CN1763007A - A kind of preparation method of 4-acetoxyl group piperidine hydrochlorate - Google Patents
A kind of preparation method of 4-acetoxyl group piperidine hydrochlorate Download PDFInfo
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- CN1763007A CN1763007A CNA2005100292763A CN200510029276A CN1763007A CN 1763007 A CN1763007 A CN 1763007A CN A2005100292763 A CNA2005100292763 A CN A2005100292763A CN 200510029276 A CN200510029276 A CN 200510029276A CN 1763007 A CN1763007 A CN 1763007A
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Abstract
The invention belongs to the field of chemical synthesis, relate to the technology of preparing of PET developer.Be specifically related to the synthetic method of a kind of 4-acetoxyl group piperidines (P4A) hydrochloride; the present invention is a raw material with the 4-hydroxyl piperidine hydrochloric acid salt; first with tert-Butyl dicarbonate in alkaline homogeneous reaction system with amido protecting; slough blocking group with diacetyl oxide after with glycoloylization again; in anhydrous diethyl ether, feed dry hydrogen chloride gas at last, obtain target product 4-acetoxyl group piperidine hydrochlorate of the present invention.The inventive method makes the productive rate of target product bring up to 71% by 57%.The entire reaction course mild condition, easy handling.
Description
Technical field
The invention belongs to the field of chemical synthesis, relate to PET developer technology of preparing, be specifically related to the synthetic method of a kind of 4-acetoxyl group piperidines (P4A) hydrochloride, this compound is 4-acetoxyl group-N-[
11C] methyl piperidine ([
11C]-MP4A) labelled precursor, for the further PET molecular image medicine of preparation brain acetylcholinesterase provides the basis.
Background technology
Positron Emission Computed Tomography (PET) can be used for carrying out brain imaging, and is highly sensitive, good resolution.In the video picture research of acetylcholine in brain (Ach), abroad find recently,
11The ACh congener of C mark (as [
11C]-MP4P, [
11C]-MP4A, [
18F]-FETP4A) enter in the human brain after, can reflect acetylcholinesterase (Acetylcholinesterase, activity AChE) by the PET video picture.Research has confirmed carrying out property of the activity minimizing of AChE in senile dementia (AD) the patient brain, with closely related (the Shinotoh H of patient's Cognitive function damage, et al.Progressive loss of cortical acetylcholinesterase activity inassociation with cognitive decline in Alzheimer ' s disease:a positron emissiontomography study.Annals neurol 2000,48:194-200.).The ACh system function is in patient AD in brain, and hippocampus isocortex cholinesterase K3 index obviously reaches more than 30% than normal people's minimizing.ACHE decline 75% (Rinne JO in the early stage patient's AD brain of report such as Rinne, et al.Brainactylcholinesterase activity in mild congnitive impairment and early Alzheimer ' sdisease.J Neurol Neurosurg Psychiatry 2003,74:113-115.).Ota etc. (2004) report [
11C]-MP4A PET video picture reflection AChE, the susceptibility of diagnosis AD reaches 92%, even in requiring mental skill [
11C]-MP4A PET as the treatment patient AD curative effect index (Sato, et al.Evaluation ofsimplified kinetic analyses for measurement of brain acetylcholinesterase activityusing N-11C Methylpiperidin-4-ylpropionate and positron emission tomography.JCereb Blood Flow Metab, 2004,24:600-611; Shinotoh H, et al.Effect of donepezilon brain acetylcholinesterase activity in patients with AD measured by PET.Neurology 2001,56:408-411).Therefore, [
11C]-MP4A is a kind of PET developer of the acetylcholinesterase of brain safely and effectively.But valuable product, domestic still do not have relevant report so far.
The synthetic method of known P4A has: with the 4-hydroxy piperidine is raw material, with the direct acetylize of Acetyl Chloride 98Min., but because amino than the easier acetylize of hydroxyl, so long reaction time and reaction yield are very low; only be 12% (Zhang, M.-R., et al; Nucl.Med.Biol.2002,29,463).
Another kind method is that earlier protection is amino, reacts with 4-hydroxy piperidine and chloroformic acid benzyl ester to obtain 4-hydroxy-n-benzyloxy carbonyl acylpiperidine, with catalytic hydrogenation protecting group is sloughed after the acetylize and obtains P4A (Scott ES, et al, Synthesis of 1-[
11C] Methylpiperidin-4-yl Propionate ([
11C] PMP) in vivoMeasurements of Acetylcholinesterase Activity.Nuclear Medicine ﹠amp; Biology, 1998,25,751-754), the direct acetylize of the productivity ratio of this route improves more, but because of using catalytic hydrogenation, operation has certain risk.
Also have a kind of amino method blocking group (Ming-Rong Zhang, et al, the N-[of tert-Butyl dicarbonate that protect as amino
18F] fluoroethyl-4-piperidyl Acetate ([
18F] FEtP4A): APET Tracer for Imaging Brain Acetylcholinesterase In Vivo.Bioorg.Med.Chem.; 2003; 11; 2519-2527.), earlier the amino in the 4-hydroxy piperidine is protected with this blocking group, again with sloughing blocking group after the diacetyl oxide acetylize; entire reaction course is all at room temperature carried out; the reaction conditions gentleness, easy and simple to handle, total recovery is 57%.But exist reaction system heterogeneous on the aforesaid method, defective such as reaction yield is low.
Summary of the invention
The objective of the invention is to solve the technology of preparing of PET developer, specifically provide a kind of preparation method of 4-acetoxyl group piperidine hydrochlorate, heterogeneous to overcome in the prior art reaction system, shortcoming such as reaction yield is low.
Reference literature of the present invention (Scott ES, et al, Synthesis of 1-[
11C] Methylpiperidin-4-ylPropionate ([
11C] PMP) in vivo Measurements of Acetylcholinesterase Activity.Nuclear Medicine ﹠amp; Biology, 1998,25,751-754; Ming-Rong Zhang, et al, N-[
18F] fluoroethyl-4-piperidyl Acetate ([
18F] FEtP4A): A PET Tracer for ImagingBrain Acetylcholinesterase In Vivo.Bioorg.Med.Chem., 2003,11,2519-2527.), synthesis technique is improved, with following route synthesized [
11C] MP4A labelled precursor P4A hydrochloride (1), provide the foundation for further preparing the PET developer.
Technical scheme of the present invention is: with the 4-hydroxyl piperidine hydrochloric acid salt is raw material; first with tert-Butyl dicarbonate in alkaline homogeneous reaction system with amido protecting; slough blocking group with diacetyl oxide after with glycoloylization again; in anhydrous diethyl ether, feed dry hydrogen chloride gas at last, obtain target product 4-acetoxyl group piperidine hydrochlorate of the present invention (1).
Method of the present invention comprises the steps:
(1) preparation of 4-hydroxy-n-tertiary butyloxycarbonyl acylpiperidine (2): with the 4-hydroxyl piperidine hydrochloric acid salt; the 1NNaOH solution of total amount 45% and add in the reaction flask with the miscible solvent of water; add tert-Butyl dicarbonate under-10 ℃～10 ℃ in batches; transfer pH with the 1N NaOH solution of total amount 55% simultaneously; 10 ℃～40 ℃ stirrings are spent the night; add water; extract with extraction agent; merge organic layer; water; 7% ammoniacal liquor; saturated sodium-chloride is washed; the organic layer drying; the pressure reducing and steaming solvent gets faint yellow oily thing, and the static after fixing that spends the night gets product 4-hydroxy-n-tertiary butyloxycarbonyl acylpiperidine (2).
The ratio of components of described step (1) reactant is: the 4-hydroxyl piperidine hydrochloric acid salt: 1N NaOH solution: tert-Butyl dicarbonate=1.0: 15-25: 1.6-2.0, weight ratio.
The miscible solvent of used in the present invention and water is 1, and a kind of in 4-dioxane, ethanol, methyl alcohol, acetone, the tetrahydrofuran (THF) is preferred 1, the 4-dioxane, and 4-hydroxyl piperidine hydrochloric acid salt and 1, the weightmeasurement ratio of 4-dioxane are 1.0: 7-13.
The pH of reaction system remains on 7-11, preferred 8-9.
Extraction agent used in the present invention is a kind of in chloroform, methylene dichloride, ethyl acetate, the ether, preferred chloroform, and the weightmeasurement ratio of 4-hydroxyl piperidine hydrochloric acid salt and chloroform is 1.0: 30-50.
(2) preparation of 4-acetoxyl group-N-tertiary butyloxycarbonyl acylpiperidine (3): add pyridine in the product that obtains in the above; add diacetyl oxide after the stirring and dissolving; stirring at room 6 hours; add ethyl acetate and water; stir 10min, divide the ester output layer, ester layer water, 7% ammoniacal liquor and saturated nacl aqueous solution are respectively given a baby a bath on the third day after its birth inferior; it is product 4-acetoxyl group-N-tertiary butyloxycarbonyl acylpiperidine (3) that ester layer anhydrous sodium sulfate drying, pressure reducing and steaming solvent get faint yellow oily thing.
(3) preparation of 4-acetoxyl group piperidines (4): add methylene dichloride in the product that obtains in the above, be chilled to 0 ℃ and drip trifluoroacetic acid, add in 0 ℃ and stirred 1 hour, the pressure reducing and steaming solvent, add 1% ammoniacal liquor in the residue, stir 10min, extraction, it is product 4-acetoxyl group piperidines (4) that anhydrous sodium sulfate drying, pressure reducing and steaming solvent get faint yellow oily thing.
(4) preparation of 4-acetoxyl group piperidine hydrochlorate (1): add anhydrous diethyl ether in the product that obtains in the above, logical people's dry hydrogen chloride, separate out solid, boil off ether and obtain white solid, add the acetonitrile heating for dissolving, add ethyl acetate while hot, crystallisation by cooling obtains the flower-shaped solid 4-of white cotton acetoxyl group piperidine hydrochlorate (1), fusing point: 167.8～170.5 ℃ (decomposition).
1H-NMR(CDCl
3)：9.68(brs，2H，NH
2 +)，5.03-5.06(m，1H，4-CH)，3.26-3.30(m，4H，H-2，H-6)，2.20-2.01(m，4H，H-3，H-5)，2.09(s，3H，COCH3)。
1H-NMR (heavy water exchange spectrum): 4.98-5.02 (m, 1H, 4-CH), 3.18-3.39 (m, 4H, H-2, H-6), 2.08 (s, 3H, COCH
3), 1.90-2.13 (m, 4H, H-3, H-5), active hydrogen NH
2Exchange is fallen.
13C-NMR(CDCl
3)：169.87(CO)，65.53(C-4)，40.34(C-2，C-6)，26.95(C-3，C-5)，21.04(CH
3)。Hydrogen is composed, its structure of carbon spectrum data acknowledgement is consistent with target compound.
Reaction formula of the present invention is as follows:
Wherein: (t-Boc)
2O (tert-Butyl dicarbonate), Boc (tertiary butyloxycarbonyl acyl group)
The present invention and known technology have carried out comparative study, and the result shows:
1) known technology
1. the first step reaction can't be reacted by the document conditional operation, reason be bibliographical information sodium hydroxide concentration very little, do not reach alkalescence, so do not react;
2. carry out because of being reflected in the water, and tert-Butyl dicarbonate solubleness in water is very little, carries out in heterogeneous, therefore the yield of influence reaction so be reflected at.
2) the present invention
1. strengthen the consumption of sodium hydroxide, make to be reflected under the alkaline condition and carry out, because of generating 2 in the reaction process, the 2-neopentanoic acid is so the present invention monitors the variation of pH in the entire reaction course, and constantly add sodium hydroxide, make the pH value of reaction mixture maintain alkalescence, the pH value is 7-11, makes reaction yield reach 75%;
2. add a certain amount of solvent that dissolves each other with water in reaction system, improved the solubleness of tert-Butyl dicarbonate, make reactant be tied to form homogeneous phase, this step reaction yield can bring up to 96%.
Four-step reaction total recovery of the present invention is increased to 64%.
Table 1 is the inventive method and the concrete comparative result of existing literature method.
Table 1
| Compound | Reaction conditions | Reaction yield (5) | ||
| Literature method | The inventive method | Literature method | The inventive method | |
| (2) | (t-Boc) 2O，NaOH/H 2O， 25℃，1h | (t-Boc) 2O，NaOH/H 2O 1，4-Dioxane， pH7-11，25℃，24h | Can't obtain product | 95.9 |
| (3) | (CH 2CO) 2O，Pyridine， 25℃，6h | (CH 2CO) 2O，Pyridine， 25℃，6h | No report | 95.1 |
| (4) | CF 3COOH，0℃，1h | CF 3COOH，0℃，1h | 57 | 71.2 |
| (1) | No report | Et 2O, dry HCl | There is not report | 63.9 |
Embodiment
Embodiment 1
The preparation of 4-hydroxy-n-tertiary butyloxycarbonyl acylpiperidine (2) (Ming-Rong Zhang literature method):
4-hydroxyl piperidine hydrochloric acid salt 10.0g (72.73mmol) is dissolved in the 20ml distilled water, add 0.5N NaOH solution 50ml and add tert-Butyl dicarbonate 18g (82.57mmol) in batches, in 25 ℃ of violent stirring 1 hour, with the reaction of going out of chloroform collection, chloroform layer, water, 27% ammoniacal liquor, saturated sodium-chloride are washed, the organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming solvent, get faint yellow oily thing, through structural identification is the 4-hydroxy piperidine, analyzes former because reaction system alkalescence is not enough, so do not have reaction to obtain testing required product.
Embodiment 2
The preparation of 4-hydroxy-n-tertiary butyloxycarbonyl acylpiperidine (2):
4-hydroxyl piperidine hydrochloric acid salt 10.0g (72.73mmol) is dissolved in 80ml 1N NaOH, the ice bath cooling down, add tert-Butyl dicarbonate 18g (82.57mmol) in batches, transfer pH to keep 8-9 (using 100ml 1N NaOH approximately) with 1N NaOH simultaneously, add and remove ice bath, stirred overnight at room temperature, with chloroform extraction (4 * 100ml), combined chloroform layer, water, 7% ammoniacal liquor, saturated sodium-chloride is respectively given a baby a bath on the third day after its birth inferior, the organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming solvent gets faint yellow oily thing, the static after fixing 11.0g that spends the night, productive rate is 75.0%, and product not purifying directly carries out next step reaction.
Embodiment 3
The preparation of 4-hydroxy-n-tertiary butyloxycarbonyl acylpiperidine (2):
4-hydroxyl piperidine hydrochloric acid salt 10.0g (72.73mmol) is dissolved in 80ml 1N NaOH and 100ml 1, in the 4-dioxane, the ice bath cooling down, add tert-Butyl dicarbonate 18g (82.57mmol) in batches, transfer pH to keep 7-8 (using 100ml 1NNaOH approximately) with 1N NaOH simultaneously, add and remove ice bath, stirred overnight at room temperature adds 100ml water again, pressure reducing and steaming 1, the 4-dioxane, with chloroform extraction (4 * 100ml), combined chloroform layer, water, 7% ammoniacal liquor, saturated sodium-chloride is respectively given a baby a bath on the third day after its birth inferior, the organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming solvent gets faint yellow oily thing, the static after fixing 14.0g that spends the night, productive rate is 94.0%, and product not purifying directly carries out next step reaction.
Embodiment 4
The preparation of 4-hydroxy-n-tertiary butyloxycarbonyl acylpiperidine (2):
4-hydroxyl piperidine hydrochloric acid salt 10.0g (72.73mmol) is dissolved in 80ml 1N NaOH and 100ml 1, in the 4-dioxane, the ice bath cooling down, add tert-Butyl dicarbonate 18g (82.57mmol) in batches, transfer pH to keep 9-11 (using 100ml 1N NaOH approximately) with 1N NaOH simultaneously, add and remove ice bath, stirred overnight at room temperature adds 100ml water again, pressure reducing and steaming 1, the 4-dioxane, with chloroform extraction (4 * 100ml), combined chloroform layer, water, 7% ammoniacal liquor, saturated sodium-chloride is respectively given a baby a bath on the third day after its birth inferior, the organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming solvent gets faint yellow oily thing, the static after fixing 14.0g that spends the night, productive rate is 94.5%, and product not purifying directly carries out next step reaction.
Embodiment 5
The preparation of 4-hydroxy-n-tertiary butyloxycarbonyl acylpiperidine (2):
(1) 4-hydroxyl piperidine hydrochloric acid salt 10.0g (72.73mmol) is dissolved in 80ml 1N NaOH and 100ml 1, in the 4-dioxane, the ice bath cooling down, add tert-Butyl dicarbonate 18g (82.57mmol) in batches, transfer pH to keep 8-9 (using 100ml 1N NaOH approximately) with 1N NaOH simultaneously, add and remove ice bath, stirred overnight at room temperature adds 100ml water again, pressure reducing and steaming 1, the 4-dioxane, with chloroform extraction (4 * 100ml), combined chloroform layer, water, 7% ammoniacal liquor, saturated sodium-chloride is respectively given a baby a bath on the third day after its birth inferior, the organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming solvent gets faint yellow oily thing, the static after fixing 14.0g that spends the night, productive rate is 95.9%, and product not purifying directly carries out next step reaction.
(2) preparation of 4-acetoxyl group-N-tertiary butyloxycarbonyl acylpiperidine (3):
In the above-mentioned product that obtains, add the 30ml pyridine, add the 10ml diacetyl oxide after the stirring and dissolving, stirring at room 6 hours adds 200ml ethyl acetate and 50ml water, stirs 10min, divide the ester output layer, ester layer water, 7% ammoniacal liquor and saturated nacl aqueous solution are respectively given a baby a bath on the third day after its birth inferior, and it is product 16.8g that ester layer anhydrous sodium sulfate drying, pressure reducing and steaming solvent get faint yellow oily thing, productive rate is 95.1%, and product not purifying directly carries out next step reaction.
(3) preparation of 4-acetoxyl group piperidines (4):
Add the 200ml methylene dichloride in the above in the product that obtains, be chilled to 0 ℃ and drip the 15ml trifluoroacetic acid, add in 0 ℃ of stirring 1 hour, the pressure reducing and steaming solvent adds 150ml 1% ammoniacal liquor in the residue, stir 10min, (4 * 50ml), it is product 7.4g that anhydrous sodium sulfate drying, pressure reducing and steaming solvent get faint yellow oily thing to dichloromethane extraction, productive rate is 71.2%, and product not purifying directly carries out next step reaction.
(4) preparation of 4-acetoxyl group piperidine hydrochlorate (1):
Add the 100ml anhydrous diethyl ether in the above in the product that obtains, logical people's dry hydrogen chloride, separate out solid, boil off ether and obtain white solid, add 30ml acetonitrile heating for dissolving, add the 100ml ethyl acetate while hot, crystallisation by cooling obtains the flower-shaped solid 8.3g of white cotton, fusing point: 167.8～170.5 ℃ (decomposition), productive rate are 63.9%.
Claims (10)
1, a kind of preparation method of 4-acetoxyl group piperidine hydrochlorate; it is characterized in that with the 4-hydroxyl piperidine hydrochloric acid salt be raw material; first with tert-Butyl dicarbonate in alkaline homogeneous reaction system with amido protecting; slough blocking group with diacetyl oxide after with glycoloylization again; in anhydrous diethyl ether, feed dry hydrogen chloride gas at last, obtain target product 4-acetoxyl group piperidine hydrochlorate.
2, by the preparation method of the described 4-acetoxyl group of claim 1 piperidine hydrochlorate, reaction formula is as follows:
Wherein: (t-Boc)
2O: tert-Butyl dicarbonate, Boc: tertiary butyloxycarbonyl acyl group.
3, by the preparation method of the described 4-acetoxyl group of claim 1 piperidine hydrochlorate, comprise the steps:
(1) preparation 4-hydroxy-n-tertiary butyloxycarbonyl acylpiperidine (2): with the 4-hydroxyl piperidine hydrochloric acid salt, the 1N NaOH solution of total amount 45%, with add in the reaction flask with the miscible solvent of water, add tert-Butyl dicarbonate under-10 ℃～10 ℃ in batches, use the 1N NaOH solution of total amount 55% simultaneously, transfer pH, 10 ℃～40 ℃ stirrings are spent the night, add water, with the extraction agent extraction, merge organic layer, water, 7% ammoniacal liquor, saturated sodium-chloride is washed, the organic layer drying, the pressure reducing and steaming solvent gets faint yellow oily thing, and the static after fixing that spends the night gets product 4-hydroxy-n-tertiary butyloxycarbonyl acylpiperidine (2);
(2) preparation of 4-acetoxyl group-N-tertiary butyloxycarbonyl acylpiperidine (3): in the product of above-mentioned gained, add pyridine, add diacetyl oxide after the stirring and dissolving, stirring at room 6 hours, add ethyl acetate and water, stir 10min, divide the ester output layer, ester layer water, 7% ammoniacal liquor and saturated nacl aqueous solution are respectively given a baby a bath on the third day after its birth inferior, it is product 4-acetoxyl group-N-tertiary butyloxycarbonyl acylpiperidine (3) that ester layer anhydrous sodium sulfate drying, pressure reducing and steaming solvent get faint yellow oily thing;
(3) preparation of 4-acetoxyl group piperidines (4): in the product of above-mentioned gained, add methylene dichloride, be chilled to 0 ℃ and drip trifluoroacetic acid, add in 0 ℃ and stirred 1 hour, the pressure reducing and steaming solvent, add 1% ammoniacal liquor in the residue, stir 10min, extraction, it is product 4-acetoxyl group piperidines (4) that anhydrous sodium sulfate drying, pressure reducing and steaming solvent get faint yellow oily thing;
(4) preparation of 4-acetoxyl group piperidine hydrochlorate (1): in the product of above-mentioned gained, add anhydrous diethyl ether, logical people's dry hydrogen chloride, separate out solid, boil off ether and obtain white solid, add the acetonitrile heating for dissolving, add ethyl acetate while hot, crystallisation by cooling obtains the flower-shaped solid 4-of white cotton acetoxyl group piperidine hydrochlorate (1).
4, press the preparation method of the described 4-acetoxyl group of claim 3 piperidine hydrochlorate, the ratio of components of wherein said step (1) reactant is: the 4-hydroxyl piperidine hydrochloric acid salt: 1N NaOH solution: tert-Butyl dicarbonate=1.0: 15-25: 1.6-2.0, weight ratio.
5, by the preparation method of the described 4-acetoxyl group of claim 3 piperidine hydrochlorate, the miscible solvent of wherein said and water is selected from 1, a kind of in 4-dioxane, ethanol, methyl alcohol, acetone or the tetrahydrofuran (THF).
6, by the preparation method of the described 4-acetoxyl group of claim 3 piperidine hydrochlorate, the miscible solvent of wherein said and water is 1, the 4-dioxane, and described 4-hydroxyl piperidine hydrochloric acid salt and 1, the weightmeasurement ratio of 4-dioxane are 1.0: 7-13.
7, by the preparation method of claim 1 or 2 or 3 described 4-acetoxyl group piperidine hydrochlorates, the pH of wherein said alkali reaction system is 7-11.
8, by the preparation method of claim 1 or 2 or 3 described 4-acetoxyl group piperidine hydrochlorates, the pH of wherein said alkali reaction system is 8-9.
9, by the preparation method of the described 4-acetoxyl group of claim 3 piperidine hydrochlorate, wherein said extraction agent is selected from chloroform, methylene dichloride, ethyl acetate or ether.
10, by the preparation method of the described 4-acetoxyl group of claim 9 piperidine hydrochlorate, wherein said extraction agent is a chloroform, and the weightmeasurement ratio of described 4-hydroxyl piperidine hydrochloric acid salt and chloroform is 1.0: 30-50.
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| CN102924350A (en) * | 2012-10-31 | 2013-02-13 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin derivatives, and preparation method and application thereof |
| CN107652227A (en) * | 2017-11-15 | 2018-02-02 | 上海皓伯化工科技有限公司 | A kind of synthetic method of the hydroxy piperidine of N benzyls 3 |
| CN107827810A (en) * | 2017-11-15 | 2018-03-23 | 上海皓伯化工科技有限公司 | The synthetic method of the hydroxy piperidine of N carbethoxyl groups 4 |
| CN108069892A (en) * | 2017-12-13 | 2018-05-25 | 盐城师范学院 | A kind of preparation method of 4-acetoxyl group piperidine hydrochlorate |
-
2005
- 2005-08-31 CN CNB2005100292763A patent/CN100335463C/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102924350A (en) * | 2012-10-31 | 2013-02-13 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin derivatives, and preparation method and application thereof |
| CN107652227A (en) * | 2017-11-15 | 2018-02-02 | 上海皓伯化工科技有限公司 | A kind of synthetic method of the hydroxy piperidine of N benzyls 3 |
| CN107827810A (en) * | 2017-11-15 | 2018-03-23 | 上海皓伯化工科技有限公司 | The synthetic method of the hydroxy piperidine of N carbethoxyl groups 4 |
| CN107652227B (en) * | 2017-11-15 | 2020-03-31 | 上海皓伯化工科技有限公司 | Synthesis method of N-benzyl-3-hydroxypiperidine |
| CN108069892A (en) * | 2017-12-13 | 2018-05-25 | 盐城师范学院 | A kind of preparation method of 4-acetoxyl group piperidine hydrochlorate |
| CN108069892B (en) * | 2017-12-13 | 2021-11-23 | 盐城师范学院 | Preparation method of 4-acetoxypiperidine hydrochloride |
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| CN100335463C (en) | 2007-09-05 |
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