CN104250233B - A kind of preparation method of 4-tertbutyloxycarbonyl-2-cyclopropyl morpholine - Google Patents
A kind of preparation method of 4-tertbutyloxycarbonyl-2-cyclopropyl morpholine Download PDFInfo
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- CN104250233B CN104250233B CN201410433502.3A CN201410433502A CN104250233B CN 104250233 B CN104250233 B CN 104250233B CN 201410433502 A CN201410433502 A CN 201410433502A CN 104250233 B CN104250233 B CN 104250233B
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Abstract
The invention discloses a kind of preparation method of 4-tertbutyloxycarbonyl-2-cyclopropyl morpholine; with ring third formaldehyde for starting raw material; obtain target product through cyaniding, reduction, condensation, cyclization, deoxidation, tertbutyloxycarbonyl protection, this compound is important medicine intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, particularly a kind of preparation method of 4-tertbutyloxycarbonyl-2-cyclopropyl morpholine.
Technical background
Compound 4-tertbutyloxycarbonyl-2-cyclopropyl morpholine, structural formula is:
This compound 4-tertbutyloxycarbonyl-2-cyclopropyl morpholine and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of current 4-tertbutyloxycarbonyl-2-cyclopropyl morpholine is comparatively difficult.Therefore, need exploitation raw material to be easy to get, easy to operate, reaction is easy to control, the synthetic method that overall yield is suitable.
Summary of the invention
The invention discloses a kind of method preparing 4-tertbutyloxycarbonyl-2-cyclopropyl morpholine, obtain target product 7 through cyaniding, reduction, condensation, cyclization, deoxidation, tertbutyloxycarbonyl protection, synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) with ring third formaldehyde for starting raw material, obtain 2 through cyanogenation;
(2) carry out reduction reaction 2, obtain 3;
(3) carry out condensation reaction 3 and obtain 4;
(4) carry out ring-closure reaction 4 and obtain 5,
(5) carry out deoxygenation 5 and obtain 6,
(6) carry out tertbutyloxycarbonyl protective reaction 6 and obtain target product 7,
One preferred embodiment in, described cyanogenation is prepared compound 2 reagent used and is selected from trimethylammonium cyaniding silicon; The reductive agent that described reduction reaction prepares compound 3 used is selected from lithium aluminium hydride; Described condensation reaction is prepared compound 4 reagent used and is selected from 2-chloroacetyl chloride; Described ring-closure reaction is prepared compound 5 alkali used and is selected from alkali and is selected from salt of wormwood; The reductive agent that described deoxygenation prepares compound 6 used is selected from lithium aluminium hydride; The reagent that described tertbutyloxycarbonyl protective reaction prepares compound 7 used is selected from tert-Butyl dicarbonate.
One preferred embodiment in, the solvent that described cyanogenation prepares compound 2 used is selected from tetrahydrofuran (THF); The solvent that described reduction reaction prepares compound 3 used is selected from tetrahydrofuran (THF); The solvent that described condensation reaction prepares compound 4 used is selected from methylene dichloride; The solvent that described ring-closure reaction prepares compound 5 used is selected from toluene; The solvent that described deoxygenation prepares compound 6 used is selected from tetrahydrofuran (THF); The solvent that described tertbutyloxycarbonyl protective reaction prepares compound 7 used is selected from methylene dichloride.
One preferred embodiment in, it is 0 DEG C that described cyanogenation prepares compound 2 temperature of reaction used; It is room temperature that described reduction reaction prepares compound 3 temperature used; It is 0 DEG C that compound 4 temperature used is prepared in described condensation reaction; Described ring-closure reaction prepares the reflux temperature that compound 5 temperature used is solvent; Described deoxygenation prepares the reflux temperature that compound 6 temperature used is solvent; It is room temperature that compound 7 temperature used is prepared in described tertbutyloxycarbonyl protective reaction.
The present invention relates to a kind of preparation method of 4-tertbutyloxycarbonyl-2-cyclopropyl morpholine, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of compound 4-tertbutyloxycarbonyl-2-cyclopropyl morpholine.
The present invention is further described by the following embodiment, and these descriptions are not be further limited content of the present invention.One skilled in the art will understand that the equivalent replacement that technical characteristic of the present invention is done, or improve accordingly, still belong within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of 2-cyclopropyl-2-hydroxyacetonitrile
36g ring third formaldehyde is joined in 600ml tetrahydrofuran (THF), adds 1.1g zinc iodide, be cooled to 0 DEG C, then drip 70g trimethylammonium cyaniding silicon, stir 10 hours at 0 DEG C, reaction solution does not need process to be directly used in next step.
(2) synthesis of 2-amino-1-cyclopropyl-ethanol
24g Lithium Aluminium Hydride is joined in the reaction solution of the first step, stirred overnight at room temperature, slowly add frozen water, filter, in filtrate, add methylene dichloride, extraction separatory, collect organic phase, separatory, drying, concentrated, on residuum, silicagel column is separated to obtain 21g2-amino-1-cyclopropyl-ethanol.
(3) synthesis of the chloro-N-of 2-(2-cyclopropyl-2-hydroxyethyl) ethanamide
20g2-amino-1-cyclopropyl-ethanol is joined in 180ml methylene dichloride, add 18ml pyridine again, be cooled to 0 DEG C, drip 29g2-chloroacetyl chloride, stir 2 hours, add dilute hydrochloric acid, separatory, extraction separatory, organic phase saturated sodium bicarbonate aqueous solution washs, collect organic phase, concentrate and obtain the chloro-N-of 25g2-(2-cyclopropyl-2-hydroxyethyl) ethanamide.
(4) synthesis of 6-cyclopropyl morpholinyl-3-ketone
Chloro-for 20g2-N-(2-cyclopropyl-2-hydroxyethyl) ethanamide is joined in 180ml toluene, add 26g salt of wormwood, reflux stirs 18 hours, be cooled to room temperature, add water and ethyl acetate, extraction separatory, collects organic phase, separatory, drying, concentrated, on residuum, silicagel column is separated to obtain 13g6-cyclopropyl morpholinyl-3-ketone.
(5) synthesis of 2-cyclopropyl morpholine
Chloro-for 10g2-N-(2-cyclopropyl-2-hydroxyethyl) ethanamide is joined in 200ml tetrahydrofuran (THF), add 8g Lithium Aluminium Hydride in batches, reflux stirs 6 hours, is cooled to room temperature, drips frozen water, filter, in filtrate, add methylene dichloride, extraction separatory, collects organic phase, separatory, drying, concentrated, on residuum, silicagel column is separated to obtain 7.5g2-cyclopropyl morpholine.
(6) 4-tertbutyloxycarbonyl-2-cyclopropyl morpholine
7g2-cyclopropyl morpholine is joined in 120ml methylene dichloride, adds 12g tert-Butyl dicarbonate in batches, stir 3 hours, add water, extraction separatory, collects organic phase, separatory, drying, concentrated, on residuum, silicagel column is separated to obtain 9.2g4-tertbutyloxycarbonyl-2-cyclopropyl morpholine.
Claims (5)
1. prepare a method for 4-tertbutyloxycarbonyl-2-cyclopropyl morpholine, with ring third formaldehyde for starting raw material, obtain target product 7 through cyaniding, reduction, condensation, cyclization, deoxidation, tertbutyloxycarbonyl protection, synthetic route is as follows:
2. method according to claim 1, is characterized in that, described cyanogenation is prepared compound 2 reagent used and is selected from trimethylammonium cyaniding silicon; Described reduction reaction is prepared compound 3 reductive agent used and is selected from the mixture of one or more in sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, sodium cyanoborohydride, lithium aluminium hydride, borine; The mixture that compound 4 reagent used is selected from a kind of in 2-chloroacetyl chloride, 2-chloro-acetyl bromide or two kinds is prepared in described condensation reaction; Described ring-closure reaction is prepared compound 5 alkali used and is selected from the mixture of one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, triethylamine, sodium bicarbonate, pyridine, triisopropylamine, saleratus; Described deoxygenation is prepared compound 6 reductive agent used and is selected from the mixture of one or more in sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, sodium cyanoborohydride, lithium aluminium hydride, borine; The reagent that described tertbutyloxycarbonyl protective reaction prepares compound 7 used is selected from tert-Butyl dicarbonate.
3. method according to claim 1, it is characterized in that, described cyanogenation prepares compound 2 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide; Described reduction reaction prepares compound 3 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, water; Described condensation reaction is prepared compound 4 solvent used and is selected from the mixture of one or more in tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, DMF, N,N-dimethylacetamide; Described ring-closure reaction is prepared compound 5 solvent used and is selected from tetrahydrofuran (THF), methylene dichloride, trichloromethane, ethyl acetate, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide; Described deoxygenation is prepared compound 6 solvent used and is selected from tetrahydrofuran (THF), methylene dichloride, trichloromethane, ethyl acetate, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide; Described tertbutyloxycarbonyl protective reaction is prepared compound 7 solvent used and is selected from tetrahydrofuran (THF), methylene dichloride, trichloromethane, ethyl acetate, toluene, o-Xylol, p-Xylol, m-xylene, N; the mixture of one or more in dinethylformamide, N,N-dimethylacetamide.
4. method according to claim 1, is characterized in that, described cyanogenation prepares the reflux temperature that compound 2 temperature of reaction used is 0 DEG C ~ solvent; Described reduction reaction prepares the reflux temperature that compound 3 temperature used is 0 DEG C ~ solvent; It is 0 DEG C ~ room temperature that compound 4 temperature used is prepared in described condensation reaction; Described ring-closure reaction prepares the reflux temperature that compound 5 temperature used is 0 DEG C ~ solvent; Described deoxygenation prepares the reflux temperature that compound 6 temperature used is 0 DEG C ~ solvent; It is 0 DEG C ~ room temperature that compound 7 temperature used is prepared in described tertbutyloxycarbonyl protective reaction.
5. method according to claim 1, is characterized in that, it is 0 DEG C that described cyanogenation prepares compound 2 temperature of reaction used; It is room temperature that described reduction reaction prepares compound 3 temperature used; It is 0 DEG C that compound 4 temperature used is prepared in described condensation reaction; Described ring-closure reaction prepares the reflux temperature that compound 5 temperature used is solvent; Described deoxygenation prepares the reflux temperature that compound 6 temperature used is solvent; It is room temperature that compound 7 temperature used is prepared in described tertbutyloxycarbonyl protective reaction.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4042584A (en) * | 1974-08-19 | 1977-08-16 | Merck & Co., Inc. | Ethynylaryl phenyl cyclopropyl thiazines and morpholines |
| CN101460462A (en) * | 2006-06-01 | 2009-06-17 | 塞诺菲-安万特股份有限公司 | Spirocyclic nitriles as protease inhibitors |
| CN101679324A (en) * | 2007-06-15 | 2010-03-24 | 田边三菱制药株式会社 | morpholine derivative |
| CN102307622A (en) * | 2008-12-04 | 2012-01-04 | 雅培制药有限公司 | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
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- 2014-08-29 CN CN201410433502.3A patent/CN104250233B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4042584A (en) * | 1974-08-19 | 1977-08-16 | Merck & Co., Inc. | Ethynylaryl phenyl cyclopropyl thiazines and morpholines |
| CN101460462A (en) * | 2006-06-01 | 2009-06-17 | 塞诺菲-安万特股份有限公司 | Spirocyclic nitriles as protease inhibitors |
| CN101679324A (en) * | 2007-06-15 | 2010-03-24 | 田边三菱制药株式会社 | morpholine derivative |
| CN102307622A (en) * | 2008-12-04 | 2012-01-04 | 雅培制药有限公司 | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
Non-Patent Citations (1)
| Title |
|---|
| Morpholine containing CB2 selective agonists;Renée Zindell et al.;《Bioorganic & Medicinal Chemistry Letters 》;20090212;第19卷;第1604-1609页 * |
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Denomination of invention: 4-tert-butyloxycarboryl-2-cyclopropyl morpholine preparation method Effective date of registration: 20200318 Granted publication date: 20160316 Pledgee: Bank of Changsha Limited by Share Ltd science and Technology Branch Pledgor: HUNAN HUATENG PHARMACEUTICAL Co.,Ltd. Registration number: Y2020980000827 |
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