CN103694142A - Preparation method of 4-N-Boc-amino cyclohexanone - Google Patents
Preparation method of 4-N-Boc-amino cyclohexanone Download PDFInfo
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- CN103694142A CN103694142A CN201310614995.6A CN201310614995A CN103694142A CN 103694142 A CN103694142 A CN 103694142A CN 201310614995 A CN201310614995 A CN 201310614995A CN 103694142 A CN103694142 A CN 103694142A
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- boc
- amino
- methylene dichloride
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- pimelinketone
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Abstract
The invention discloses a preparation method of 4-N-Boc-amino cyclohexanone. The method includes the following steps: a. adding 4-amino cyclohexanol hydrochloride, poly guanidine and Boc anhydride in a weight ratio of 1:2:1.5 into a reaction kettle, and reacting for 12-24 h at room temperature; filtering, washing, drying, removing solvent by rotary evaporation to obtain white solid 4-N-Boc-amino cyclohexanol; and b. adding the 4-N-Boc-amino cyclohexanol into a sodium hypochlorite or sodium chlorite solution, adding acid, stirring for 1-2 h, separating the liquid, taking an organic layer, washing by water, drying and removing dichloromethane by rotary evaporation to obtain white solid 4-N-Boc-amino cyclohexanone. The invention employs recyclable alkali to replace triethylamine to prepare 4-N-Boc-amino cyclohexanol and employs pollution-free green oxidation for preparation of 4-N-Boc-amino cyclohexanone. The whole production process has stable operation and high yield; through pilot plant verification and large-scale trial production, the method can completely satisfy the requirements of large production. The method has simple reaction process and low cost, and is suitable for large industrial production.
Description
Technical field
The present invention relates to the preparation method of the amino pimelinketone of compound 4-N-Boc-.
Background technology
A kind of important intermediate that the amino pimelinketone of 4-N-Boc-is preparation medicine.A lot of documents and patent all relate to the synthetic method of this compound.The synthesis preparation method adopting at present be all a kind of method: adopting 4-Trans-4-Amino Cyclohexanol is raw material, under triethylamine effect, after Boc acid anhydrides is protected, obtains 4-N-Boc-Trans-4-Amino Cyclohexanol, through KMnO
4oxidation obtains the amino pimelinketone of 4-N-Boc-.Above method is polluted large, complicated operation (US2010032009,
2010; Investigational New Drugs,
2009, 27 (2), 131-139; US2005021515,2005).In US20040019058, two pieces of patents of US2003055876, adopting 4-Trans-4-Amino Cyclohexanol is raw material; under NaOH effect, after the protection of Boc acid anhydrides, obtain 4-N-Boc-Trans-4-Amino Cyclohexanol, utilize n-Pr4N+ RuO4-to obtain the amino pimelinketone of 4-N-Boc-as catalyst oxidation.This process utilizes precious metal as catalyzer, long reaction time.Take 4-Trans-4-Amino Cyclohexanol equally as raw material, under N-methylmorpholine effect, after the protection of Boc acid anhydrides, obtain 4-N-Boc-Trans-4-Amino Cyclohexanol, through polite oxidizing reaction (Swern Oxidation), obtain the amino pimelinketone of 4-N-Boc-.This oxidising process needs low temperature, the loaded down with trivial details (US2004050024 for the treatment of processes; Bioorganic & Medicinal Chemistry Letters,
2004, 14 (12), 3103-3107; Heterocycles,
2002, 58,471-504).
Summary of the invention
The object of the present invention is to provide the preparation method of the amino pimelinketone of 4-N-Boc-.We mainly around how improving processing condition have done and have studied in great detail and be optimized and select as the feeding intake of reaction, temperature of reaction, reaction times etc., and processing condition are gradually improved, and yield is improved.
The technical solution adopted in the present invention is as follows:
A preparation method for the amino pimelinketone of 4-N-Boc-, comprises the following steps:
A. in reactor, drop into 4-Trans-4-Amino Cyclohexanol hydrochloride, poly-guanidine, Boc acid anhydrides, three's mass ratio is respectively 1:2:1.5, and temperature of reaction is room temperature, and the reaction times is 12-24h; Filter, wash, be dried, revolve to desolventize and obtain white solid 4-N-Boc-Trans-4-Amino Cyclohexanol;
B. described 4-N-Boc-Trans-4-Amino Cyclohexanol is joined in clorox or sodium chlorite solution, add acid, stirring reaction 1-2 hour, separatory, gets organic layer, washes, is dried, revolves to obtain the amino pimelinketone of white solid 4-N-Boc-except methylene dichloride.
In described step a, adopting poly-guanidine is alkali, and poly-guanidine, after filtration, after NaOH processes, can reuse.
The acid adopting in described step b is hydrochloric acid or acetic acid.
An application for described method, except being applicable to, the amino pimelinketone of 4-N-Boc-, to be also applicable to the amino pimelinketone of 3-N-Boc-, 3-N-Boc-amino cyclopentyl ketone.
A preparation method for the amino pimelinketone of 4-N-Boc-, comprises the following steps:
The 4-Trans-4-Amino Cyclohexanol hydrochloride of take is raw material, joins in methylene dichloride, then adds poly-guanidine, drips subsequently Boc acid anhydrides, after stirring reaction 12-24h, filters washing under room temperature; Directly dichloromethane solution is added drop-wise in clorox or sodium chlorite solution, stirring reaction 4-8 hour, separatory, gets organic layer, washes, is dried, revolves to obtain the amino pimelinketone of white solid 4-N-Boc-except methylene dichloride.
A preparation method for the amino pimelinketone of 4-N-Boc-, comprises the following steps:
The 4-Trans-4-Amino Cyclohexanol hydrochloride of take is raw material, join in appropriate methylene dichloride, then add poly-guanidine, drip subsequently Boc acid anhydrides, under room temperature, after stirring reaction 12-24h, clorox or sodium chlorite solution are added to stirring reaction 1-2 hour, filtration, separatory, get organic layer, wash, be dried, revolve and obtain the amino pimelinketone of white solid 4-N-Boc-except methylene dichloride.
Beneficial effect of the present invention: the alternative triethylamine of alkali with recoverable is prepared 4-N-Boc-Trans-4-Amino Cyclohexanol, and the amino pimelinketone of green non-pollution oxidation preparation 4-N-Boc-, whole production technique stable operation, yield are higher, through pilot scale, verify, large production test-manufactured, and can be applicable to large production requirement completely.The method reaction process is simple, cost is low, is applicable to large industrial production.
Embodiment
The present invention is described further below.
A. the 4-Trans-4-Amino Cyclohexanol hydrochloride of take is raw material, joins in appropriate methylene dichloride, then add poly-guanidine (its synthetic route reference:
j. Org. Chem. 1961,
26, 4122.), drip subsequently Boc acid anhydrides, under room temperature after stirring reaction 12-24h, filter, wash, be dried, revolve and obtain white solid 4-N-Boc-Trans-4-Amino Cyclohexanol except methylene dichloride.
B. the 4-N-Boc-Trans-4-Amino Cyclohexanol obtaining is dissolved in methylene dichloride, then be added drop-wise in clorox or sodium chlorite solution, stirring reaction 1-2 hour, separatory, gets organic layer, washes, is dried, revolves to obtain the amino pimelinketone of white solid 4-N-Boc-except methylene dichloride.
If the 4-Trans-4-Amino Cyclohexanol hydrochloride of take is raw material, join in appropriate methylene dichloride, then add poly-guanidine, drip subsequently Boc acid anhydrides, under room temperature, after stirring reaction 12-24h, filter washing.Directly dichloromethane solution is added drop-wise in clorox or sodium chlorite solution, stirring reaction 1-2 hour, separatory, gets organic layer, washes, is dried, revolves to obtain the amino pimelinketone of white solid 4-N-Boc-except methylene dichloride.
If the 4-Trans-4-Amino Cyclohexanol hydrochloride of take is raw material, join in appropriate methylene dichloride, then add poly-guanidine, drip subsequently Boc acid anhydrides, under room temperature, after stirring reaction 12-24h, directly in this reaction solution, drip in clorox or sodium chlorite solution stirring reaction 1-2 hour, separatory, get organic layer, wash, be dried, revolve and obtain the amino pimelinketone of white solid 4-N-Boc-except methylene dichloride.
Above-mentioned reaction scheme is:
Below by embodiment, the present invention is further elaborated.
embodiment 1
4-Trans-4-Amino Cyclohexanol hydrochloride (30g) is joined in 200ml methylene dichloride, add subsequently poly-guanidine 20g, slowly drip Boc acid anhydrides under stirring at room, time for adding continues 30 minutes.After dropwising, at room temperature continue stirring reaction 12h.Solids removed by filtration, by filtrate washing (100ml * 2), then by anhydrous sodium sulphate, filtrate is dry, revolve and obtain white solid 4-N-Boc-Trans-4-Amino Cyclohexanol (30g, 70%) except methylene dichloride.
embodiment 2
4-Trans-4-Amino Cyclohexanol hydrochloride (30g) is joined in 200ml methylene dichloride, add subsequently poly-guanidine 50g, slowly drip Boc acid anhydrides under stirring at room, time for adding continues 30 minutes.After dropwising, at room temperature continue stirring reaction 12h.Solids removed by filtration, by filtrate washing (100ml * 2), then by anhydrous sodium sulphate, filtrate is dry, revolve and obtain white solid 4-N-Boc-Trans-4-Amino Cyclohexanol (37g, 86%) except methylene dichloride.
embodiment 3
4-Trans-4-Amino Cyclohexanol hydrochloride (30g) is joined in 200ml methylene dichloride, add subsequently poly-guanidine 50g, slowly drip Boc acid anhydrides under stirring at room, time for adding continues 30 minutes.After dropwising, at room temperature continue stirring reaction 18h.Solids removed by filtration, by filtrate washing (100ml * 2), then by anhydrous sodium sulphate, filtrate is dry, revolve and obtain white solid 4-N-Boc-Trans-4-Amino Cyclohexanol (40g, 93%) except methylene dichloride.
embodiment 4
4-Trans-4-Amino Cyclohexanol hydrochloride (30g) is joined in 200ml methylene dichloride, add subsequently poly-guanidine 50g, slowly drip Boc acid anhydrides under stirring at room, time for adding continues 30 minutes.After dropwising, at room temperature continue stirring reaction 24h.Solids removed by filtration, by filtrate washing (100ml * 2), then by anhydrous sodium sulphate, filtrate is dry, revolve and obtain white solid 4-N-Boc-Trans-4-Amino Cyclohexanol (40.2g, 93%) except methylene dichloride.
embodiment 5
4-N-Boc-Trans-4-Amino Cyclohexanol (21.5 g) is dissolved in methylene dichloride 100ml, is joined in chlorine bleach liquor, add subsequently 0.5gTEMPO, slowly drip Glacial acetic acid, control temperature of reaction below 20 degree, after stirring reaction 1h, detection does not have raw material, stopped reaction.Separatory, methylene dichloride for the aqueous solution (50ml * 2) extraction, merges organic layer, washing, anhydrous sodium sulfate drying, revolves except methylene dichloride, obtains the amino pimelinketone (19.4 g, 89%) of 4-N-Boc-
1h NMR (300 MHz, CDCl
3), ppm 4.46 (m, 1H), 3.93 (s, 4H), 3.51 (m, 1H), 1.94 (m, 2H), 1.47-1.89 (m, 7H), 1.44 (s, 9H);
13c NMR (75 MHz, CDCl
3) ppm 155.3,108.0,79.2,64.3,64.2,48.1,33.1,30.2,28.4.
embodiment 6
4-N-Boc-Trans-4-Amino Cyclohexanol (21.5 g) is dissolved in methylene dichloride 100ml, is joined in sodium chlorite solution, add subsequently 0.5gTEMPO, slowly drip Glacial acetic acid, control temperature of reaction below 20 degree, after stirring reaction 1h, detection does not have raw material, stopped reaction.Separatory, methylene dichloride for the aqueous solution (50ml * 2) extraction, merges organic layer, washing, anhydrous sodium sulfate drying, revolves except methylene dichloride, obtains the amino pimelinketone (20.7 g, 96%) of 4-N-Boc-.
embodiment 7
4-Trans-4-Amino Cyclohexanol hydrochloride (30 g) is joined in 200ml methylene dichloride, add subsequently poly-guanidine 50g, slowly drip Boc acid anhydrides under stirring at room, time for adding continues 30 minutes.After dropwising, at room temperature continue stirring reaction 12h.Solids removed by filtration, joins filtrate in chlorine bleach liquor, adds subsequently 0.5gTEMPO, slowly drips Glacial acetic acid, controls temperature of reaction below 20 degree, after stirring reaction 1h, detects and there is no raw material, stopped reaction.Separatory, methylene dichloride for the aqueous solution (50ml * 2) extraction, merges organic layer, washing, anhydrous sodium sulfate drying, revolves except methylene dichloride, obtains the amino pimelinketone (40.1g, 93%) of 4-N-Boc-.
embodiment 8
4-Trans-4-Amino Cyclohexanol hydrochloride (30 g) is joined in 200ml methylene dichloride, add subsequently poly-guanidine 50g, slowly drip Boc acid anhydrides under stirring at room, time for adding continues 30 minutes.After dropwising, at room temperature continue stirring reaction 12h.Solids removed by filtration, joins filtrate in sodium chlorite solution, adds subsequently 0.5gTEMPO, slowly drips Glacial acetic acid, controls temperature of reaction below 20 degree, after stirring reaction 1h, detects and there is no raw material, stopped reaction.Separatory, methylene dichloride for the aqueous solution (100ml * 2) extraction, merges organic layer, washing, anhydrous sodium sulfate drying, revolves except methylene dichloride, obtains the amino pimelinketone (41 g, 95%) of 4-N-Boc-.
embodiment 9
4-Trans-4-Amino Cyclohexanol hydrochloride (30g) is joined in 200ml methylene dichloride, add subsequently poly-guanidine 50g, slowly drip Boc acid anhydrides under stirring at room, time for adding continues 30 minutes.After dropwising, at room temperature continue stirring reaction 12h.With adding 0.5gTEMPO in backward this reaction solution, then drip sodium chlorite aqueous solution, control temperature of reaction below 20 degree, after stirring reaction 1h, detect and there is no raw material, stopped reaction.Separatory, methylene dichloride for the aqueous solution (100ml * 2) extraction, merges organic layer, washing, anhydrous sodium sulfate drying, revolves except methylene dichloride, obtains the amino pimelinketone (40.8 g, 93%) of 4-N-Boc-.
Claims (6)
1. a preparation method for the amino pimelinketone of 4-N-Boc-, is characterized in that, the method comprises the following steps:
A. in reactor, drop into 4-Trans-4-Amino Cyclohexanol hydrochloride, poly-guanidine, Boc acid anhydrides, three's mass ratio is respectively 1:2:1.5, and temperature of reaction is room temperature, and the reaction times is 12-24h; Filter, wash, be dried, revolve to desolventize and obtain white solid 4-N-Boc-Trans-4-Amino Cyclohexanol;
B. described 4-N-Boc-Trans-4-Amino Cyclohexanol is joined in clorox or sodium chlorite solution, add acid, stirring reaction 1-2 hour, separatory, gets organic layer, washes, is dried, revolves to obtain the amino pimelinketone of white solid 4-N-Boc-except methylene dichloride.
2. method according to claim 1, is characterized in that, in described step a, adopting poly-guanidine is alkali, and poly-guanidine, after filtration, after NaOH processes, can reuse.
3. method according to claim 1, is characterized in that, the acid adopting in described step b is hydrochloric acid or acetic acid.
4. an application for method according to claim 1, is characterized in that, except being applicable to, the amino pimelinketone of 4-N-Boc-, to be also applicable to the amino pimelinketone of 3-N-Boc-, 3-N-Boc-amino cyclopentyl ketone.
5. a preparation method for the amino pimelinketone of 4-N-Boc-, is characterized in that, the method comprises the following steps:
The 4-Trans-4-Amino Cyclohexanol hydrochloride of take is raw material, joins in methylene dichloride, then adds poly-guanidine, drips subsequently Boc acid anhydrides, after stirring reaction 12-24h, filters washing under room temperature; Directly dichloromethane solution is added drop-wise in clorox or sodium chlorite solution, stirring reaction 4-8 hour, separatory, gets organic layer, washes, is dried, revolves to obtain the amino pimelinketone of white solid 4-N-Boc-except methylene dichloride.
6. a preparation method for the amino pimelinketone of 4-N-Boc-, is characterized in that, the method comprises the following steps:
The 4-Trans-4-Amino Cyclohexanol hydrochloride of take is raw material, join in appropriate methylene dichloride, then add poly-guanidine, drip subsequently Boc acid anhydrides, under room temperature, after stirring reaction 12-24h, clorox or sodium chlorite solution are added to stirring reaction 1-2 hour, filtration, separatory, get organic layer, wash, be dried, revolve and obtain the amino pimelinketone of white solid 4-N-Boc-except methylene dichloride.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107501059A (en) * | 2017-08-14 | 2017-12-22 | 渭南高新区海泰新型电子材料有限责任公司 | A kind of green 4（4 ' alkyl-cyclohexyls）The synthetic method of cyclohexanone |
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Application publication date: 20140402 |