CN104628625A - Synthesis method of N-boc-4-hydroxypiperidine - Google Patents
Synthesis method of N-boc-4-hydroxypiperidine Download PDFInfo
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- CN104628625A CN104628625A CN201410814714.6A CN201410814714A CN104628625A CN 104628625 A CN104628625 A CN 104628625A CN 201410814714 A CN201410814714 A CN 201410814714A CN 104628625 A CN104628625 A CN 104628625A
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- Prior art keywords
- add
- piperidone
- hydroxy piperidine
- magnesium sulfate
- anhydrous magnesium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—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
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a synthesis method of N-boc-4-hydroxypiperidine, which comprises the following steps: taking 4-piperidone hydrochloride hydrate, adding distilled water, introducing liquid ammonia to alkalinity, extracting with toluene, drying with anhydrous magnesium sulfate, and carrying out vacuum filtration to obtain 4-piperidone; dissolving in methanol, adding sodium borohydride, refluxing, concentrating, adding dilute hydrochloric acid to regulate the pH value, adding dichloromethane to separate out the water layer, maintaining the organic phase, drying with anhydrous magnesium sulfate over night, carrying out vacuum filtration, maintaining the organic phase, concentrating, adding n-hexane, refrigerating to crystallize, carrying out vacuum filtration, adding methanol, potassium carbonate and di-tert-butyl dicarbonate, refluxing, filtering, concentrating, adding petroleum ether, and refrigerating to crystallize, thereby obtaining the final white crystal product. The method has the advantages of accessible raw materials, high reaction yield, low cost, favorable selectivity and the like, is simple to operate and can easily implement industrialization. The product has the advantages of high purity and stable properties, and completely conforms to the operating requirements as a drug intermediate.
Description
Technical field
The present invention relates generally to field of medicaments, particularly relates to N-boc-4-hydroxy piperidine synthetic method.
Background technology
N-boc-4-hydroxy piperidine is used for the treatment of the antitumor medicine intermediate waiting medicine, and be a kind of important fine-chemical intermediate, have been widely used at pharmaceutical industries tool, the report of current related methods of synthesis is less, and is all not too applicable to suitability for industrialized production.
Summary of the invention
The object of the invention is exactly to provide a kind of N-boc-4-hydroxy piperidine synthetic method.
The present invention is achieved by the following technical solutions:
A kind of N-boc-4-hydroxy piperidine synthetic method, comprises the following steps:
(1) 4-piperidone synthesis
In 100ml tri-mouthfuls of vials, add 4-piperidone hydrochloride hydrate 20 grams, adding distil water 30ml, pass into liquefied ammonia to alkalescence, three times are extracted, anhydrous magnesium sulfate drying 10-12h, suction filtration anhydrous magnesium sulfate with toluene, retain organic phase, be concentrated into thickness for subsequent use, obtain 4-piperidone;
(2) 4-hydroxy piperidine synthesis
The above-mentioned 12 grams of 4-piperidone synthesized are added in 100ml tri-mouthfuls of vials, add 48-50ml dissolve with methanol, open and stir, control temperature adds 5-8 gram of sodium borohydride at 25-30 DEG C, add in control 26-30 minute, then back flow reaction 7-10h, concentrated methyl alcohol occurs to there being a small amount of solid, the dilute hydrochloric acid adding 5% adjusts PH to be 7-8, add methylene chloride 48-50ml, water-yielding stratum is divided with separating funnel, retain organic phase, anhydrous magnesium sulfate drying spends the night, suction filtration, retain organic phase, be concentrated into thickness, add the freezing crystallization of normal hexane 10-15ml, suction filtration, obtain white crystal, for 4-hydroxy piperidine,
(3) N-boc-4-hydroxy piperidine synthesis
The above-mentioned 4-hydroxy piperidine synthesized is added in 100ml tri-mouthfuls of vials, add 48-50ml methyl alcohol, 9-10 gram of salt of wormwood, adds 12-15 gram of di-tert-butyl dicarbonic acid ester, back flow reaction 6-8h at 25-30 DEG C, filter insolubles, concentrated methanol phase, to thickness, adds sherwood oil 20-25ml, freezing crystallization, can obtain final white crystal product.
Advantage of the present invention is:
Method of the present invention has that raw material is easy to get, easy and simple to handle, reaction yield is high, cost is low, good selective, and be easy to realize industrialization, and product purity is high, stable in properties, meets the service requirements as medicine intermediate completely.
Embodiment
Embodiment 1
A kind of N-boc-4-hydroxy piperidine synthetic method, is characterized in that comprising the following steps:
(1) 4-piperidone synthesis
In 100ml tri-mouthfuls of vials, add 4-piperidone hydrochloride hydrate 20 grams, adding distil water 30ml, pass into liquefied ammonia to alkalescence, extract three times with toluene, anhydrous magnesium sulfate drying 12h, suction filtration anhydrous magnesium sulfate, retain organic phase, be concentrated into thickness for subsequent use, obtain 12 grams;
(2) 4-hydroxy piperidine synthesis
The above-mentioned 12 grams of 4-piperidone synthesized are added in 100ml tri-mouthfuls of vials, add 50ml dissolve with methanol, open and stir, control temperature adds 8 grams of sodium borohydrides at 30 DEG C, control to add in 30 minutes, then back flow reaction 10h, concentrated methyl alcohol occurs to there being a small amount of solid, the dilute hydrochloric acid adding 5% adjusts PH to be 7, add methylene chloride 50ml, water-yielding stratum is divided with separating funnel, retain organic phase, anhydrous magnesium sulfate drying spends the night, suction filtration, retain organic phase, be concentrated into thickness, add the freezing crystallization of normal hexane 10-15ml, suction filtration, obtain 10 white crystals, GC detects 98.9%,
(3) N-boc-4-hydroxy piperidine synthesis
The above-mentioned 4-hydroxy piperidine synthesized is added in 100ml tri-mouthfuls of vials, add 50ml methyl alcohol, 10 grams of salt of wormwood, at 30 DEG C, add 15 grams of di-tert-butyl dicarbonic acid esters, back flow reaction 8h, filter insolubles, concentrated methanol phase, to thickness, add sherwood oil 20-25ml, freezing crystallization, can obtain final white crystal product, and GC detects 99.5%.
Performance Detection:
Claims (1)
1. a N-boc-4-hydroxy piperidine synthetic method, is characterized in that comprising the following steps:
(1) 4-piperidone synthesis
In 100ml tri-mouthfuls of vials, add 4-piperidone hydrochloride hydrate 20 grams, adding distil water 30ml, pass into liquefied ammonia to alkalescence, three times are extracted, anhydrous magnesium sulfate drying 10-12h, suction filtration anhydrous magnesium sulfate with toluene, retain organic phase, be concentrated into thickness for subsequent use, obtain 4-piperidone;
(2) 4-hydroxy piperidine synthesis
The above-mentioned 12 grams of 4-piperidone synthesized are added in 100 ml, tri-mouthfuls of vials, add 48-50ml dissolve with methanol, open and stir, control temperature adds 5-8 gram of sodium borohydride at 25-30 DEG C, add in control 26-30 minute, then back flow reaction 7-10h, concentrated methyl alcohol occurs to there being a small amount of solid, the dilute hydrochloric acid adding 5% adjusts PH to be 7-8, add methylene chloride 48-50ml, water-yielding stratum is divided with separating funnel, retain organic phase, anhydrous magnesium sulfate drying spends the night, suction filtration, retain organic phase, be concentrated into thickness, add the freezing crystallization of normal hexane 10-15ml, suction filtration, obtain white crystal, for 4-hydroxy piperidine,
(3) N-boc-4-hydroxy piperidine synthesis
The above-mentioned 4-hydroxy piperidine synthesized is added in 100 ml, tri-mouthfuls of vials, add 48-50ml methyl alcohol, 9-10 gram of salt of wormwood, adds 12-15 gram of di-tert-butyl dicarbonic acid ester, back flow reaction 6-8h at 25-30 DEG C, filter insolubles, concentrated methanol phase, to thickness, adds sherwood oil 20-25ml, freezing crystallization, can obtain final white crystal product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410814714.6A CN104628625A (en) | 2014-12-23 | 2014-12-23 | Synthesis method of N-boc-4-hydroxypiperidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410814714.6A CN104628625A (en) | 2014-12-23 | 2014-12-23 | Synthesis method of N-boc-4-hydroxypiperidine |
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| Publication Number | Publication Date |
|---|---|
| CN104628625A true CN104628625A (en) | 2015-05-20 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410814714.6A Pending CN104628625A (en) | 2014-12-23 | 2014-12-23 | Synthesis method of N-boc-4-hydroxypiperidine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107663184A (en) * | 2017-11-15 | 2018-02-06 | 上海皓伯化工科技有限公司 | A kind of synthetic method of the hydroxy piperidines of N Boc 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1243505A (en) * | 1997-01-17 | 2000-02-02 | 味之素株式会社 | Benzamidine derivatives |
| WO2001030780A2 (en) * | 1999-10-27 | 2001-05-03 | Cor Therapeutics, Inc. | Pyridyl-containing spirocyclic compounds as inhibitors of fibrinogen-dependent platelet aggregation |
| WO2010054279A1 (en) * | 2008-11-10 | 2010-05-14 | Schering Corporation | Compounds for the treatment of inflammatory disorders |
-
2014
- 2014-12-23 CN CN201410814714.6A patent/CN104628625A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1243505A (en) * | 1997-01-17 | 2000-02-02 | 味之素株式会社 | Benzamidine derivatives |
| WO2001030780A2 (en) * | 1999-10-27 | 2001-05-03 | Cor Therapeutics, Inc. | Pyridyl-containing spirocyclic compounds as inhibitors of fibrinogen-dependent platelet aggregation |
| WO2010054279A1 (en) * | 2008-11-10 | 2010-05-14 | Schering Corporation | Compounds for the treatment of inflammatory disorders |
Non-Patent Citations (1)
| Title |
|---|
| 魏金霞等: "4-氯哌啶盐酸盐的合成", 《山东化工》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107663184A (en) * | 2017-11-15 | 2018-02-06 | 上海皓伯化工科技有限公司 | A kind of synthetic method of the hydroxy piperidines of N Boc 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 |
| CN108069892B (en) * | 2017-12-13 | 2021-11-23 | 盐城师范学院 | Preparation method of 4-acetoxypiperidine hydrochloride |
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| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150520 |
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| RJ01 | Rejection of invention patent application after publication |