CN104788352A - Preparation methods of N-phenylacetyl-L-proline, and N-(1-(phenylacetyl)-L-prolyl)glycine ethyl ester - Google Patents
Preparation methods of N-phenylacetyl-L-proline, and N-(1-(phenylacetyl)-L-prolyl)glycine ethyl ester Download PDFInfo
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- CN104788352A CN104788352A CN201410028081.6A CN201410028081A CN104788352A CN 104788352 A CN104788352 A CN 104788352A CN 201410028081 A CN201410028081 A CN 201410028081A CN 104788352 A CN104788352 A CN 104788352A
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
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Abstract
The invention provides a preparation method of N-phenylacetyl-L-proline. The preparation method comprises following steps: 1) L-proline is mixed with a strong base solution a, and phenylacetyl chloride and a strong base solution b are added via double dropwise adding for reaction; 2) after reaction of the step 1), ethyl acetate is used for extraction, and an ethyl acetate layer is removed so as to obtain a product aqueous layer; 3) pH value of the product aqueous layer obtained via step 2) is adjusted to be lower than 7, dichloromethane is used for extraction, and a water layer is removed; and 4) a neutral drying agent is added, an obtained mixture is filtered, and an obtained filtrate is subjected to distillation and cooling so as to obtain N-phenylacetyl-L-proline. The invention also discloses a preparation method of N-(1-(phenylacetyl)-L-prolyl)glycine ethyl ester. Operation of the preparation methods is simple; and preparation efficiency is high.
Description
Technical field
The present invention relates to chemicals synthesis field, particularly relate to the preparation method of N-phenylacetyl-L-PROLINE and N-[1-(phenyl acetyl)-L-prolyl] glycine ethyl ester.
Background technology
N-[1-(phenyl acetyl)-L-prolyl] glycine ethyl ester; trade(brand)name NOOPEPT; as diseases such as treatment obesity, alcohol dependence sexual involution or toxic injuries; at present, domestic also not to the report of the synthesis technique of this compound, the external synthesis technique occurred; combined coefficient is lower; synthesis content is lower, and purity is poor, is unfavorable for industrial production.
Summary of the invention
The present invention proposes the method for effectively producing N-[1-(phenyl acetyl)-L-prolyl] glycine ethyl ester.
The technical solution adopted in the present invention is as follows:
Find in the research of the synthesis technique of N-[1-(phenyl acetyl)-L-prolyl] glycine ethyl ester; the purity of intermediate product N-phenylacetyl-L-PROLINE is to final reacting product N-[1-(phenyl acetyl)-L-prolyl] glycine ethyl ester important, and the purity improving N-phenylacetyl-L-PROLINE improves the key of final end product.
One aspect of the present invention provides the preparation method of a kind of N-phenylacetyl-L-PROLINE, and step is as follows:
1) L-PROLINE and strong base solution a mix, two dripping method add phenyllacetyl chloride and strong base solution b react;
2) after step 1) reaction terminates, utilize ethyl acetate to extract, remove ethyl acetate layer, obtain product water layer;
3) regulating step 2) product water layer to acid, utilize dichloromethane extraction, remove water layer;
4) add neutral siccative, filter, after filtrate distillation cooling, obtain N-phenylacetyl-L-PROLINE.
Preferably, described strong base solution a and strong base solution b is selected from sodium hydroxide solution or potassium hydroxide solution; The concentration of described strong base solution a is 2mol/L, and the concentration of described strong base solution b is 4mol/L.。
Preferably, the molar ratio of described L-PROLINE and 2mol/L strong base solution a is 0.8-1:1.
Preferably, the molar ratio of the strong base solution b of described phenyllacetyl chloride and 4mol/L is 0.8-1:1.
Preferably, described phenyllacetyl chloride and the ratio of L-PROLINE are 0.8-1:1.
Preferably, the temperature of reaction of described step 1) is-5 to-10 DEG C.
Preferably, the neutral siccative described in step 4) is Calcium Chloride Powder Anhydrous or sodium sulfate.
The present invention utilizes the preparation method providing a kind of N-[1-(phenyl acetyl)-L-prolyl] glycine ethyl ester on the other hand, the N-utilizing aforesaid method to prepare phenylacetyl-L-PROLINE, and step is as follows:
1) N-phenylacetyl-L-PROLINE and tetrahydrofuran (THF) mixing, at the temperature of-5 to-10 DEG C, drip isobutyl chlorocarbonate, drip stirring reaction 25-40 minute;
2) insulation continues the mixed solution dripping glycine ethyl ester, triethylamine and tetrahydrofuran (THF), dropwises, insulation reaction 25-40 minute;
3) at 15-25 DEG C, insulation 1-2 hour, filters, and filtrate decompression is distilled, and obtains residue;
4) methylene dichloride dissolution residual substance, utilizes acid salt solution to wash twice, then uses salt acid elution, and anhydrate layer;
5) add neutral desiccant dryness, filtration, underpressure distillation obtain oily matter;
6) at 18-22 DEG C, oily matter in ethanol to step 5) is added; Stir 2-4 hour, crystallization is filtered, and dries and obtain N-[1-(phenyl acetyl)-L-prolyl] glycine ethyl ester.
Preferably, the molar ratio of described N-phenylacetyl-L-PROLINE, tetrahydrofuran (THF) and isobutyl chlorocarbonate is 2-4:11-13:2-3; The mixed solution of described glycine ethyl ester, triethylamine and tetrahydrofuran (THF), the molar ratio of its glycine ethyl ester, triethylamine and tetrahydrofuran (THF) is 0.05-0.2:0.5-2:2-3; Described N-phenylacetyl-L-PROLINE and the molar ratio of glycine ethyl ester are 15:0.8-1.2.
Preferably, described acid salt is sodium bicarbonate, and its concentration is 4-6%; The concentration of the hydrochloric acid in described step 4) is 1mol/L; Described neutral siccative is Calcium Chloride Powder Anhydrous or sodium sulfate.
Beneficial effect of the present invention is as follows:
1) preparation method of N-phenylacetyl-L-PROLINE provided by the invention, wherein preparation method is simple to operate, and preparation efficiency is high, can obtain highly purified N-phenylacetyl-L-PROLINE.
2) preparation method of N-provided by the invention [1-(phenyl acetyl)-L-prolyl] glycine ethyl ester, wherein, utilize highly purified N-phenylacetyl-L-PROLINE, preparation method's efficiency is high, and preparation effect is high.
Accompanying drawing explanation
Fig. 1 is that the HPCL of N-[1-(phenyl acetyl)-L-prolyl] glycine ethyl ester prepared by the embodiment of the present invention 5 detects figure.
Embodiment
Below in conjunction with the accompanying drawing in the embodiment of the present invention, be clearly and completely described the technical scheme in the embodiment of the present invention, obviously, described embodiment is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.
The preparation method of embodiment 1N-phenylacetyl-L-PROLINE
57.5kg L-PROLINE is dropped into reactor, drop into 250L2mol/l NaOH liquid again, stir 30 minutes, temperature controls at-10 to-5 DEG C of degree, then the 4mol/l NaOH liquid of two dropping phenyllacetyl chloride 66L and 125L, temperature controls at-10 to-5 DEG C of degree, drip insulation 15 minutes, 300L extraction into ethyl acetate is used after terminating, layering, remove ethyl acetate layer, PH=3 is adjusted with 2mol/L hydrochloric acid, use 300L dichloromethane extraction again, subregion water layer, dichloromethane layer is dry with 20kg anhydrous Na SO4, filter, filtrate decompression is distilled, obtain oily matter 62kg, N-phenylacetyl-L-PROLINE is obtained after cooling, its purity is 99.6%.
The preparation method of embodiment 2N-phenylacetyl-L-PROLINE
50kg L-PROLINE is dropped into reactor, drop into 250L2mol/l potassium hydroxide solution again, stir 30 minutes, temperature controls at-10 to-5 DEG C of degree, then the 4mol/l potassium hydroxide solution of two dropping phenyllacetyl chloride 56L and 125L, temperature controls at-10 to-5 DEG C of degree, drip insulation 15 minutes, 300L extraction into ethyl acetate is used after terminating, layering, remove ethyl acetate layer, PH=1.2 is adjusted with 2mol/L hydrochloric acid, use 300L dichloromethane extraction again, subregion water layer, dichloromethane layer is dry with 20kg anhydrous Na SO4, filter, filtrate decompression is distilled, obtain oily matter 62kg, N-phenylacetyl-L-PROLINE is obtained after cooling, purity is 99.7%.
The preparation method of embodiment 3N-phenylacetyl-L-PROLINE
57.5kg L-PROLINE is dropped into reactor, drop into 250L2mol/l potassium hydroxide solution again, stir 30 minutes, temperature controls at-10 to-5 DEG C of degree, then the 4mol/l potassium hydroxide solution of phenyllacetyl chloride 60L and 125L is dripped, temperature controls at-10 to-5 DEG C of degree, drip insulation 15 minutes, 300L extraction into ethyl acetate is used after terminating, layering, remove ethyl acetate layer, PH=1.2 is adjusted with 2mol/L hydrochloric acid, use 300L dichloromethane extraction again, subregion water layer, dichloromethane layer is dry with 20kg Calcium Chloride Powder Anhydrous, filter, filtrate decompression is distilled, obtain oily matter 62kg, N-phenylacetyl-L-PROLINE is obtained after cooling, its purity is 99.5%.
N-phenylacetyl-the L-PROLINE of above-mentioned preparation detects through NMR, mass spectrum and HPLC;
NMR ultimate analysis (C7H11NO3): C53.8%, H7.01%, N9.2%; Theoretical value: C53.5%, H7.01%, N8.92%.
The detect parameters of mass spectrum and HPLC: the mass spectrum post selecting Luna C18150*2mm5uM, moving phase is methanol/ethanol mixed solution; Flow velocity: 1.0ml/min, column temperature 15-20 DEG C; Detection molecules amount is 158.09; The detection purity of N-phenylacetyl-L-PROLINE prepared by embodiment 1-3 is followed successively by: 99.6%, 99.7%, 99.5%.
The preparation method of embodiment 4N-[1-(phenyl acetyl)-L-prolyl] glycine ethyl ester
Embodiment 1 gained N-phenylacetyl-L-PROLINE 233kg is dropped in reactor, add 430kg tetrahydrofuran (THF) again to stir, start to drip 139L triethylamine, then isobutyl chlorocarbonate 134L is dripped, dropping temperature remains on-10 to-5 DEG C, dropwise stirring 30 minutes, continue the mixed solution dripping 14kg glycine ethyl ester and 139L triethylamine and 250L tetrahydrofuran (THF).Dropwise, be incubated 30 minutes.Start to be warming up to normal temperature and be incubated 1.5 hours; then filter; filtrate decompression is distilled; add methylene dichloride residue is dissolved; secondary washing is divided with 5%NaHCO3 liquid 800kg; branch vibration layer; use 1mol/l salt acid elution again, layering, dry with 30kg anhydrous Na 2SO4; filtration, underpressure distillation obtain oily matter; be cooled to 20 degree, add alcohol 200L crystallization, stir after 3 hours; finished product N-[1-(phenyl acetyl)-L-prolyl] the glycine ethyl ester 166kg filtering, dry, purity is 99.6%.
The preparation method of embodiment 5N-[1-(phenyl acetyl)-L-prolyl] glycine ethyl ester
Embodiment 1 gained N-phenylacetyl-L-PROLINE 200kg is dropped in reactor, add 450kg tetrahydrofuran (THF) again to stir, start to drip 150L triethylamine, then isobutyl chlorocarbonate 134L is dripped, dropping temperature remains on-10 to-5 DEG C, dropwise stirring 30 minutes, continue the mixed solution dripping 9kg glycine ethyl ester and 150L triethylamine and 260L tetrahydrofuran (THF).Dropwise, be incubated 30 minutes.Start to be warming up to normal temperature and be incubated 1.5 hours, then filter, filtrate decompression is distilled; add methylene dichloride residue is dissolved, divide secondary washing, branch vibration layer with 5%NaHCO3 liquid 800kg; use 1N salt acid elution again, layering, dry with 30kg Calcium Chloride Powder Anhydrous; filtration, underpressure distillation obtain oily matter; be cooled to 20 degree, add alcohol 200L crystallization, stir after 3 hours; finished product N-[1-(phenyl acetyl)-L-prolyl] the glycine ethyl ester 166kg filtering, dry, purity is 99.6%.
The preparation method of embodiment 6N-[1-(phenyl acetyl)-L-prolyl] glycine ethyl ester
Embodiment 1 gained N-phenylacetyl-L-PROLINE 250kg is dropped in reactor, add 450kg tetrahydrofuran (THF) again to stir, start to drip 129L triethylamine, then isobutyl chlorocarbonate 134L is dripped, dropping temperature remains on-10 to-5 DEG C, dropwise stirring 30 minutes, continue the mixed solution dripping 9kg glycine ethyl ester and 150L triethylamine and 260L tetrahydrofuran (THF).Dropwise, be incubated 30 minutes.Start to be warming up to normal temperature and be incubated 1.5 hours, then filter, filtrate decompression is distilled; add methylene dichloride residue is dissolved, divide secondary washing, branch vibration layer with 5%NaHCO3 liquid 800kg; use 1N salt acid elution again, layering, dry with 30kg Calcium Chloride Powder Anhydrous; filtration, underpressure distillation obtain oily matter; be cooled to 20 degree, add alcohol 200L crystallization, stir after 3 hours; finished product N-[1-(phenyl acetyl)-L-prolyl] the glycine ethyl ester 166kg filtering, dry, purity is 99.6%.
N-[1-(the phenyl acetyl)-L-prolyl] glycine ethyl ester prepared of above-described embodiment is through the detection of NMR, mass spectrum and HPLC;
NMR ultimate analysis (C17H22N2O4): C64.68%, H7.32%, N8.98%; Theoretical value: C64.18%, H6.92%, N8.81%.
The detect parameters of mass spectrum and HPLC: the mass spectrum post selecting Luna C18150*2mm5uM, moving phase is ether; Flow velocity: 1.0ml/min, column temperature 15-20 DEG C; Detection molecules amount is 318.1; The detection purity of N-phenylacetyl-L-PROLINE prepared by embodiment 4-6 is followed successively by: 99.6%, 99.74%, 99.6%.
N-[1-(phenyl acetyl)-L-prolyl] glycine ethyl ester prepared by embodiment 5 carries out HPLC detection, as shown in Figure 1, utilizes 230nm wavelength detecting to detect, as shown in table 1,
Table 1HPLC detects real time data
| Peak | Retention time | Area | Highly | Area % | Height % |
| 1 | 3.02 | 4578 | 516 | 0.049 | 0.054 |
| 2 | 3.336 | 17070 | 1868 | 0.182 | 0.196 |
| 3 | 4.062 | 9366132 | 950797 | 99.74 | 99.712 |
| 4 | 4.537 | 2785 | 366 | 0.030 | 0.038 |
| Amount to | 9390566 | 953548 | 100.00 | 100.00 |
Wherein, N-[1-(the phenyl acetyl)-L-prolyl] glycine ethyl ester that peak 3 is prepared for the present invention detects data, and its moderate purity is 99.74%.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (10)
- The preparation method of 1.N-phenylacetyl-L-PROLINE, it is characterized in that, step is as follows:1) L-PROLINE and strong base solution a mix, two dripping method add phenyllacetyl chloride and strong base solution b react;2) after step 1) reaction terminates, utilize ethyl acetate to extract, remove ethyl acetate layer, obtain product water layer;3) regulating step 2) product water layer to acid, utilize dichloromethane extraction, remove water layer;4) add neutral siccative, filter, after filtrate distillation cooling, obtain N-phenylacetyl-L-PROLINE.
- 2. preparation method as claimed in claim 1, is characterized in that: described strong base solution a and strong base solution b is selected from sodium hydroxide solution or potassium hydroxide solution; The concentration of described strong base solution a is 2mol/L, and the concentration of described strong base solution b is 4mol/L.
- 3. preparation method as claimed in claim 1, is characterized in that: described L-PROLINE and strong base solution molar ratio are 0.8-1:1.
- 4. preparation method as claimed in claim 1, is characterized in that: described phenyllacetyl chloride and the molar ratio of strong base solution are 0.8-1:1.
- 5. preparation method as claimed in claim 1, is characterized in that: described phenyllacetyl chloride and the molar ratio of L-PROLINE are 0.8-1:1; The temperature of reaction of described step 1) is-10 to-5 DEG C.
- 6. preparation method as claimed in claim 1, is characterized in that: in described step 3), utilizes the hydrochloric acid regulating step 2 of 2mol/l) the pH of product water layer be 1-3.
- 7. preparation method as claimed in claim 1, is characterized in that: the neutral siccative described in step 4) is Calcium Chloride Powder Anhydrous or sodium sulfate.
- 8. a preparation method for N-[1-(phenyl acetyl)-L-prolyl] glycine ethyl ester, it is characterized in that, utilize the N-phenylacetyl-L-PROLINE prepared by claim 1, step is as follows:1) N-phenylacetyl-L-PROLINE and tetrahydrofuran (THF) mixing, at the temperature of-10 to-5 DEG C, drip isobutyl chlorocarbonate, drip stirring reaction 25-40 minute;2) insulation continues the mixed solution dripping glycine ethyl ester, triethylamine and tetrahydrofuran (THF), dropwises, insulation reaction 25-40 minute;3) at 15-25 DEG C, insulation 1-2 hour, filters, and filtrate decompression is distilled, and obtains residue;4) methylene dichloride dissolution residual substance, utilizes acid salt solution to wash twice, then uses salt acid elution, and anhydrate layer;5) add neutral desiccant dryness, filtration, underpressure distillation obtain oily matter;6) at 18-22 DEG C, oily matter in ethanol to step 5) is added; Stir 2-4 hour, crystallization is filtered, and dries and obtain N-[1-(phenyl acetyl)-L-prolyl] glycine ethyl ester.
- 9. preparation method as claimed in claim 8, is characterized in that: the molar ratio of described N-phenylacetyl-L-PROLINE, tetrahydrofuran (THF) and isobutyl chlorocarbonate is 2-4:11-13:2-3; The mixed solution of described glycine ethyl ester, triethylamine and tetrahydrofuran (THF), the molar ratio of its glycine ethyl ester, triethylamine and tetrahydrofuran (THF) is 0.05-0.2:0.5-2:2-3; Described N-phenylacetyl-L-PROLINE and the molar ratio of glycine ethyl ester are 15:0.8-1.2.
- 10. preparation method as claimed in claim 8, it is characterized in that: described acid salt is sodium bicarbonate, its concentration is 4-6%; The concentration of the hydrochloric acid in described step 4) is 1mol/L; Neutral siccative in described step 5) is Calcium Chloride Powder Anhydrous or sodium sulfate.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109369494A (en) * | 2018-11-21 | 2019-02-22 | 中北大学 | A kind of preparation method of N-phenylacetyl-L-proline |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109369494A (en) * | 2018-11-21 | 2019-02-22 | 中北大学 | A kind of preparation method of N-phenylacetyl-L-proline |
| CN109369494B (en) * | 2018-11-21 | 2021-10-15 | 中北大学 | A kind of preparation method of N-phenylacetyl-L-proline |
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Application publication date: 20150722 |