CN108299332A - (3R, 6R and 3S, 6S)-morpholine -2, the synthetic method of 5- diketone - Google Patents
(3R, 6R and 3S, 6S)-morpholine -2, the synthetic method of 5- diketone Download PDFInfo
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- CN108299332A CN108299332A CN201810159522.4A CN201810159522A CN108299332A CN 108299332 A CN108299332 A CN 108299332A CN 201810159522 A CN201810159522 A CN 201810159522A CN 108299332 A CN108299332 A CN 108299332A
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- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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Abstract
One kind (3R, 6R and 3S, 6S) morpholine 2, the synthetic method of 5 diketone, the synthetic method synthesize γ benzyls N (2 bromo propionyl) L glutamic acid (BBPG) using 2 bromo propionyl chlorides and γ benzyl L glutamic acid as intitation reagents first；Then under certain condition by BBPG, 2,5 diketone (BCEM) of (3R, 6R and 3S, 6S) 3 (benzyloxycarbonyl group ethylene group) 6 methyl morpholine is synthesized through ring closure reaction.Present invention process is simple, easy to operate, easy to implement, and product purity is high, can be used as new bio degradability medical high polymer-polylactic acid glutamic acid synthesis monomer used.
Description
Technical field
The invention belongs to technical field of macromolecules, are related to biological medical polymer.More particularly to a kind of (3R, 6R and 3S,
6S) the synthetic method of -3- (benzyloxycarbonyl group-ethylene group) -6- Methyl-morpholine -2,5- diketone.
Background technology
Polylactic acid modified is the hot spot studied at present：The product made of polylactic acid has simultaneously in addition to energy is biodegradable
Biocompatibility, glossiness, the transparency, feel and heat-resist also have certain antibiotic property, anti-flammability and ultraviolet-resistent property,
Therefore purposes is very extensive, can be used as packaging material, fiber and non-woven fabric etc., is mainly used for clothes (underwear, coat), industry
The fields such as (building, agricultural, forestry, papermaking) and health care.And by amino acid segment introduce polylactic acid, can to polylactic acid into
Row is modified, and the copolymer thus prepared will have both the excellent performance of two Type of Collective objects.Morpholine diketone is 'alpha '-hydroxy acids (lactic acid, second
Alkyd) product that shrinks with the intermolecular cyclization of a-amino acid, morpholine -2, it is total that 5- derovatives with polylactic acid carry out open loop
It is poly-, amino acid group is introduced into polylactic acid chain, the constituent content by adjusting amino acid improves polylactic acid to a certain extent
Crystallinity, adjust polylactic acid degradation behavior, improve the hydrophilicity of material, such copolymer material can be preferably applied for
Tissue engineering bracket, medicine controlled release carrier etc..Therefore the synthesis of morpholine diketone is increasingly taken seriously.
Although preparation method is simple, when cyclic, in addition to molecule inner ring condensation generates product, there is also intermolecular condensation generation is low
The shortcomings that side reaction of polymers, low yield, significantly limits the development of this technology.In recent years, related morpholine -2,5- bis-
The study on the synthesis report of each analog derivative of ketone is more, and also relative maturity, yield are greatly improved synthetic method, but for 3- benzyls
The study on the synthesis of oxygen carbonyl ethylidene -6- Methyl-morpholine -2,5- diketone is less.Therefore, in state natural sciences fund
(NO.21204039) under subsidy, we have synthesized (3R, 6R and 3S, 6S) -3- (benzyloxycarbonyl group-ethylene group) -6- methyl -
Quinoline -2,5- diketone (BCEM).
Invention content
The purpose of the present invention is to solve to prepare through catalysis orientation ring-opening polymerisation there is regular molecule to found structure and excellent heat engine
The pure optical configuration of monomer-(3R, 6R and 3S, 6S) -3- (benzyloxy carbonyls of biological degradability polylactic acid-glutamic acid of tool performance
Base-ethylene group) -6- Methyl-morpholine -2,5- diketone (BCEM) and its synthesis the problem of.
The present invention selects that γ-benzyl-is made first as intitation reagents using 2- bromos propionyl chloride and γ-benzyl-Pidolidone
N- (2- bromos propionyl)-Pidolidone (BBPG), in n,N-Dimethylformamide (DMF)/triethylamine (NEt3) occur in solvent
Intramolecular cyclization reaction generates 3- (benzyloxycarbonyl group-ethylene group) -6- Methyl-morpholine -2,5- diketone (BCEM).By obtained BCEM
With chloroform, ethyl acetate dissolving, water, saturated common salt water washing, (3R, 6R and 3S, the 6S)-of isolated pure optical configuration
BCEM monocrystalline enantiomers, the molecular structure of BCEM is determined with X-ray diffraction method.
The simple process, easy to implement, product purity height, further to prepare new bio degradability by ring-opening polymerisation
, can be used for biological medicine, the polylactic acid-glutamic acid in the fields such as organizational project is laid a good foundation.
Technical scheme of the present invention
A kind of (3R, 6R and 3S, 6S)-morpholine -2,5- diketone --- (3R, 6R and 3S, 6S) -3- (benzyloxycarbonyl groups-ethylene
Base) -6- Methyl-morpholine -2,5- diketone synthetic method, the synthetic method is with 2- bromos propionyl chloride and γ-benzyl-Pidolidone
Synthesize γ-benzyl-N- (2- bromos propionyl)-Pidolidone (BBPG) first for intitation reagents；Then by BBPG in DMF, warp
Ring closure reaction synthesizes (3R, 6R and 3S, 6S) -3- (benzyloxycarbonyl group-ethylene group) -6- Methyl-morpholines -2,5- diketone (BCEM), letter
Write as (3R, 6R and 3S, 6S)-BCEM；Structural formula is as follows：
Synthesis step is as follows：
1) 1-4mL 2- bromo propionyl chlorides are dissolved in 5-80mL DMF, strong hereinafter, under the conditions of being passed through argon gas at 0 DEG C
It under strong stirring, is slowly added drop-wise in the 40-100mL DMF white turbids dissolved with 2.5-5.0g γ-benzyl-Pidolidone, is added dropwise
After complete, suspension gradually becomes light yellow transparent solution.Then the 1.7-3.4mL triethylamines for being dissolved in 5-30mL DMF are slowly dripped
It is added in said mixture, solution becomes milky.After dripping, the reaction was continued when solution temperature reverts to room temperature, and 6-10 is small
When.Precipitation is filtered off after reaction, and filtrate is yellowish supernatant liquid γ-benzyl-N- (2- bromos propionyl)-Pidolidone
(BBPG), it is directly used in the reaction of next step.
2) under protection of argon gas, 1.5-4.5mL triethylamines are slowly added drop-wise to above-mentioned containing γ-benzyl-N- (2- bromos third
Acyl)-Pidolidone (BBPG) DMF solution in, be heated to 110-130 DEG C react 4-6 hours, yellowish clear solution color by
Gradually deepen, is finally yellowish-brown.After reaction, decompression boils off solvent, obtains brown oil.By crude product ethyl acetate
It is dissolved with chloroform, is washed 3 times with water, saturation NaCl solution respectively, collect ethyl acetate organic phase, formed after volatilizing naturally brilliant
Body, as (3R, 6R and 3S, 6S) -3- (benzyloxycarbonyl group-ethylene group) -6- Methyl-morpholine -2,5- diketone, yield 3-
34.8%, purity>99%.
The reaction mechanism of the present invention
The advantages and positive effects of the present invention：
It is somebody's turn to do the preparation of (3R, 6R and 3S, 6S) -3- (benzyloxycarbonyl group-ethylene group) -6- Methyl-morpholine -2,5- diketone, technique
Simply, easy to operate, easy to implement, products pure degree is high, can be used as the modifying agent of biological medical polymer material, enhancing it can
Degradability weakens its toxicity etc..The product qualities that method discussed in the present invention synthesizes are good, can be used for new bio degradability
Medical high polymer polylactic acid-glutamic acid synthesis monomer.
Specific implementation mode
Embodiment 1：
At 0 DEG C hereinafter, under the conditions of being passed through argon gas, 1.0ml (0.01mol) 2- bromo propionyl chlorides are dissolved in 5mL DMF and (have been located
Reason) in, under vigorous stirring, slowly it is added drop-wise to the 40mLDMF dissolved with 2.5000g (0.011mol) γ-benzyl-Pidolidone
In (processed) white turbid, after dripping, suspension gradually becomes light yellow transparent solution.Then it will be dissolved in 5mLDMF's
1.7mL (0.012mol) triethylamine is slowly added drop-wise in said mixture, and solution becomes milky.After dripping, solution temperature is waited for
The reaction was continued 6 hours when degree reverts to room temperature.Precipitation is filtered off after reaction, and filtrate is yellowish supernatant liquid, is directly used in
The reaction of next step.
1.5mL (0.01mol) triethylamine is added in above-mentioned DMF solution under protection of argon gas, is heated to 110 DEG C of reactions 4
Hour, faint yellow clear solution color is gradually deepened, and is finally yellowish-brown.After reaction, decompression boils off solvent, obtains brown
Grease.Crude product is dissolved with ethyl acetate, is washed 3 times with water, saturation NaCl solution respectively, obtains brown organic phase.It collects
Organic phase dries 12h with anhydrous magnesium sulfate, filters out vacuum distillation removing solvent after drier, obtains brownish red grease.By this
Grease is dissolved in ethyl acetate, makees leacheate with ethyl acetate, carries out silica gel chromatography, after obtained solution evaporation solvent
Still be grease, this grease is dissolved in ethyl acetate, slowly instill hexane solution in formed precipitation, obtain it is light yellow and
White hybrid solid is carried out after purification, obtaining product, yield 3.4% with ether.
Embodiment 2：
At 0 DEG C hereinafter, under the conditions of being passed through argon gas, 2.0ml (0.02mol) 2- bromo propionyl chlorides 80mL DMF have been dissolved in (
Processing) in, under vigorous stirring, slowly it is added drop-wise to the 100mL dissolved with 5.0000g (0.022mol) γ-benzyl-Pidolidone
In (processed) the white turbids of DMF, after dripping, suspension gradually becomes light yellow transparent solution.Then 30mLDMF will be dissolved in
3.4mL (0.024mol) triethylamine be slowly added drop-wise in said mixture, solution becomes milky.After dripping, solution is waited for
The reaction was continued 10 hours when temperature reverts to room temperature.Precipitation is filtered off after reaction, and filtrate is yellowish supernatant liquid, is directly used
In the reaction of next step.
4.5mL (0.03mol) triethylamine is added in above-mentioned DMF solution under protection of argon gas, is heated to 130 DEG C of reactions 6
Hour, faint yellow clear solution color is gradually deepened, and is finally yellowish-brown.After reaction, decompression boils off solvent, obtains brown
Grease.Crude product is dissolved with ethyl acetate, is washed 3 times with water, saturation NaCl solution respectively, obtains brown organic phase.It collects
Organic phase dries 12h with anhydrous magnesium sulfate, filters out vacuum distillation removing solvent after drier, obtains brownish red grease.By this
Grease is dissolved in ethyl acetate, makees leacheate with ethyl acetate/petroleum ether, carries out silica gel column chromatography separation, obtains solution nature
Crystal, yield 6.8% are formed after volatilization.
Embodiment 3：
At 0 DEG C hereinafter, under the conditions of being passed through argon gas, 2.0mL (0.02mol) 2- bromo propionyl chlorides are dissolved in 10mLDMF,
Under strong stirring, it is slowly added drop-wise to the 80mLDMF white turbids dissolved with 5.0000g (0.022mol) γ-benzyl-Pidolidone
In, after dripping, suspension gradually becomes light yellow transparent solution.Then the 3.4mL (0.024mol) three of 10mLDMF will be dissolved in
Ethamine is slowly added drop-wise in said mixture, and solution becomes milky.After dripping, continue when solution temperature reverts to room temperature
Reaction 6 hours.Precipitation is filtered off after reaction, and filtrate is yellowish supernatant liquid, is directly used in the reaction of next step.
3.0mL (0.021mol) triethylamine is slowly added drop-wise in above-mentioned DMF solution under protection of argon gas, is heated to 110
DEG C reaction 4 hours, faint yellow clear solution color is gradually deepened, and is finally yellowish-brown.After reaction, decompression boils off solvent,
Obtain brown oil.Crude product ethyl acetate and chloroform are dissolved, is washed 3 times, is received with water, saturation NaCl solution respectively
Collect ethyl acetate organic phase, crystal is formed after volatilizing naturally.Yield is 34.8%.
Claims (1)
1. a kind of (3R, 6R and 3S, 6S)-morpholine -2,5- diketone --- (3R, 6R and 3S, 6S) -3- (benzyloxycarbonyl group-ethylene group) -
The synthetic method of 6- Methyl-morpholine -2,5- diketone, the synthetic method are with 2- bromos propionyl chloride and γ-benzyl-Pidolidone
Beginning reagent synthesizes γ-benzyl-N- (2- bromos propionyl)-Pidolidone (BBPG) first；Then by BBPG in DMF, through cyclization
Reaction synthesis (3R, 6R and 3S, 6S) -3- (benzyloxycarbonyl group-ethylene group) -6- Methyl-morpholines -2,5- diketone (BCEM), writes a Chinese character in simplified form into
(3R, 6R and 3S, 6S)-BCEM, structural formula are as follows：
The specific synthesis step of the product is as follows：
1) 1-4mL 2- bromo propionyl chlorides are dissolved in 5-80mL DMF, are being stirred strongly hereinafter, under the conditions of being passed through argon gas at 0 DEG C
It mixes down, is slowly added drop-wise in the 40-100mL DMF white turbids dissolved with 2.5-5.0g γ-benzyl-Pidolidone, after dripping,
Suspension gradually becomes light yellow transparent solution；Then the 1.7-3.4mL triethylamines for being dissolved in 5-30mLDMF are slowly added drop-wise to
It states in mixture, solution becomes milky；After dripping, the reaction was continued when solution temperature reverts to room temperature 6-10 hours；Instead
Precipitation is filtered off after answering, filtrate is yellowish supernatant liquid γ-benzyl-N- (2- bromos propionyl)-Pidolidone (BBPG), directly
Connect the reaction for next step；
2) under protection of argon gas, 1.5-4.5mL triethylamines are slowly added drop-wise to above-mentioned containing γ-benzyl-N- (2- bromos propionyl)-L-
In the DMF solution of glutamic acid (BBPG), it is heated to 110-130 DEG C and reacts 4-6 hours, yellowish clear solution color gradually adds
It is deep, it is finally yellowish-brown；After reaction, decompression boils off solvent, obtains brown oil；By crude product ethyl acetate and three
Chloromethanes dissolves, and is washed respectively with water, saturation NaCl solution, collects ethyl acetate organic phase, form crystal after volatilizing naturally, i.e.,
For (3R, 6R and 3S, 6S) -3- (benzyloxycarbonyl group-ethylene group) -6- Methyl-morpholine -2,5- diketone, yield 3-34.8%, purity
>99%.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810159522.4A CN108299332A (en) | 2018-02-26 | 2018-02-26 | (3R, 6R and 3S, 6S)-morpholine -2, the synthetic method of 5- diketone |
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| CN201810159522.4A CN108299332A (en) | 2018-02-26 | 2018-02-26 | (3R, 6R and 3S, 6S)-morpholine -2, the synthetic method of 5- diketone |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2696099C1 (en) * | 2019-01-14 | 2019-07-31 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) | Chemoenzymatic synthesis of 2,5-diketomorfoline derivatives |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102408389A (en) * | 2011-09-15 | 2012-04-11 | 南开大学 | Lactic acid-glutamic acid morpholine dione and synthetic process method thereof |
-
2018
- 2018-02-26 CN CN201810159522.4A patent/CN108299332A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102408389A (en) * | 2011-09-15 | 2012-04-11 | 南开大学 | Lactic acid-glutamic acid morpholine dione and synthetic process method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 庞子博: "有机胍盐催化吗啉二酮活性及立体专一性开环聚合研究", 《南开大学博士学位论文》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2696099C1 (en) * | 2019-01-14 | 2019-07-31 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) | Chemoenzymatic synthesis of 2,5-diketomorfoline derivatives |
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