CN104557674A - Preparation method of (S)-N-Boc-3-hydroxypiperidine - Google Patents
Preparation method of (S)-N-Boc-3-hydroxypiperidine Download PDFInfo
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- 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
- C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
- C07D211/36—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 no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention relates to a preparation method of (S)-N-Boc-3-hydroxypiperidine. The preparation method comprises the following steps: (1) carrying out ammonia displacement on 3-hydroxypiperidine and L-camphor ammonium sulfonate; (2) resolving the 3-hydroxypiperidine in the step (1) in an ethanol-methyl tertiary butyl ether (MTBE) system so as to prepare (S)-3-hydroxypiperidine-L-camphorsulfonic crystal salt ((S)-crystal salt in short); and (3) converting the (S)-crystal salt in the step (2) into (S)-N-Boc-3-hydroxypiperidine under the catalysis of ammonia water. On the basis of the method disclosed by the invention, the yield of the (S)-N-Boc-3-hydroxypiperidine prepared from the 3-hydroxypiperidine through chiral resolution reaches above 29%, chiral purity is above 99.2% and gas chromatograph (GC) purity is above 99.1%; and in the process of a t-butyloxycarboryl (BOC) protecting group on the S-crystal salt, the yield of recovering a resolving agent from the S-crystal salt reaches above 95% and the purity is higher than 98%.
Description
Technical field
The invention belongs to field of medicine and chemical technology, relate to the preparation method of (S)-N-Boc-3-hydroxy piperidine.
Background technology
(S)-N-Boc-3-hydroxy piperidine is synthesis non-natural medicine congestion DHF medicine card not Rayleigh (Bio.Med.Chem.2003,11,581 – 590), bruton's tyrosine kinase (BKT) inhibitor drenches important intermediate (the Tetrahedron Lett.1989 of the medicines such as amine (isonitramine) and nitraria schoberi alkali (sibirine) for the different white thorn quinoline of Buddhist nun, crude substance according to Shandong, 30,2301 – 2304; J.Org.Chem.1984,49,1688 – 1691.), be with a wide range of applications.
(S)-N-Boc-3-hydroxy piperidine can be prepared by chemosynthesis and biocatalysis two kinds of methods at present.Biological catalysis mainly contains following approach: (1) with N-Boc-3-piperidone for raw material, reduced by ketoreductase and introduce chiral centre, although this method can maximally utilise substrate, and chiral purity reaches more than 99%, but the prices such as the serum lactic dehydrogenase of ketoreductase used, coenzyme and regeneration thereof are high, and easy in inactivation, so approach still rests on laboratory development at present; (2) selectivity fractionation is carried out with lipase, can obtain step by step (S)-and the 3-hydroxy piperidine of (R)-type, but lipase splits the same with chemical resolution, obtaining (S) with the highest yield of theory of (R)-3-piperidine alcohols is 50%, and the separation of product and purifying need column chromatography, suitability for industrialized production difficulty.Another defect that enzyme splits is difficult to racemization starting raw material thing to obtain higher yield, and current raw material racemization does not still have feasible short-cut method, and thus the fractionation cost of lipase also remains high.Chemical method is mainly divided into two approach: (1), with the acid of the natural chiral such as L MALIC ACID, L-Glu or L-Asp for raw material, through the polystep reaction such as condensation, reduction, complex procedures, and chiral starting materials and to go back original reagent expensive, be difficult to industry and amplify; (2) with the 3-hydroxy piperidine of racemization for raw material, after (2S, 3S)-N-(4-chloro-phenyl-)-2,3-dihydroxyl succinamic acid, L-camphorsulfonic acid etc. split, obtain chiral alcohol by recrystallization.Chemical resolution method relative ease, realized the suitability for industrialized production of (S)-N-Boc-3-hydroxy piperidine already, but due to resolution yield low, and resolving agent price is more expensive, causes product cost relatively high.For this reason, process optimization need be carried out to reduce production cost to chemical resolution, and the comprehensive utilization that mother liquor was applied mechanically, split to the efficient recovery of resolving agent is the current both direction can improving improvement.
In patent WO2004064730A2, adopt L-camphorsulfonic acid to split 3-hydroxy piperidine, gained (S)-brilliant salt is at NaHCO
3effect under, in methylene dichloride-aqueous systems, change into (S)-N-Boc-3-hydroxy piperidine, due to NaHCO
3in this system, solvent degree is less, causes system heterogeneous, and the reaction times is relatively long, and during aftertreatment, organic solvent and water consumption are comparatively large, and aftertreatment precipitation energy consumption is high.Most importantly, resolving agent is changed into L-sodium camphorsulfonate by this method, and this sodium salt is owing to having hydrophilic and hydrophobic both sexes, and separation and purification difficulty, and needs before applying mechanically to carry out strong acid acidification to it, cause the rate of recovery and purity on the low side, apply mechanically fractionation weak effect.Need to select a kind ofly to be convenient to method for splitting that resolving agent reclaims and the operational path of upper BOC protecting group for this reason.
Summary of the invention
The object of this invention is to provide a kind of 3-hydroxy piperidine through L-camphorsulfonic acid ammonium chiral separation, under the prerequisite that ensure that resolution yield and chiral purity, solve resolving agent reclaim difficulty, yield and purity low, apply mechanically and split the undesirable technical problem of effect.
For achieving the above object, the present invention is by the following technical solutions:
A kind of preparation method of (S)-N-Boc-3-hydroxy piperidine, comprises the following steps:
(1) 3-hydroxy piperidine carries out ammonia displacement with L-camphorsulfonic acid ammonium;
(2) the 3-hydroxy piperidine in step (1) is split in ethanol and methyl tertiary butyl ether system the brilliant salt of preparation (S)-3-hydroxy piperidine-L-camphorsulfonic acid;
(3) brilliant for (the S)-3-hydroxy piperidine-L-camphorsulfonic acid in step (2) salt is changed into (S)-N-Boc-3-hydroxy piperidine under the catalysis of ammoniacal liquor.
Described preparation method also comprises the refining of (S)-N-Boc-3-hydroxy piperidine: get (the S)-N-Boc-3-hydroxy piperidine in step (3), be that 1:2 ~ 3 (g/mL) add normal hexane by the quality of (S)-N-Boc-3-hydroxy piperidine and the volume ratio of normal hexane, reflux divides water 2-4h, be cooled to 0-5 DEG C gradually, micro-stirring and crystallizing, after solid-liquid separation, adopt normal hexane drip washing solid, drain, in 30 DEG C, decompression drying under-0.1Mpa.
Described preparation method also comprises the recovery of resolving agent: get the aqueous phase in step (3), adopt washed with dichloromethane, wash Bi Shuixiang in 70 DEG C, under-0.1Mpa decompression dehydration to slurry, then in 70 DEG C, under-0.1Mpa decompression drying to water content lower than 0.5%, obtain L-camphorsulfonic acid ammonium, directly can overlap and be used in the middle of step (1).
As improvement, in step (1), backflow solvent used is non-alcohols, the middle low polar solvents such as ether, ethyl acetate, butylacetate, methylene dichloride, trichloromethane, tetrachloromethane, is preferably ethyl acetate, methylene dichloride, trichloromethane; And the time that 3-hydroxy piperidine and L-camphorsulfonic acid ammonium reflux replace ammonia is 0.5-4h, be preferably 2-3h.
As improvement, step (2) splits in the process of the brilliant salt of crystallization preparation (S)-3-hydroxy piperidine-L-camphorsulfonic acid, solvent used is dehydrated alcohol and methyl tertiary butyl ether, its consumption is m (3-hydroxy piperidine): V (ethanol)=1:2, V (ethanol): V (methyl tertiary butyl ether)=1:5 ~ 12, preferably V (ethanol): V (methyl tertiary butyl ether)=2:6 ~ 9; The stirring and crystallizing time is 12 ~ 60h, is preferably 24 ~ 48h;
As improvement, step (2) splits in the process of the brilliant salt of crystallization preparation (S)-3-hydroxy piperidine-L-camphorsulfonic acid, the solvent that slightly the brilliant salt recrystallization of (S)-3-hydroxy piperidine-L-camphorsulfonic acid is used is dehydrated alcohol, consumption is m (lump salt): V (ethanol)=1:0.8 ~ 2.5 (g/mL), preferably m (lump salt): V (ethanol)=1:0.8 ~ 1.5 (g/mL).
As improvement, BOC blocking group on the brilliant salt of (S)-3-hydroxy piperidine-L-camphorsulfonic acid in step (3), methylene chloride used and water, proportioning is m (the brilliant salt of S-): V (methylene dichloride): V (water)=1:3:3 (g/mL/mL); The consumption of ammoniacal liquor used is 1.5 ~ 5 times of molar equivalents of the brilliant salt of (S)-3-hydroxy piperidine-L-camphorsulfonic acid, is preferably 2 ~ 3 times of molar equivalents; BOC acid anhydrides consumption used is 1.0 ~ 1.2 times of molar equivalents of the brilliant salt of (S)-3-hydroxy piperidine-L-camphorsulfonic acid, is preferably 1.02 ~ 1.1 times of molar equivalents.
As improvement, in step (4) (S)-N-Boc-3-hydroxy piperidine treating process in, recrystallization solvent used is normal hexane, consumption is m [(S)-N-Boc-3-hydroxy piperidine]: V (normal hexane)=1:1 ~ 5 (g/mL), be preferably m [(S)-N-Boc-3-hydroxy piperidine]: V (normal hexane)=1:2 ~ 3 (g/mL), and increase division box in reflux course.
As improvement, in the recovery of step (5) resolving agent, aqueous phase need adopt washed with dichloromethane, and consumption is V (aqueous phase): V (methylene dichloride)=1:2, point 2 ~ 4 washings.
3-hydroxy piperidine is prepared (S)-N-Boc-3-hydroxy piperidine through L-camphorsulfonic acid ammonium chiral separation and is reclaimed the technique of resolving agent, specifically comprises following processing step:
(1) 3-hydroxy piperidine and L-camphorsulfonic acid ammonium carry out ammonia displacement: the L-camphorsulfonic acid ammonium getting 3-hydroxy piperidine and 0.5 times of molar equivalent is dissolved in the organic solvent of 3 times of volumes, reflux displacement ammonia with absorption by Hydrochloric Acid; Then organic solvent is reclaimed in underpressure distillation, obtains concentrated oily matter;
(2) the brilliant salt of crystallization preparation (S)-3-hydroxy piperidine-L-camphorsulfonic acid is split: add ethanol, methyl tertiary butyl ether (MTBE) organic solvent successively to the enriched material in step (1), stirring and crystallizing at 15 DEG C, and add the brilliant salt of a small amount of (S)-3-hydroxy piperidine-L-camphorsulfonic acid as crystal seed, after stirring and crystallizing, after solid-liquid separation, solid adopts V (ethanol): the mixed solution of V (methyl tertiary butyl ether)=1:2 washs 2 times, each washing liq product is equal with 3-hydroxy piperidine total mass number, washes to finish to dry; Then lump salt adopts dissolve with ethanol, after reflux 1h, micro-stirring and crystallizing at 25 DEG C, after solid-liquid separation, solid adopts V (ethanol): the mixed solution of V (methyl tertiary butyl ether)=1:2 washs 2 times, the overall product of washings is equal with the total mass number of lump salt, washes to finish to dry;
(3) the brilliant salt of (S)-3-hydroxy piperidine-L-camphorsulfonic acid changes into (S)-N-Boc-3-hydroxy piperidine: be dissolved in methylene dichloride-aqueous systems by brilliant for (the S)-3-hydroxy piperidine-L-camphorsulfonic acid in step (2) salt, ammoniacal liquor using 20% is as catalyzer, BOC acid anhydrides is dripped at 0-5 DEG C, drip and finish, leave standstill after rising to stirred at ambient temperature 2-4h, after layering, methylene dichloride adopts isopyknic saturated NaCl solution to divide 2 washings mutually, namely obtains oil product (S)-N-Boc-3-hydroxy piperidine after precipitation;
(4) (S)-N-Boc-3-hydroxy piperidine is refining: oil product (the S)-N-Boc-3-hydroxy piperidine got in step (3) joins in normal hexane, reflux divides water 2-4h, be cooled to 0-5 DEG C gradually, micro-stirring and crystallizing, after solid-liquid separation, adopt normal hexane drip washing solid, drain, in 30 DEG C, decompression drying under-0.1Mpa;
(5) recovery of resolving agent: get the aqueous phase in step (3), adopt washed with dichloromethane, wash Bi Shuixiang in 70 DEG C, under-0.1Mpa decompression dehydration to slurry, then in 70 DEG C, under-0.1Mpa decompression drying to water content lower than 0.5%, obtain L-camphorsulfonic acid ammonium, directly can overlap and be used in the middle of step (1).
Beneficial effect:
1, resolving agent used is L-camphorsulfonic acid ammonium, and splitting the brilliant salt of gained (S)-3-hydroxy piperidine-L-camphorsulfonic acid is unconventional NaHCO at ammoniacal liquor
3, upper BOC blocking group under the mineral alkali catalysis such as NaOH, resolving agent directly can be reclaimed with the form of L-camphorsulfonic acid ammonium like this, and the rate of recovery reaches more than 95%, returns and kept away NaHCO
3, in NaOH catalysis during BOC, the separation and purification difficulty brought when L-camphorsulfonic acid exists with its sodium-salt form, apply mechanically before need strong acid acidifying, the rate of recovery and purity on the low side, apply mechanically drawbacks such as splitting weak effect, ensure that resolution yield and chiral purity.
2, in chiral resolution process, make use of the easy volatile of ammonia and the low character of solubleness in organic solvent thereof, carry out ammonia displacement, carried out the fractionation salification process of L-camphorsulfonic acid and 3-hydroxy piperidine salify.
3, split the brilliant salt of gained (S)-3-hydroxy piperidine-L-camphorsulfonic acid chirality, using ammoniacal liquor as catalyzer in methylene dichloride-aqueous systems, be homogeneous phase with system during BOC anhydride reaction, speed of reaction is fast, convenient product separation.
Embodiment
Below in conjunction with specific embodiment, the present invention is annotated.(S) the brilliant salt of-3-hydroxy piperidine-L-camphorsulfonic acid is called for short (S)-brilliant salt
Embodiment 1
(1) 3-hydroxy piperidine and L-camphorsulfonic acid ammonium carry out ammonia displacement: the three-necked flask getting 100mL, add 3-hydroxy piperidine 10.1g, L-camphorsulfonic acid ammonium 12.47g, butylacetate 30mL, be uniformly mixed, reflux, the ammonia displaced adopts concentrated hydrochloric acid to absorb by prolong; Backflow 0.5h, is cooled to 50 DEG C, underpressure distillation under-0.1Mpa, reclaims butylacetate to flowing out without cut; Then be warming up to 70 DEG C, under-0.1Mpa, residual butylacetate is sloughed in underpressure distillation;
(2) the brilliant salt of crystallization preparation (S)-3-hydroxy piperidine-L-camphorsulfonic acid is split: take out the enriched material in step (1), in the middle of the three-necked flask being transferred to 250mL, then dehydrated alcohol 20.2mL is added, stirring adds 101mL methyl tertiary butyl ether after making it dissolving, and add the brilliant salt of 0.5g (S)-3-hydroxy piperidine-L-camphorsulfonic acid as crystal seed, at 15 DEG C after stirring and crystallizing 12h, solid-liquid separation.Gained solid adopts V (ethanol): the mixed solution of V (methyl tertiary butyl ether)=1:2 washs 2 times, and each consumption 10mL, washes complete, drains and vacuum-drying, obtains the brilliant salt 11.57g of thick S-; This brilliant salt adopts 9.3mL anhydrous alcohol solution, after reflux 1h, micro-stirring and crystallizing 12h at 25 DEG C, after solid-liquid separation, gained solid adopts V (ethanol): the mixed solution of V (methyl tertiary butyl ether)=1:2 washs 2 times, each 6mL, dry, wash complete, drain and vacuum-drying, obtain the brilliant salt 9.95g of S-;
(3) the brilliant salt of (S)-3-hydroxy piperidine-L-camphorsulfonic acid changes into (S)-N-Boc-3-hydroxy piperidine: be dissolved in 30mL water by brilliant for (the S)-3-hydroxy piperidine-L-camphorsulfonic acid in step (2) salt, then 30mL methylene dichloride is added, 20% ammoniacal liquor 3.8g, after inserting ice bath stirring 0.5h, drip BOC acid anhydrides 6.51g; Drip to finish to go to after stirred at ambient temperature 2h and leave standstill, after layering, methylene dichloride adopts the saturated NaCl solution of 15mL to wash 2 times mutually; Namely oil product (S)-N-Boc-3-hydroxy piperidine 6.61g is obtained, GC purity 98.5%, chiral purity 99.0% after organic phase precipitation.
Embodiment 2
(1) 3-hydroxy piperidine and L-camphorsulfonic acid ammonium carry out ammonia displacement: the three-necked flask getting 250mL, add 3-hydroxy piperidine 30g, L-camphorsulfonic acid ammonium 36.97g, ethyl acetate 90mL, are uniformly mixed, reflux; After backflow 2h, be cooled to 50 DEG C, underpressure distillation under-0.1Mpa, reclaim ethyl acetate to flowing out without cut; Then be warming up to 70 DEG C, under-0.1Mpa, residual ethyl acetate is sloughed in underpressure distillation;
(2) the brilliant salt of crystallization preparation (S)-3-hydroxy piperidine-L-camphorsulfonic acid is split: take out the enriched material in step (1), in the middle of the three-necked flask being transferred to 500mL, then dehydrated alcohol 60mL is added, stirring adds 360mL methyl tertiary butyl ether after making it dissolving, and add the brilliant salt of 0.5g (S)-3-hydroxy piperidine-L-camphorsulfonic acid as crystal seed, at 15 DEG C after stirring and crystallizing 24h, solid-liquid separation.Gained solid adopts V (ethanol): the mixed solution of V (methyl tertiary butyl ether)=1:2 washs 2 times, and each consumption 30mL, washes complete, drains and vacuum-drying, obtains the brilliant salt 34.68g of thick S-; This brilliant salt adopts 35mL anhydrous alcohol solution, after reflux 1h, micro-stirring and crystallizing 12h at 25 DEG C, after solid-liquid separation, gained solid adopts V (ethanol): the mixed solution of V (methyl tertiary butyl ether)=1:2 washs 2 times, each 17mL, dry, wash complete, drain and vacuum-drying, obtain the brilliant salt 29.6g of S-;
(3) the brilliant salt of (S)-3-hydroxy piperidine-L-camphorsulfonic acid changes into (S)-N-Boc-3-hydroxy piperidine: be dissolved in 90mL water by brilliant for (the S)-3-hydroxy piperidine-L-camphorsulfonic acid in step (2) salt, then 90mL methylene dichloride is added, 20% ammoniacal liquor 15.1g, after inserting ice bath stirring 0.5h, drip BOC acid anhydrides 19.76g; Drip to finish to go to after stirred at ambient temperature 2h and leave standstill, after layering, methylene dichloride adopts the saturated NaCl solution of 45mL to wash 2 times mutually; Namely oil product (S)-N-Boc-3-hydroxy piperidine 18.11g is obtained after organic phase precipitation;
(4) (S)-N-Boc-3-hydroxy piperidine is refining: oil product (the S)-N-Boc-3-hydroxy piperidine got in step (3) joins in 36mL normal hexane, after reflux divides water 2h, be cooled to 0-5 DEG C gradually, after micro-stirring and crystallizing 12h, after solid-liquid separation, after adopting normal hexane drip washing, drain, in 30 DEG C, decompression drying under-0.1Mpa, obtain (S)-N-Boc-3-hydroxy piperidine white crystal 17.4g, GC purity 99.5%, chiral purity 99.4%;
(5) recovery of resolving agent: get the aqueous phase in step (3), adopt washed with dichloromethane 2 times, each consumption 45mL, wash Bi Shuixiang in 70 DEG C, under-0.1Mpa decompression dehydration to slurry, then in 70 DEG C, under-0.1Mpa decompression drying to water content lower than 0.5%, reclaim L-camphorsulfonic acid ammonium 21.4g, purity 98.6%, the yield reclaiming resolving agent from the brilliant salt of (S)-3-hydroxy piperidine-L-camphorsulfonic acid is 95.3%.
Embodiment 3
(1) 3-hydroxy piperidine and L-camphorsulfonic acid ammonium carry out ammonia displacement: the three-necked flask getting 1L, add 3-hydroxy piperidine 200g, L-camphorsulfonic acid ammonium 246.5g, trichloromethane 600mL, be uniformly mixed, reflux, the ammonia displaced adopts concentrated hydrochloric acid to absorb by prolong; After backflow 3h, be cooled to 40 DEG C, underpressure distillation under-0.1Mpa, reclaim trichloromethane to flowing out without cut; Then be warming up to 70 DEG C, under-0.1Mpa, residual trichloromethane is sloughed in underpressure distillation;
(2) the brilliant salt of crystallization preparation (S)-3-hydroxy piperidine-L-camphorsulfonic acid is split: take out the enriched material in step (1), in the middle of the three-necked flask being transferred to 5L, then dehydrated alcohol 400mL is added, stirring makes it dissolving and adds 3600mL methyl tertiary butyl ether, and add the brilliant salt of 2g (S)-3-hydroxy piperidine-L-camphorsulfonic acid as crystal seed, at 15 DEG C after stirring and crystallizing 48h, solid-liquid separation.Gained solid adopts V (ethanol): the mixed solution of V (methyl tertiary butyl ether)=1:2 washs 2 times, and each consumption 200mL, washes complete, drains and vacuum-drying, obtains the brilliant salt 249.6g of thick S-; This brilliant salt adopts 375mL anhydrous alcohol solution, after reflux 1h, micro-stirring and crystallizing 12h at 25 DEG C, after solid-liquid separation, gained solid adopts V (ethanol): the mixed solution of V (methyl tertiary butyl ether)=1:2 washs 2 times, each 125mL, dry, wash complete, drain and vacuum-drying, obtain the brilliant salt 215.9g of S-;
(3) the brilliant salt of (S)-3-hydroxy piperidine-L-camphorsulfonic acid changes into (S)-N-Boc-3-hydroxy piperidine: be dissolved in 650mL water by brilliant for (the S)-3-hydroxy piperidine-L-camphorsulfonic acid in step (2) salt, then 650mL methylene dichloride is added, 20% ammoniacal liquor 165.1g, after inserting ice bath stirring 0.5h, drip BOC acid anhydrides 155.4g; Drip to finish to go to after stirred at ambient temperature 3h and leave standstill, after layering, methylene dichloride adopts the saturated NaCl solution of 325mL to wash 2 times mutually; Namely oil product (S)-N-Boc-3-hydroxy piperidine 132.5g is obtained after organic phase precipitation;
(4) (S)-N-Boc-3-hydroxy piperidine is refining: oil product (the S)-N-Boc-3-hydroxy piperidine got in step (3) joins in 400mL normal hexane, after reflux divides water 3h, be cooled to 0-5 DEG C gradually, after micro-stirring and crystallizing 12h, after solid-liquid separation, after adopting normal hexane drip washing, drain, in 30 DEG C, decompression drying under-0.1Mpa, obtain (S)-N-Boc-3-hydroxy piperidine white crystal 125.3g, GC purity 99.3%, chiral purity 99.2%;
(5) recovery of resolving agent: get the aqueous phase in step (3), adopt washed with dichloromethane 2 times, each 480mL, wash Bi Shuixiang in 70 DEG C, under-0.1Mpa decompression dehydration to slurry, then in 70 DEG C, under-0.1Mpa decompression drying to water content lower than 0.5%, reclaim L-camphorsulfonic acid ammonium 156.5g, purity 98.3%, the yield reclaiming resolving agent from the brilliant salt of (S)-3-hydroxy piperidine-L-camphorsulfonic acid is 95.4%.
Embodiment 4
(1) 3-hydroxy piperidine and L-camphorsulfonic acid ammonium carry out ammonia displacement: in the glass reaction still of 50L, drop into 3-hydroxy piperidine 2.5kg, L-camphorsulfonic acid ammonium 3.08kg, methylene dichloride 7.5L successively, be uniformly mixed, reflux, the ammonia displaced adopts concentrated hydrochloric acid to absorb by prolong; After backflow 4h, be cooled to 40 DEG C, underpressure distillation under-0.1Mpa, reclaim methylene dichloride to flowing out without cut; Then be warming up to 60 DEG C, under-0.1Mpa, residual methylene dichloride is sloughed in underpressure distillation;
(2) the brilliant salt of crystallization preparation (S)-3-hydroxy piperidine-L-camphorsulfonic acid is split: the enriched material in step (1) is added dehydrated alcohol 5L, stirring makes it dissolving and adds 60L methyl tertiary butyl ether, and add the brilliant salt of 30g (S)-3-as crystal seed, at 15 DEG C after stirring and crystallizing 60h, solid-liquid separation.Gained solid adopts V (ethanol): the mixed solution of V (methyl tertiary butyl ether)=1:2 washs 2 times, and each consumption 2.5L, washes complete, drains and vacuum-drying, obtains the brilliant salt 3.25kg of thick S-; This brilliant salt adopts 8.1L anhydrous alcohol solution, after reflux 1h, micro-stirring and crystallizing 12h at 25 DEG C, after solid-liquid separation, gained solid adopts V (ethanol): the mixed solution of V (methyl tertiary butyl ether)=1:2 washs 2 times, each 1.6L, dry, wash complete, drain and vacuum-drying, obtain the brilliant salt 2.82kg of S-;
(3) the brilliant salt of (S)-3-hydroxy piperidine-L-camphorsulfonic acid changes into (S)-N-Boc-3-hydroxy piperidine: be transferred in 50L glass reaction still by brilliant for (the S)-3-hydroxy piperidine-L-camphorsulfonic acid in step (2) salt, add water, each 8.5L of methylene dichloride successively, and add 20% ammoniacal liquor 3.6kg, after inserting ice bath stirring 0.5h, drip BOC acid anhydrides 2.21kg; Drip to finish and go to stratification after stirred at ambient temperature 4h, methylene dichloride adopts the saturated NaCl solution of 4.25L to wash 2 times mutually; Namely oil product (S)-N-Boc-3-hydroxy piperidine 1.73kg is obtained after organic phase precipitation;
(4) (S)-N-Boc-3-hydroxy piperidine is refining: oil product (the S)-N-Boc-3-hydroxy piperidine got in step (3) joins in 8.6L normal hexane, after reflux divides water 4h, be cooled to 0-5 DEG C gradually, after micro-stirring and crystallizing 12h, after solid-liquid separation, after adopting normal hexane drip washing, drain, in 30 DEG C, decompression drying under-0.1Mpa, obtain (S)-N-Boc-3-hydroxy piperidine white crystal 1.6kg, GC purity 99.2%, chiral purity 99.3%;
(5) recovery of resolving agent: get the aqueous phase in step (3), adopt washed with dichloromethane 3 times, each 5.6L, wash Bi Shuixiang in 70 DEG C, under-0.1Mpa decompression dehydration to slurry, then in 70 DEG C, under-0.1Mpa decompression drying to water content lower than 0.5%, reclaim L-camphorsulfonic acid ammonium 2.07kg, purity 98.2%, the yield reclaiming resolving agent from (S)-3-hydroxy piperidine-L-camphorsulfonic acid is 96.3%.
Can know; above-described embodiment is only in order to illustrate the illustrative embodiments that inventive principle adopts; but the present invention is not limited only to this; those skilled in the art are not departing under real situation of the present invention; can make various improvement and change, these improve and change and also belong to protection scope of the present invention.
Claims (10)
1. a preparation method for (S)-N-Boc-3-hydroxy piperidine, comprises the following steps:
(1) 3-hydroxy piperidine carries out ammonia displacement with L-camphorsulfonic acid ammonium;
(2) the 3-hydroxy piperidine in step (1) is split in ethanol and methyl tertiary butyl ether system the brilliant salt of preparation (S)-3-hydroxy piperidine-L-camphorsulfonic acid;
(3) brilliant for (the S)-3-hydroxy piperidine-L-camphorsulfonic acid in step (2) salt is changed into (S)-N-Boc-3-hydroxy piperidine under the catalysis of ammoniacal liquor.
2. the preparation method of (S)-N-Boc-3-hydroxy piperidine according to claim 1, is characterized in that: described preparation method is further comprising the steps of:
(S)-N-Boc-3-hydroxy piperidine is refining: (the S)-N-Boc-3-hydroxy piperidine got in step (3) joins in the middle of normal hexane, (S) quality of-N-Boc-3-hydroxy piperidine and the volume ratio of normal hexane are 1:2 ~ 3 (g/mL), reflux divides water 2-4h, be cooled to 0-5 DEG C gradually, micro-stirring and crystallizing, after solid-liquid separation, adopts normal hexane drip washing solid, drain, in 30 DEG C, decompression drying under-0.1Mpa.
3. the preparation method of (S)-N-Boc-3-hydroxy piperidine according to claim 1, is characterized in that: described preparation method is further comprising the steps of:
The recovery of resolving agent: get the aqueous phase in step (3), adopt washed with dichloromethane, wash Bi Shuixiang in 70 DEG C, under-0.1Mpa decompression dehydration to slurry, then in 70 DEG C, decompression drying, to water content lower than 0.5%, obtains L-camphorsulfonic acid ammonium under-0.1Mpa.
4. the preparation method of (S)-N-Boc-3-hydroxy piperidine according to claim 1, is characterized in that: solvent used in step (1) is ether, ethyl acetate, butylacetate, methylene dichloride, trichloromethane, tetrachloromethane; The time that 3-hydroxy piperidine and L-camphorsulfonic acid ammonium reflux replace ammonia is 0.5-4h.
5. the preparation method of (S)-N-Boc-3-hydroxy piperidine according to claim 4, is characterized in that: solvent used in step (1) is ethyl acetate, methylene dichloride, trichloromethane; The time that 3-hydroxy piperidine and L-camphorsulfonic acid ammonium reflux replace ammonia is 2-3h.
6. the preparation method of (S)-N-Boc-3-hydroxy piperidine according to claim 1, it is characterized in that: solvent used in step (2) is dehydrated alcohol and methyl tertiary butyl ether, the quality of its 3-hydroxy piperidine and the volume ratio of ethanol are 1:2 (g/mL), ethanol and methyl tertiary butyl ether volume ratio are 1:5 ~ 12, and the stirring and crystallizing time is 12 ~ 60h.
7. the preparation method of (S)-N-Boc-3-hydroxy piperidine according to claim 6, is characterized in that: in step (2), the volume ratio of dehydrated alcohol and methyl tertiary butyl ether is 2:6 ~ 9; The stirring and crystallizing time is 24 ~ 48h.
8. the preparation method of (S)-N-Boc-3-hydroxy piperidine according to claim 1, it is characterized in that: the solvent that in step (2), the brilliant salt recrystallization of thick (S)-3-hydroxy piperidine-L-camphorsulfonic acid is used is dehydrated alcohol, the brilliant quality of salt of thick (S)-3-hydroxy piperidine-L-camphorsulfonic acid and the volume ratio of ethanol are 1:0.8 ~ 2.5 (g/mL).
9. the preparation method of (S)-N-Boc-3-hydroxy piperidine according to claim 1, it is characterized in that: catalyzer used in step (3) is ammoniacal liquor, consumption is 1.5 ~ 5 times of molar equivalents of the brilliant salt of (S)-3-hydroxy piperidine-L-camphorsulfonic acid; Solvent used is methylene dichloride and water, and the volume ratio of the brilliant quality of salt of (S)-3-hydroxy piperidine-L-camphorsulfonic acid and the volume of methylene dichloride and water is 1:3:3 (g/mL/mL); BOC acid anhydrides consumption used is 1.0 ~ 1.2 times of molar equivalents of the brilliant salt of (S)-3-hydroxy piperidine-L-camphorsulfonic acid.
10. the preparation method of (S)-N-Boc-3-hydroxy piperidine according to claim 9, it is characterized in that: catalyzer used in step (3) is ammoniacal liquor, consumption is 2 ~ 3 times of molar equivalents of the brilliant salt of (S)-3-hydroxy piperidine-L-camphorsulfonic acid; BOC acid anhydrides consumption used is 1.02 ~ 1.10 times of molar equivalents of the brilliant salt of (S)-3-hydroxy piperidine-L-camphorsulfonic acid.
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| CN105439939A (en) * | 2015-11-12 | 2016-03-30 | 四川恒康科技发展有限公司 | Synthetic method of (S)-N-Boc-3-hydroxypiperidine |
| CN104693108B (en) * | 2013-12-06 | 2017-05-31 | 重庆博腾制药科技股份有限公司 | A kind of preparation method of bruton's tyrosine kinase (Btk) intermediate |
| CN109134351A (en) * | 2018-09-21 | 2019-01-04 | 武汉理工大学 | S-3-(4- aminophenyl) piperidines synthetic method |
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| CN103864673A (en) * | 2014-03-04 | 2014-06-18 | 雅本化学股份有限公司 | Preparation of chirality-1-t-butyloxycarboryl-3-hydroxy piperidine and method for chirality turning |
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| CN101045693A (en) * | 2006-03-29 | 2007-10-03 | 宝山钢铁股份有限公司 | Preparation method of para-hydroxybenzol gylcine |
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| CN105439939A (en) * | 2015-11-12 | 2016-03-30 | 四川恒康科技发展有限公司 | Synthetic method of (S)-N-Boc-3-hydroxypiperidine |
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| CN109134351A (en) * | 2018-09-21 | 2019-01-04 | 武汉理工大学 | S-3-(4- aminophenyl) piperidines synthetic method |
| CN109134351B (en) * | 2018-09-21 | 2022-03-11 | 武汉理工大学 | Synthesis method of S-3- (4-aminophenyl) piperidine |
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