washes Bi Shuixiang in decompression dehydration under 70 DEG C, -0.1Mpa to slurry, then in decompression drying under 70 DEG C, -0.1Mpa to containing
Water is less than 0.5%, reclaims L- camphorsulfonic acid ammonium 21.4g, and purity 98.6% is brilliant from (S) -3- hydroxy piperidine-L- camphorsulfonic acids
The yield that resolving agent is reclaimed in salt is 95.3%.
Embodiment 3
(1) 3- hydroxy piperidines carry out ammonia displacement with L- camphorsulfonic acids ammonium：The three-neck flask of 1L is taken, 3- hydroxy piperidines are added
200g, L- camphorsulfonic acid ammonium 246.5g, chloroform 600mL, stirring mixing, are heated to reflux, and the ammonia for displacing is by condensation
Pipe is absorbed using concentrated hydrochloric acid；After backflow 3h, be cooled to 40 DEG C, vacuum distillation under -0.1Mpa, reclaim chloroform to flowing out without cut
Go out；70 DEG C are then heated to, the chloroform of residual is sloughed in vacuum distillation under -0.1Mpa；
(2) split crystallization and prepare (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt：The concentrate in step (1) is taken out, is turned
Move in the middle of the three-neck flask of 5L, be subsequently adding absolute ethyl alcohol 400mL, stirring is allowed to dissolving and adds 3600mL methyl tertbutyls
Ether, and 2g (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt is added as crystal seed, at 15 DEG C after stirring and crystallizing 48h, solid-liquid point
From.Gained solid uses V (ethanol)：V (methyl tertiary butyl ether(MTBE))=1:2 mixed liquor is washed 2 times, and each consumption 200mL is washed
Finish, drain and be vacuum dried, obtain thick S- crystalline substance salt 249.6g；The brilliant salt uses 375mL anhydrous alcohol solutions, is heated to reflux 1h
Afterwards, in micro- stirring and crystallizing 12h at 25 DEG C, after separation of solid and liquid, gained solid uses V (ethanol)：V (methyl tertiary butyl ether(MTBE))=1:2
Mixed liquor wash 2 times, each 125mL, drying washes complete, drains and is vacuum dried, and obtains S- crystalline substances salt 215.9g；
(3) (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt changes into (S)-N-Boc-3- hydroxy piperidines：By step (2)
In (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt be dissolved in 650mL water, be subsequently adding 650mL dichloromethane, 20% ammoniacal liquor
165.1g, after inserting ice bath stirring 0.5h, is added dropwise BOC acid anhydrides 155.4g；Drop is complete to go to standing, layering after stirring 3h at room temperature
Afterwards, dichloromethane is mutually washed 2 times using the saturation NaCl solution of 325mL；Oil product (S)-N- is obtained final product after organic phase precipitation
Boc-3- hydroxy piperidines 132.5g；
(4) (S)-N-Boc-3- hydroxy piperidines is refined：Take oil product (the S)-N-Boc-3- hydroxyl piperazines in step (3)
Pyridine is added in 400mL normal hexanes, after being heated to reflux point water 3h, is gradually cooled to 0-5 DEG C, after micro- stirring and crystallizing 12h, solid-liquid point
From rear, using normal hexane drip washing after, drain, in decompression drying under 30 DEG C, -0.1Mpa, obtain (S)-N-Boc-3- hydroxy piperidines white
Color crystal 125.3g, GC purity 99.3%, chiral purity 99.2%；
(5) recovery of resolving agent：The water phase in step (3) is taken, is washed 2 times using dichloromethane, each 480mL,
Bi Shuixiang is washed in decompression dehydration under 70 DEG C, -0.1Mpa to slurry, it is then low to water content in decompression drying under 70 DEG C, -0.1Mpa
In 0.5%, L- camphorsulfonic acid ammonium 156.5g are reclaimed, purity 98.3% is returned from (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt
The yield for receiving resolving agent is 95.4%.
Embodiment 4
(1) 3- hydroxy piperidines carry out ammonia displacement with L- camphorsulfonic acids ammonium：In the glass reaction kettle of 50L, 3- is put into successively
Hydroxy piperidine 2.5kg, L- camphorsulfonic acid ammonium 3.08kg, dichloromethane 7.5L, stirring mixing, are heated to reflux, the ammonia for displacing
Absorbed using concentrated hydrochloric acid by condenser pipe；After backflow 4h, be cooled to 40 DEG C, vacuum distillation under -0.1Mpa, reclaim dichloromethane extremely
Flowing out without cut goes out；60 DEG C are then heated to, the dichloromethane of residual is sloughed in vacuum distillation under -0.1Mpa；
(2) split crystallization and prepare (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt：Concentrate in step (1) is added
Absolute ethyl alcohol 5L, stirring is allowed to dissolving and adds 60L methyl tertiary butyl ether(MTBE)s, and adds 30g (S) -3- crystalline substance salt as crystal seed, at 15 DEG C
After stirring and crystallizing 60h, separation of solid and liquid.Gained solid uses V (ethanol)：V (methyl tertiary butyl ether(MTBE))=1:2 mixed liquor washing 2
Secondary, each consumption 2.5L washes complete, drains and is vacuum dried, and obtains thick S- crystalline substance salt 3.25kg；The brilliant salt uses 8.1L absolute ethyl alcohols
Dissolving, after being heated to reflux 1h, in micro- stirring and crystallizing 12h at 25 DEG C, after separation of solid and liquid, gained solid uses V (ethanol)：V (methyl
Tertbutyl ether)=1:2 mixed liquor is washed 2 times, each 1.6L, drying, washes complete, is drained and is vacuum dried, and obtains S- crystalline substance salt
2.82kg；
(3) (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt changes into (S)-N-Boc-3- hydroxy piperidines：By step (2)
In (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt be transferred in 50L glass reaction kettles, sequentially add water, dichloromethane each
8.5L, and 20% ammoniacal liquor 3.6kg is added, after inserting ice bath stirring 0.5h, BOC acid anhydrides 2.21kg is added dropwise；Drop is complete to be gone at room temperature
Stratification after stirring 4h, dichloromethane is mutually washed 2 times using the saturation NaCl solution of 4.25L；Oil is obtained final product after organic phase precipitation
Shape product (S)-N-Boc-3- hydroxy piperidines 1.73kg；
(4) (S)-N-Boc-3- hydroxy piperidines is refined：Take oil product (the S)-N-Boc-3- hydroxyl piperazines in step (3)
Pyridine is added in 8.6L normal hexanes, after being heated to reflux point water 4h, is gradually cooled to 0-5 DEG C, after micro- stirring and crystallizing 12h, solid-liquid point
From rear, using normal hexane drip washing after, drain, in decompression drying under 30 DEG C, -0.1Mpa, obtain (S)-N-Boc-3- hydroxy piperidines white
Color crystal 1.6kg, GC purity 99.2%, chiral purity 99.3%；
(5) recovery of resolving agent：The water phase in step (3) is taken, is washed 3 times using dichloromethane, each 5.6L is washed
Then Bi Shuixiang is less than in decompression dehydration under 70 DEG C, -0.1Mpa to slurry in decompression drying to water content under 70 DEG C, -0.1Mpa
0.5%, L- camphorsulfonic acid ammonium 2.07kg are reclaimed, purity 98.2% is reclaimed from (S) -3- hydroxy piperidine-L- camphorsulfonic acids and split
The yield of agent is 96.3%.
It is recognised that the illustrative embodiments that above-described embodiment is used only for explanation inventive principle, but this hair
Bright to be not limited only to this, those skilled in the art can make various improvement and change in the case where real situation of the present invention is not departed from, this
A little improvement and change fall within protection scope of the present invention.
Claims (10)
1. a kind of preparation method of (S)-N-Boc-3- hydroxy piperidines, comprises the following steps：
(1) 3- hydroxy piperidines carry out ammonia displacement with L- camphorsulfonic acids ammonium；
(2) by the 3- hydroxy piperidines in step (1), fractionation prepares (S) -3- hydroxyl piperazines in ethanol and methyl tertiary butyl ether(MTBE) system
Pyridine-L- camphorsulfonic acids crystalline substance salt；
(3) (the S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt in step (2) is changed into (S)-N- under the catalysis of ammoniacal liquor
Boc-3- hydroxy piperidines.
2. the preparation method of (S)-N-Boc-3- hydroxy piperidines according to claim 1, it is characterised in that：Described preparation
Method is further comprising the steps of：
(S)-N-Boc-3- hydroxy piperidines is refined：(the S)-N-Boc-3- hydroxy piperidines taken in step (3) are added to normal hexane
Central, the quality of (S)-N-Boc-3- hydroxy piperidines is 1: 2~3 (g/mL) with the volume ratio of normal hexane, is heated to reflux a point water 2-
4h, is gradually cooled to 0-5 DEG C, and micro- stirring and crystallizing after separation of solid and liquid, using normal hexane drip washing solid, is drained, in 30 DEG C ,-
Decompression drying under 0.1Mpa.
3. the preparation method of (S)-N-Boc-3- hydroxy piperidines according to claim 1, it is characterised in that：Described preparation
Method is further comprising the steps of：
The recovery of resolving agent：Take the water phase in step (3), using dichloromethane wash, wash Bi Shuixiang in 70 DEG C ,-
Then decompression dehydration is less than 0.5% to slurry in decompression drying under 70 DEG C, -0.1Mpa to water content under 0.1Mpa, obtains final product L- camphor trees
Brain ichthyodin.
4. the preparation method of (S)-N-Boc-3- hydroxy piperidines according to claim 1, it is characterised in that：In step (1)
The operating condition of use is：Solvent is ether, ethyl acetate, butyl acetate, dichloromethane, chloroform, tetrachloromethane；3- hydroxyls
The time that phenylpiperidines are heated to reflux replacing ammonia with L- camphorsulfonic acid ammoniums is 0.5-4h.
5. the preparation method of (S)-N-Boc-3- hydroxy piperidines according to claim 4, it is characterised in that：In step (1)
Solvent used is ethyl acetate, dichloromethane, chloroform；3- hydroxy piperidines are heated to reflux replacing ammonia with L- camphorsulfonic acid ammoniums
Time be 2-3h.
6. the preparation method of (S)-N-Boc-3- hydroxy piperidines according to claim 1, it is characterised in that：In step (2)
The operating condition of use is：Solvent is absolute ethyl alcohol and methyl tertiary butyl ether(MTBE), the quality of its 3- hydroxy piperidine and the volume of ethanol
Than being 1: 2 (g/mL), ethanol is 1: 5~12 with methyl tertiary butyl ether(MTBE) volume ratio, and the stirring and crystallizing time is 12~60h.
7. the preparation method of (S)-N-Boc-3- hydroxy piperidines according to claim 6, it is characterised in that：In step (2)
Absolute ethyl alcohol is 2: 6~9 with the volume ratio of methyl tertiary butyl ether(MTBE)；The stirring and crystallizing time is 24~48h.
8. the preparation method of (S)-N-Boc-3- hydroxy piperidines according to claim 1, it is characterised in that：In step (2)
Slightly (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt is recrystallized, and recrystallization solvent used is absolute ethyl alcohol, thick (S) -3-
The quality of hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt and the volume ratio of ethanol are 1: 0.8~2.5 (g/mL).
9. the preparation method of (S)-N-Boc-3- hydroxy piperidines according to claim 1, it is characterised in that：In step (3)
The operating condition of use is：Ammonia volume used is 1.5~5 times moles of (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt
Equivalent；It is solvent, the quality of (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt and the body of dichloromethane to use dichloromethane and water
Product is 1: 3: 3 (g/mL/mL) with the volume ratio of water；Using BOC acid anhydrides, the consumption of BOC acid anhydrides is (S) -3- hydroxy piperidine-L- camphor trees
1.0~1.2 times of molar equivalents of brain sulfonic acid crystalline substance salt.
10. the preparation method of (S)-N-Boc-3- hydroxy piperidines according to claim 9, it is characterised in that：In step (3)
Ammonia volume used is 2~3 times of molar equivalents of (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt；BOC acid anhydrides used is used
It is 1.02~1.10 times of molar equivalents of (S) -3- hydroxy piperidine-L- camphorsulfonic acids crystalline substance salt to measure.
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